Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 347 appraisals
CPT: pharmacometrics & systems pharmacology
Structured Schemas for Provenance-Rich, LLM-Assisted QSP Model Calibration
Quantitative systems pharmacology (QSP) models require calibration data from literature, yet manual curation is inconsistently documented and large language model (LLM) extraction can hallucinate values and fabricate citations. We present MAPLE (Model-Aware Parameterization from Literature Evidence), which uses structured validation schemas as a collaboration interface between LLMs and modelers. Two schemas span two scales: the SubmodelTarget schema for isolated experiments constraining individual parameters, and the CalibrationTarget schema for clinical and in vivo endpoints constraining the full model. Both separate data extraction from modeling decisions, recording every value with full provenance. Targeted validators catch characteristic LLM errors by matching values to source snippets, resolving DOIs, and executing code. For a pancreatic ductal adenocarcinoma QSP model, we used MAPLE to extract and curate 37 SubmodelTargets and 45 CalibrationTargets. Before any human review, the validators triggered 50 automated retries; every value carries a direct quote from its source and a verified citation; and 11 of 19 parameters are supported by more than one independent source. The LLM drafted usable forward models and code from context, while the modeler supplied the context and scientific judgment it cannot infer, revising forward-model choices in 65% of SubmodelTargets, priors in 46%, and source relevance in all files. This evaluation covers one model in one disease area, by a single group, so it characterizes the framework rather than establishing how broadly it generalizes. MAPLE records the modeler's reasoning in a form that can be re-run and independently checked, so it is not lost when the modeling team changes.
2 Aug 2026
Read appraisal →Journal of pharmacokinetics and pharmacodynamics
Diffusion models for virtual populations and pharmacometric simulations
To evaluate diffusion model-based artificial intelligence approaches for generating virtual populations with physiological determinants of drug dosing (PDODD) and pharmacokinetic (PK) profiles. A denoising diffusion probabilistic model (DDPM) was applied to a 31-variable dataset of PDODD covariates (18 continuous, 13 binary) from the National Health and Nutrition Examination Survey and compared to a tabular variational autoencoder (TVAE). For nivolumab PK data (12,000 patients, 13 time points, 5 covariates), sequence-based diffusion model (SDM) and a time-aware diffusion model (TDM) with temporal self-attention were evaluated. The predictive performance of the TDM was evaluated by imputing masked time points. All models were trained and tested on 80%:20% partitions of the data using univariate, bivariate, and multivariate distributional similarity metrics. The diffusion model satisfactorily approximated the univariate distributions of continuous PDODD biomarkers (mean Kolmogorov-Smirnov D-statistic, KSD = 0.014), disease status frequencies (mean absolute error, MAE = 0.31%), and preserved bivariate correlations (MAE = 0.033). DDPM outperformed TVAE for categorical variables (0.31% vs. 1.07% MAE) and correlation (0.033 vs. 0.091 MAE). For nivolumab PK, SDM has KSD of 0.047 and a relative error of 1.36%. TDM accurately imputed missing PK timepoints (KSD = 0.014), reconstructing masked Day 1, Peak concentration (Cmax) Dose-9, and Terminal phase concentrations with MAE of 0.43%, 0.25%, and 0.76%, and correlations ≥ 0.999. Diffusion models demonstrated strong performance in generating cross-sectional PK covariate data and longitudinal PK profiles, capturing complex distributional and temporal dependencies. Diffusion-based approaches provide a flexible and robust framework for virtual simulations in pharmacometrics.
1 Aug 2026
Read appraisal →Journal of chemical information and modeling
HyperDC: A Non-Uniform Hypergraph Framework for Dual- and Higher-Order Drug Combination Recommendation Across Diverse Complex Diseases
Complex diseases are commonly characterized by dysregulation across multiple targets and pathways, making drug combinations an important therapeutic strategy. This creates a growing need for computational methods to prioritize candidate combinations, yet current methods face several practical challenges, including cross-disease application, unified prediction of dual- and multidrug combinations, lack of reliable negative labels, and prediction for low-resource diseases. In this study, we proposed HyperDC, a unified cross-disease drug combination recommendation framework. HyperDC constructs a nonuniform hypergraph based on clinical and knowledge-driven drug-disease association data, representing single drugs and dual- and multidrug combinations in a unified modeling space. It further integrates knowledge graph pretraining and adversarial negative sampling to enhance model discrimination across tasks with different difficulty levels. In the unified dual-drug benchmark and disease-specific prediction tasks, HyperDC outperformed representative methods by up to 12.8 and 30.0 percentage points, respectively. In fixed-anchor clinical ranking tasks, HyperDC showed superior performance across multiple top-ranked recall settings and preferentially recalled FDA-approved dual-drug combinations and clinically supported three-drug combinations. In the data-sparse metabolic dysfunction-associated steatohepatitis (MASH) scenario, HyperDC completed a full workflow from anchor-drug identification and combination partner prioritization to in vitro experimental validation: 70% of the top 10 single-drug candidates were supported by recent literature, and 4 of 6 tested combinations showed synergistic lipid-lowering and anti-inflammatory effects, yielding a hit rate of 66.7%. Overall, HyperDC may narrow the screening space, improve prioritization efficiency, and provide methodological support for the development of combination therapy strategies for complex diseases.
29 July 2026
Read appraisal →Journal of chemical information and modeling
A Unified Molecular Graph and Protein Language Model Framework for Predicting Human Drug-Hormone Receptor Interactions with Structure-Aware Validation
Hormones regulate many essential biological processes by interacting with specific receptors that control gene expression, metabolism, growth, and immune function. Because numerous therapeutic compounds can influence or disrupt hormone signaling pathways, understanding drug-hormone receptor interactions (DHRI) is crucial for ensuring both therapeutic efficacy and endocrine safety. However, computational approaches for predicting DHRI remain limited, and most existing models do not explicitly incorporate hormone receptor-specific information. In this study, we propose a receptor-aware deep learning framework for DHRI prediction that integrates structural drug features with contextually embedded hormone receptor information. Drug molecules are represented using a hybrid encoding strategy that combines Morgan fingerprints and graph transformer-based molecular features to capture both global chemical properties and local structural information, while hormone receptor sequences are encoded using the pretrained ESM2 protein language model to obtain biologically meaningful sequence representations. The fused drug-hormone receptor features are then processed through a multilayer neural network to predict interaction probabilities. Model performance was evaluated using three splitting strategies, including random split, cold-drug split, and scaffold-based split, to assess both predictive accuracy and generalization ability. Under the random split setting, the model achieved an accuracy of 0.93, sensitivity of 0.94, specificity and precision of 0.92, F1-score of 0.93, and MCC of 0.86 on an independent data set, while also maintaining comparable performance under the more stringent cold-drug and scaffold-based settings. Feature importance analysis showed that atomic identity, hybridization, atom degree, and bond type were key shared determinants, while receptor-stratified results revealed receptor-dependent contributions from secondary features such as aromaticity, chirality, etc. In addition, t-SNE visualization showed clear class separation after training, and molecular docking across estrogen, androgen, and glucocorticoid receptors further supported the biological relevance of the predictions. Together, these findings demonstrate that incorporating hormone receptor-specific sequence information enables more reliable and biologically meaningful prediction of drug-hormone receptor interactions.
28 July 2026
Read appraisal →Medicine
Survival benefit of concurrent beta-blocker use in cancer patients treated with radiotherapy: A systematic review and meta-analysis
BACKGROUND: Both preclinical and retrospective studies have implicated β-adrenergic signaling in cancer progression, leading to interest in β-blockers (BBs) as adjunctive anticancer agents. There is evidence that they may enhance the sensitivity of cancer cells to radiotherapy and other conventional therapies. We conducted a systematic review and meta-analysis to explore the radiosensitizing effects of BBs. METHODS: PubMed, the Cochrane Library, Embase, Web of Science, the China National Knowledge Infrastructure, the China biology medicine database, Wan fang Data, and the VIP database were searched for articles in both English and Chinese from the establishment of the databases to September 8, 2025, to identify studies comparing outcomes according to beta-blocker use (yes vs no) in patients with solid tumors treated with radiotherapy. The primary endpoint was overall Survival (OS), Secondary objectives included 1, 2, 5-Year Survival, disease-free survival, distant metastasis-free survival, locoregional progression-free survival and progression-free survival (PFS). RESULTS: 8 studies (3165 patients), including 7 retrospective cohort studies and 1 randomized controlled trial, were analyzed. The most common cancer was non-small cell lung cancer (n = 5). BB use was associated with significantly improved OS (hazard ratio [HR] 0.73, 95% confidence interval: 0.64-0.83). Benefits were also observed for disease-free survival (HR 0.69) and Distant Metastasis-Free Survival (HR 0.62), indicating reduced recurrence and metastasis. CONCLUSION: In this meta-analysis, the use of BBs during or around radiotherapy may be associated with longer OS in cancer patients, suggesting that it may enhance the efficacy of radiotherapy and provide a survival benefit. Alternatively, the effect of β-blockers on survival may shift from a nonspecific effect to an intriguing cancer-specific effect over time. Beta-blockers are an intriguing option to explore in prospective studies of patients with solid tumors undergoing radiotherapy.
26 July 2026
Read appraisal →Medicine
Role of antazoline in cardioversion of atrial fibrillation: A PRISMA-compliant systematic review and meta-analysis
BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Antazoline, a first-generation antihistamine with antiarrhythmic properties, has shown efficacy in the rapid conversion of recent-onset AF to sinus rhythm; however, direct comparative evidence against standard antiarrhythmic agents remains limited. This study aims to systematically evaluate the efficacy and safety of antazoline for pharmacological cardioversion of AF, in comparison with standard antiarrhythmic agents such as amiodarone and propafenone. METHODS: The methodology of this systematic review and meta-analysis adhered to the preferred reporting items for systematic reviews and meta-analyses guidelines. A systematic search was conducted in ScienceDirect, Embase, PubMed, and Cochrane Library from inception to April 2025, including citation and reference screening. Statistical analyses were performed using R version 2025.05.0 + 496. RESULTS: From 172 records, 5 studies comparing antazoline with propafenone (n = 5) or amiodarone (n = 3) for AF were included. For antazoline vs propafenone, conversion to sinus rhythm favored antazoline (risk ratio [RR] 1.13 [95% confidence interval (CI): 1.04-1.23], P = .017). No significant difference was observed in time to conversion (mean difference -10.98 [95% CI: -124.93-102.98], P = .436), bradycardia (RR 0.84 [95% CI: 0.35-2.03], P = .478), hypotension (RR 0.40 [95% CI: 0.14-1.12], P = .056), or other adverse events (RR 1.24 [95% CI: 0.01-247.13], P = .694). For antazoline vs amiodarone, conversion to sinus rhythm favored antazoline (RR 1.22 [95% CI: 1.08-1.36], P = .018, I2 = 0%), with no significant differences in bradycardia (RR 1.36 [95% CI: 0-1072357.09], P = .823) or hypotension (RR 1.05 [95% CI: 0.04-26.16], P = .877). CONCLUSION: Antazoline might be more effective than propafenone and amiodarone in achieving sinus rhythm in AF, with no significant differences in safety outcomes.
26 July 2026
Read appraisal →mAbs
Optimization strategies for monoclonal antibody production: advances in simulation and artificial intelligence in bioprocessing
The rapid growth of monoclonal antibody (mAb) therapies has increased the need for efficient, scalable, and affordable manufacturing processes. However, mAb production remains complex because of nonlinear upstream cell culture behavior, expensive downstream purification, especially Protein-A chromatography, and plant-level bottlenecks that can increase cost, cycle time, and manuacturing uncertainty. This review examines recent developments in mAb manufacturing with focus on process simulation, mathematical optimization, and artificial intelligence/machine learning (AI/ML) across upstream processing (USP), downstream processing (DSP), and integrated plant-level operation. In USP, media optimization, dynamic feeding, high-density cultures, and continuous perfusion bioreactors are discussed in relation to productivity and critical quality attributes (CQAs). In DSP, alternative and intensified purification strategies are reviewed with a focus on recovery, impurity clearance, scalability, cost, and technology maturity. AI/ML applications are also discussed from early-stage development and cell-line screening to upstream control, CQA prediction, chromatography optimization, and downstream decision support. Despite these advancements, challenges such as data heterogeneity, limited standardized datasets, model transferability, and regulatory constraints remain important barriers to implementation. Overall, this review uniquely connects simulation and AI/ML approaches to practical optimization across the full mAb manufacturing workflow, including design, scheduling, debottlenecking, purification, monitoring, and quality prediction. The combination of process simulation, continuous bioprocessing, and AI/ML-based decision support may enable more flexible, reliable, and cost-effective mAb manufacturing. However, these benefits depend on validation through robust models, process-specific case studies, and technoeconomic analysis.
25 July 2026
Read appraisal →Journal of medical Internet research
Model and Task-Aware Test-Time Scaling Strategies for Large Language and Vision-Language Models in Medicine: Evaluation Study
BACKGROUND: Test-time scaling has emerged as a promising method to enhance the reasoning capabilities of large language models (LLMs) and vision-language models (VLMs) during inference without additional training. While foundational studies established scaling paradigms in general domains, their applicability to the unique complexities of medical AI remains underexplored. OBJECTIVE: This study aims to conduct a comprehensive investigation of test-time scaling in the medical domain. We evaluate the impact of scaling across different model sizes and task complexities. Furthermore, we seek to identify domain-specific bottlenecks and assess model robustness against user-driven perturbations, such as misleading clinical authority. METHODS: This study evaluated a diverse set of general and medical-specific LLMs and VLMs. Experiments used five textual medical benchmarks comprising over 5500 questions and two multimodal benchmarks comprising 7000 samples. Performance was measured under three scaling conditions: increasing token budgets, iterative sequential scaling, and parallel scaling. Robustness was tested by embedding misleading hints with varying tones and levels of simulated clinical expertise into prompts. RESULTS: For nonreasoning LLMs, accuracy saturated quickly, with token usage often remaining under 500 tokens regardless of budget increases. Reasoning models demonstrated significant performance gains on complex tasks as token budgets increased. Notably, we identified distinct domain-specific behaviors. First, current VLMs showed a structural bottleneck in integrating visual clues and experienced limited benefit from token expansion. Second, medically fine-tuned LLMs excelled in clinical question answering but exhibited degraded scaling efficiency on calculation tasks compared to general-domain models. This reflects a disparity between qualitative clinical alignment and procedural logic. Third, while optimal scaling improved robustness, models exhibited a cognitive vulnerability by readily abandoning correct reasoning when confronted with misleading expert physician hints. Regarding scaling strategies, parallel scaling outperformed sequential scaling on easier tasks. Conversely, extended sequential scaling or increased budgets proved essential for complex problem-solving. CONCLUSIONS: Test-time scaling rules from general domains do not perfectly translate to medical AI. Longer reasoning is not universally beneficial. Concise reasoning with parallel scaling is optimal for simpler tasks. An extended chain of thought via sequential scaling or increased budgets is required for complex problems. Furthermore, safe clinical deployment requires addressing fundamental vision-language alignment, balancing clinical and procedural reasoning, and mitigating vulnerabilities to perceived clinical authority.
24 July 2026
Read appraisal →Journal of computer-aided molecular design
Artificial intelligence in impurity prediction: current landscape, challenges, and future directions
Earlier identification, regulation of impurities in pharmaceutical products is critical throughout the medication development process because they have a high impact on drug quality, safety, and regulatory approval. Traditional analytical methods like LC-MS and NMR are frequently used, but they are labour intensive, time consuming and have limited capacity to detect unknown or trace level impurities. New opportunities to forecast impurity formation before experimental observation have been enabled by developments in cheminformatics and computer modelling. This study covers advanced chemical representation techniques, data generation, data curation, and model validation with highlighting recent advances in machine learning and deep learning algorithms for impurity prediction. In association with forecasting synthetic by products, degradation products, and harmful contaminants, traditional QSAR techniques, and contemporary deep learning models such as graph neural networks, transformer based architectures, and generative frameworks are examined. Additionally, discussed the increasing significance of explainable models for regulatory body acceptability. Lastly, newly developed advanced techniques like digital twins, automated impurity profiling, integrated reaction degradation modelling, and real-time monitoring are examined, demonstrating how computational methods are transforming impurity assessment from a reactive effort into a predictive and preventive procedure.
23 July 2026
Read appraisal →JMIR mental health
Optimizing Treatment Strategies in the Bipolar Disorder Spectrum With Classical AI Approaches: Systematic Review of Performance, Bias, and Clinical Applicability
BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric condition, characterized by fluctuating clinical courses that affect approximately 1%-2% of the global population in their lifetime. Despite pharmacological advances, treatment response varies significantly among patients, making the identification of individualized treatment strategies a major challenge. Artificial Intelligence (AI), through its classical approaches, has emerged as a powerful tool in precision psychiatry to identify subtle patterns in complex data and inform personalized clinical decisions. OBJECTIVE: The present systematic review aimed to examine the current evidence on classical AI-supported treatment optimization in the BD spectrum. METHODS: The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. Four databases (PubMed, Web of Science, Scopus, and Embase) were searched for original studies published after 2015 on the application of classical AI in the treatment of BD in adult patients. Publication bias was evaluated by visual inspection of a funnel plot. The methodological quality, risk of bias, and clinical applicability of the predictive models were assessed using the Prediction Model Risk Of Bias Assessment Tool for prediction models using regression or AI methods (PROBAST+AI; PROBAST+AI Working Group) tool. RESULTS: A total of 35 studies were included and classified into 5 outcome-based categories, including acute symptomatic response, long-term maintenance response, relapse and readmission risk, safety and dose optimization, and brain aging and phenotyping. Acute symptomatic response models performed modestly (pooled area under the curve [AUC] 0.68), while imaging improved accuracy (74%-77%). Long-term maintenance response models showed moderate-to-high performance (pooled AUC 0.80), with biomarker- and cellular-based models reaching 96%-99% accuracy. Relapse and readmission prediction achieved a pooled AUC of 0.71, with digital phenotyping and rule-based methods performing best (AUC 0.85-0.88). Safety and dose optimization models achieved 85%-97% accuracy. Brain aging and phenotyping studies highlighted accelerated brain aging in BD, partially mitigated by lithium, and revealed novel data-driven subgroups. However, 3 studies were considered at high risk of bias due to small sample sizes associated with disproportionately high-performance estimates. An additional study was identified as potentially biased because it lay markedly distant from the funnel plot's confidence line. Finally, the PROBAST+AI assessment revealed a high risk of bias in most studies, primarily due to data analysis limitations, small sample sizes, and lack of external validation. CONCLUSIONS: The adoption of classical AI tools in BD serves as a driver for therapeutic optimization, although current AI tools in BD should still be considered exploratory rather than ready for clinical use. Effective implementation in real-world clinical scenarios requires more robust, transparent, and externally validated models to ensure reliability and generalizability.
22 July 2026
Read appraisal →Environmental science & technology
Bridging the Gap between External and Internal Exposure: Challenges and a Machine Learning Approach Validated Using Benzene Ring-Containing Pollutants
Establishing quantitative linkages between external and internal exposures is essential for accurate exposure and health risk assessment, yet this goal remains hindered by multiple challenges. This Perspective systematically reviews major challenges limiting the quantitative linkage across three dimensions: (i) External exposure: complex multimedia and multipathway exposure, environmental factor variability, and substantial data gaps; (ii) Internal exposure: difficulties in biological sample collection, large-scale biomonitoring, and appropriate biomarker selection; and (iii) External-internal exposure linkage: interindividual variability, scarce toxicokinetic parameters, and methodological limitations. In this context, the Perspective proposes ML-EIExpLink (machine learning-based external-internal exposure linkage), a framework integrating multisource, multidimensional variables, including pollutant physicochemical properties, ADME parameters, exposure factors, environmental conditions, and socioeconomic indicators, to model complex external-internal exposure relationships. An exploratory case study on benzene ring-containing pollutants demonstrates the framework's feasibility and reliability. Using gradient boosting decision trees as the core predictive engine, the model achieved robust predictive performance, with an external validation Qext2 of 0.784. Most key variables, including external air concentration, molecular planarity, and temperature, exhibited nonlinear and threshold effects on predicted blood concentrations. This Perspective introduces a novel ML-based framework for establishing robust, interpretable external-internal exposure linkages, thereby providing a useful basis for improved exposure assessment and health risk evaluation.
22 July 2026
Read appraisal →European journal of clinical pharmacology
Clinical decision support systems for polypharmacy optimization in older patients: a narrative review
PURPOSE: Multimorbidity and polypharmacy are increasingly prevalent in the older population and are associated with a higher risk of potentially inappropriate medications (PIM), drug-drug interactions (DDI), and adverse drug reactions (ADR). Although medication review (MR) and deprescribing are effective strategies, their manual implementation can be complex, time-consuming, and prone to clinical variability. Clinical Decision Support Systems (CDSS) offer advanced digital solutions to optimize polypharmacy by analyzing multidimensional clinical data and generating personalized recommendations. METHODS: A narrative review was conducted to identify and compare the main CDSS developed for the polypharmacy management, MR and deprescribing in older adults and patients with multimorbidity. Systems were classified as manual, hybrid, or automated according to their data acquisition modalities. Operational characteristics, integration into clinical workflows, decision-support functions, generated outputs, and available validation evidence across different healthcare settings were assessed. Owing to the narrative nature of the review and the heterogeneity of the included evidence, no formal risk-of-bias assessment or certainty-of-evidence evaluation was performed. RESULTS: Manual CDSS require direct data entry by clinicians and are associated with a high operational burden. Hybrid systems combine automatic data acquisition with manual integration, balancing efficiency and clinical oversight. Automated systems, integrated into electronic health records (EHR), provide real-time decision support with minimal human intervention. Considerable heterogeneity was observed across identified platforms in terms of automation, implementation characteristics, and stage of validation, with evidence ranging from development and feasibility studies to observational analyses and randomized controlled trials (RCT). CONCLUSION: CDSS represent promising tools for safer and more effective management of polypharmacy in complex patients. Advanced integration into clinical workflows and systematic use of multidimensional data may enhance their impact. However, the heterogeneity of available systems and the variability in their level of clinical validation highlight the need for comparative studies, pragmatic trials, and real-world implementation evaluations. Such studies are necessary to clarify the impact of different CDSS models on prescribing appropriateness, medication-related risks, patient outcomes, and long-term sustainability within routine healthcare settings.
20 July 2026
Read appraisal →ACS synthetic biology
LysePred: A Multiscale Convolutional Neural Network for Predicting Hemolytic Activity of Antimicrobial Peptides
Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics, yet hemolytic toxicity remains a critical barrier to clinical translation, with approximately 70% of known AMPs exhibiting high or moderate hemolytic activity. Existing computational prediction methods are often constrained by deficiencies, including high computational complexities, the inability to capture multiscale sequence patterns, and insufficient generalization across diverse datasets. We present LysePred, a multiscale convolutional neural network to address these deficiencies concurrently by employing parallel branches with exponentially spaced kernel sizes to simultaneously capture local amino acid motifs (bigrams, 4-g) and longer-range amphipathic patterns (8- to 32-g). LysePred achieves top-tier performance on six benchmark datasets, exceeding the performance of the second-best method by 9.13% in MCC and 3.65% in ACC on average, while maintaining exceptional stability (MCC CV < 6.92%, ACC CV < 2.73%). Furthermore, independent validation on the HemoPI2 dataset demonstrates that LysePred delivers highly competitive results with a computationally parsimonious design (∼0.55 M parameters). This represents a reduction in parameter density of 1 to 2 orders of magnitude compared to Transformer-based approaches, such as the 8M-parameter ESM-2 or the 110M-parameter BERT Base while maintaining linear complexity for high-throughput screening. Ablation studies validate that the multiscale architecture contributes meaningfully to performance, with single-scale variants showing up to 13.35% MCC degradation. Interpretability analyses via t-SNE visualization and SHAP feature importance reveal that LysePred learns biologically meaningful representations integrating both local sequence motifs and global structural patterns. LysePred offers a practical, efficient, and interpretable tool for rapid hemolytic toxicity prediction in antimicrobial peptide development. Code and data are available at https://github.com/lincubator/LysePred.
20 July 2026
Read appraisal →Renal failure
Effects on mortality of different blood purification techniques in sepsis patients: an umbrella review of systematic reviews and meta-analyses
Sepsis remains a leading cause of mortality worldwide, and extracorporeal blood purification has been widely implemented despite ongoing uncertainty regarding its survival benefit. We conducted an umbrella review of 42 systematic reviews and meta-analyses evaluating mortality across major extracorporeal blood purification modalities. Mortality estimates generally favored extracorporeal blood purification over conventional care, but effect sizes and consistency varied substantially by modality, and the overall certainty of evidence for mortality was low. At the review level, polymyxin B hemoperfusion showed a relatively consistent direction toward lower mortality, whereas renal replacement therapy-based strategies were typically closer to the null. However, most included reviews were of low or critically low methodological quality, with downgrading driven by risk of bias, inconsistency, and potential publication bias. Therefore, these findings should be interpreted cautiously and should not be considered definitive evidence of survival benefit. They highlight persistent evidentiary fragility and underscore the need for rigorously designed, phenotype-informed trials to clarify modality-specific effects in sepsis. What is known: Extracorporeal blood purification has been widely used as an adjunctive therapy for sepsis, but its mortality benefit remains uncertain across different modalities.What this study adds: This umbrella review synthesizes evidence from 42 systematic reviews and meta-analyses and shows that mortality estimates generally favor extracorporeal blood purification, although effects vary substantially by modality and the overall certainty of evidence remains low.Potential impact: These findings support cautious, modality- and phenotype-informed interpretation of extracorporeal blood purification in sepsis and highlight the need for rigorously designed trials with standardized protocols.
19 July 2026
Read appraisal →Analytical methods : advancing methods and applications
Spatial metabolomics in medicinal plant research: current advances, technical challenges, and future perspectives
Secondary metabolites derived from medicinal plants represent a critical resource for drug discovery and play an indispensable role in the prevention and treatment of major human diseases. Spatial metabolomics has emerged as a transformative approach that overcomes the inherent limitations of traditional metabolomics, particularly tissue homogenisation, by enabling precise, in situ profiling of the spatial heterogeneity and dynamic accumulation of key bioactive compounds. When integrated with complementary technologies such as spatial multi-omics (SMO), single-cell analysis, and artificial intelligence (AI)-assisted imaging, this paradigm provides a powerful framework for deciphering the spatiotemporal regulatory networks that govern secondary metabolite biosynthesis. This review systematically compares conventional and spatial metabolomics, synthesises recent advances in medicinal plant research, critically evaluates current technical challenges and optimisation strategies, and outlines future directions enabled by multi-omics integration and intelligent computational analytics. Collectively, these insights aim to establish a theoretical foundation for the in-depth investigation of medicinal plants and to support their translational application and industrial advancement.
19 July 2026
Read appraisal →Critical care explorations
Drug Clearance and Dosing During CytoSorb Hemoadsorption: A Systematic Review
OBJECTIVE: CytoSorb (CS) hemoadsorption is increasingly used in critical care and cardiac surgery to remove inflammatory mediators and select drugs. This systematic review aimed to summarize available evidence on intentional drug removal as well as unintentional drug removal during CS therapy. DATA SOURCES: PubMed, congress abstracts, and CytoSorbents online literature database. STUDY SELECTION: Eligible studies included benchtop, animal, and human pharmacokinetic investigations of drug removal during CS therapy as well as clinical reports describing CS use for drug overdose. DATA EXTRACTION: Data from the eligible studies were extracted independently by two authors into Microsoft Excel. DATA SYNTHESIS: Data were identified for drugs across multiple therapeutic classes, including analgesics, antiarrhythmics, anticonvulsants, antidepressants, antihypertensives, anti-infectives, antithrombotics, anxiolytics, and immunosuppressants. Drugs were categorized into low (< 30%), moderate (30-60%), or high (> 60%) removal rate, or by the relative increase in clearance attributable to CS: negligible (< 25%), low (25-100%), moderate (100-400%), or high (> 400%). Based on the assembled data and considering drug-, patient-, and circuit-specific factors, general dosing recommendations for concomitant medications were developed. CONCLUSIONS: CS therapy can alter drug concentrations for select agents with variable clinical relevance. CS can reduce perioperative bleeding risk through antithrombotic removal and treat certain drug overdoses. Unintentional drug removal during CS therapy may occur and practical guidance is provided for drugs with known susceptibility to removal.
16 July 2026
Read appraisal →International journal of cancer
Drug repurposing in oncology: Bridging computational discovery to clinical application.
Drug repurposing, the identification of new therapeutic applications for existing drugs, has emerged as a pragmatic and cost-efficient strategy to accelerate oncology drug discovery. Faced with rising development costs, protracted timelines, and high attrition rates associated with traditional de novo drug development, repurposing leverages known pharmacokinetics, safety profiles, and manufacturing processes to expedite clinical translation. This review synthesizes current advances in computational and experimental methodologies and mechanistic insights that drive drug repurposing for cancer therapy. In silico strategies, including molecular docking, machine learning, transcriptomic-proteomic signature reversal, and network-based modeling, have enabled rapid identification of repurposable agents by mining multi-omics and historical pharmacological data. Experimental pipelines spanning high-throughput screening, phenotypic assays, biochemical validations, and functional animal models remain essential to establish efficacy and delineate mechanisms of action. Notably, repurposed drugs exhibit anticancer activity by modulating key pathways, including phosphatidylinositol 3-kinase/Ak strain transforming/mechanistic target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase, wingless-related integration site/β-catenin signaling, as well as redox homeostasis and DNA response. Despite their promise, repurposed candidates face barriers including limited intellectual property protections, dose optimization challenges, and regulatory uncertainty. Moreover, clinical translation is often hindered by insufficient mechanistic understanding and a lack of predictive biomarkers. Integration of multi-omics datasets, explainable artificial intelligence, patient-derived organoids, and clustered regularly interspaced short palindromic repeats-based genetic screens now offers unprecedented precision in identifying context-specific drug effects and synthetic lethal interactions. With cancer causing one in six global deaths and marked by therapeutic resistance and molecular heterogeneity, drug repurposing provides a scalable solution. This approach bridged preclinical insight with clinical application, potentially transforming cancer therapeutics through rational, data-driven innovation.
15 July 2026
Read appraisal →Journal of ethnopharmacology
Efficacy of Wendan Decoction combined with conventional medicine for depression: a systematic review and meta-analysis
ETHNOPHARMACOLOGICAL RELEVANCE: Wendan Decoction is well-known traditional Chinese medicine formula commonly used in China for the treatment of gastrointestinal disorders and mood disorders related to phlegm-dampness and spleen deficiency. In clinical practice, depending on different symptoms, additional herbs may be included, resulting in a modified formula known as modified Wendan Decoction. AIM OF THE STUDY: To evaluate the efficacy of modified Wendan Decoction plus conventional medicine in the treatment of depression. MATERIALS AND METHODS: We independently conducted a meta-analysis of studies on the efficacy of modified Wendan Decoction for depression from inception to February 28, 2025, using electronic databases, including PubMed, Embase, Cochrane, Web of Science, Wanfang, VIP and SinoMed. Data from randomized controlled trials were extracted to evaluate treatment outcomes based on depression scales. RESULTS: A total of 402 articles were identified through database searches, and 13 studies, encompassing 1117 patients, were included. The initial pooled analysis revealed a significant treatment effect of the experimental group, yielding a standardized mean difference (SMD) of -4.84 (95% CI: -7.54 to -2.14), with high heterogeneity (I2 = 99%). Sensitivity analysis, excluding studies with high risk of bias, demonstrated an SMD of -4.18 (95% CI: -5.26 to -3.10) with moderate heterogeneity (I2 = 83%). Notable regional differences were found, with the study in Southern region exhibiting greater efficacy (SMD = -4.81, 95% CI: -6.38 to -3.23) compared to the study in Northern region (SMD = -3.03, 95% CI: -3.73 to -2.32). CONCLUSIONS: Our meta-analysis supports the efficacy of combining modified Wendan Decoction with conventional medicine for treating depression. Exploratory subgroup results suggest slightly greater improvements in Southern China, though this finding requires cautious interpretation and confirmation in future high-quality trials. PROSPERO Registration ID: CRD420251015690.
15 July 2026
Read appraisal →European journal of clinical pharmacology
Impact of carvedilol versus metoprolol on ventricular arrhythmia burden and ICD therapies: a systematic review and meta-analysis
BACKGROUND: Ventricular arrhythmias (VA) are major causes of morbidity and mortality in patients with cardiovascular disease. Implantable cardioverter-defibrillators (ICDs) are commonly used to prevent sudden cardiac death. However, patients with ICDs frequently experience recurrent arrhythmias and inappropriate shocks, which impact quality of life. Beta-blockers, specifically carvedilol and metoprolol, are commonly prescribed in this context. This meta-analysis aims to compare the impact of both medications in this patient population. METHODS: Comprehensive literature search was conducted to identify relevant studies comparing carvedilol to metoprolol in patients with VA or ICDs. Study outcomes included all-cause mortality, recurrent VA, and inappropriate ICD shocks. Effect estimates are presented as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Five independent study populations, reported across six publications, including 7,777 patients (5,138 on carvedilol, 2,639 on metoprolol) were analyzed. Carvedilol was associated with a significantly lower risk of inappropriate ICD shocks (HR = 0.66, 95% CI: 0.48-0.90, P = 0.009) and inappropriate anti-tachycardia pacing (HR = 0.67, 95% CI: 0.49-0.91, P = 0.01) compared with metoprolol. There were no significant differences between the two beta-blockers in recurrent ventricular tachyarrhythmias or all-cause mortality. CONCLUSION: Carvedilol may provide additional benefit over metoprolol in reducing inappropriate ICD therapies and anti-tachycardia pacing, while no significant differences were found in recurrent ventricular arrhythmias or all-cause mortality. These findings support consideration of carvedilol in patients with ICDs, but further research is warranted to guide optimal beta-blocker selection.
15 July 2026
Read appraisal →Nucleic acids research
DeepCYP: an integrated deep learning web server for the holistic 'pathway-site product' prediction of CYP450 metabolism
CYP450 (cytochrome P450)-mediated drug metabolism is a critical determinant of pharmacokinetics and clinical safety, making comprehensive metabolic profiling essential for rational drug discovery. Here, we present DeepCYP (https://deepcyp.scbdd.com), a freely accessible deep-learning web server for end-to-end CYP450 metabolic profiling. Trained on an expanded dataset and a mechanism-based reaction rule library, DeepCYP uses a multi-task graph neural network (GNN) combined with multi-scale descriptors. Operating directly on 2D molecular graphs, this architecture bridges the entire "pathway-site-product" continuum across nine major CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) within a unified pipeline. Benchmarking demonstrates that DeepCYP outperforms established tools, including FAME3, SMARTCyp, and BioTransformer 3.0, improving Top-1 and Top-2 ranking metrics by over 10%. Furthermore, the server supports high-throughput batch processing, capable of evaluating ~280 molecules per minute. DeepCYP also enhances interpretability through an interactive visualization interface, featuring susceptibility radar charts and dynamic transformation tables. By translating abstract predictions into biological insights, DeepCYP provides a practical tool to accelerate lead optimization and mitigate toxicity risks.
13 July 2026
Read appraisal →Depression and anxiety
A Systematic Review of Community Pharmacy-Led Depression Services: Service Components, Outcomes, and Implementation Barriers and Facilitators
BACKGROUND: Depression is the most common mental ill health condition, and its prevalence is increasing. Despite this, its treatment is variable often due to a lack of capacity within healthcare systems to support this vulnerable population. Community pharmacy staff could offer additional support. This systematic review identifies depression services led by community pharmacy staff, their service components, outcomes, and barriers/facilitators to their implementation. METHODS: Four bibliographic databases were searched (Medline, EMBASE, PsycINFO, and CINAHL) from 2000 onwards. Title/abstract and full-text screening was conducted. Data on the service components were mapped to the Template for Intervention Description and Replication (TIDieR). Clinical, humanistic, economic, and service outcomes were charted. Barriers and facilitators were mapped to the Consolidated Framework for Implementation Research (CFIR). Quality assessment was performed using the Quality Assessment with Diverse Studies (QuADS) tool. RESULTS: Fifty studies were included. Seventeen studies identified general attitudes regarding community pharmacy services for depression, which were generally supportive. The majority (n = 33) explored an implemented depression service focusing on depression advice/education (n = 15), screening (n = 12), medication adherence (n = 4), medication review (n = 1), and disease therapy management (DTM) (n = 1). Clinical outcomes were the most commonly reported types of outcomes, with varied results. Key facilitators were linked to the pharmacy 'inner setting', including accessibility of community pharmacies, the use of private consultation rooms, and skills/training of staff. Barriers to service delivery related often to the external 'outer setting', especially societal stigma, low public awareness of pharmacy roles, funding constraints, and limited collaboration with other healthcare professionals. CONCLUSION: This international review identified a range of different services that community pharmacy staff can deliver to support people with depression, ranging from supporting diagnosis, health literacy, and management plans. The accessibility of community pharmacies for depression service delivery warrants further investigation. However, limited empirical evidence of clinical and economic outcomes and reported implementation barriers may complicate broader implementation.
13 July 2026
Read appraisal →BMC medical informatics and decision making
A systematic review of patient decision aids for hypertension
BACKGROUND: Hypertension is a major cause of premature death and a modifiable risk factor for cardiovascular disease. Effective management includes both pharmacological treatment strategies, including antihypertensive medications, and non-pharmacological treatment strategies, such as lifestyle changes. Shared decision making (SDM) between patients and healthcare professionals is essential to determine the most appropriate treatment for hypertension. Patient decision aids (PDAs) facilitate SDM by providing information on treatment options and helping patients to clarify their values and preferences. However, there is no comprehensive comparison of PDAs for hypertension. OBJECTIVE: This systematic review aimed to identify and evaluate PDAs for arterial hypertension using the International Patient Decision Aid Standards (IPDAS) criteria. METHODS: A comprehensive search of bibliographic databases (PubMed, Embase) and gray literature (Google Scholar, Google) was performed in October 2023 and updated in April 2026. Studies and tools were included if they presented a PDA for patients with arterial hypertension, met the IPDAS definition of a PDA and were in German or English. Two researchers screened the literature, extracted data and assessed the quality of the PDAs using the IPDAS Minimal Criteria. Data were synthesized narratively. RESULTS: Of 1,874 records screened, five PDAs met the inclusion criteria. These PDAs were developed between 2019 and 2024 and originated from the United States, United Kingdom, and Germany. All PDAs addressed the two option areas of medication and lifestyle but differed in the number of individual treatment options presented (range: 2-12 options) and the level of detail in which the options were addressed. All five PDAs were accessible online. Common design features of the PDAs included an option grid format for presenting treatment options with associated benefits and adverse effects, visuals and graphics to enhance comprehension, and value clarification. Quality assessments showed varying levels of compliance with the IPDAS criteria, with overall scores ranging from 49/116 to 87/116. CONCLUSIONS: Few PDAs exist despite the prevalence of hypertension. PDAs varied in quality and format, highlighting gaps in the development process. Further research is needed to evaluate the effectiveness of PDAs for hypertension and to determine which formats are most effective in supporting SDM in different patient populations. CLINICAL TRIAL NUMBER: Not applicable.
13 July 2026
Read appraisal →ACS infectious diseases
Machine Learning Approaches Using High-Throughput Profiling Data for Antibiotic Discovery
Antibiotic-resistant bacterial infections continue to increase globally, creating an urgent need for new antibacterials with novel mechanisms of action. Early stages of antibiotic discovery are often limited by the difficulty of identifying compounds that act through previously unrecognized pathways and by challenges in determining their mechanisms. Machine learning (ML) integrated with high-throughput profiling now provides systematic approaches to overcome these barriers. Beyond initial hit discovery, multilayer profiling using morphological phenotyping, transposon sequencing, transcriptomics, proteomics, and metabolomics captures cellular responses that reflect the mechanisms of action. Because profiling data sets are typically high-dimensional and contain defined features and variables, ML can extract complex patterns associated with pathway-level responses and predict mechanisms for unknown compounds. In this review, we summarize current progress in high-throughput profiling and describe how ML applied to each data set can accelerate the identification of antibacterials with new mechanisms. These approaches accelerate the transition from large-scale compound screening to mechanistic validation and enable effective prioritization of lead compounds in early-stage antibiotic discovery.
11 July 2026
Read appraisal →Journal of medicinal chemistry
Machine Learning-Based Models to Predict Drug-Induced Liver Injury (DILI) to Assist Medicinal Chemistry
Drug-induced liver injury (DILI) is a leading cause of drug failure and post-market withdrawals. Traditional preclinical methods fail to detect up to 40-45% of clinical hepatotoxicity cases. Computational approaches, particularly those based on machine learning and deep learning (DL), are emerging as promising tools to support medicinal chemistry and early drug discovery, though their predictive capabilities remain under active investigation. In this perspective, we review the development of DILI annotation data sets, tracing their growth from small collections to large, comprehensive resources. We also outline the evolution of computational methods, from simple descriptor-based models to advanced DL and ensemble approaches that incorporate interpretable features. Finally, we highlight recent efforts to integrate standardized causality frameworks, pharmacogenomics, and mechanistic models, aiming to connect computational advances with clinical relevance. This perspective provides valuable insight for researchers and promotes the development of more robust and consensual DILI prediction strategies.
10 July 2026
Read appraisal →Cell host & microbe
Adjunctive fecal microbiota transplantation for major depressive disorder: A randomized, double-blind, placebo-controlled trial
Gut microbiota may influence antidepressant treatment outcomes, yet whether targeted modulation can enhance efficacy remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in patients with major depressive disorder, administering a 2-week course of fecal microbiota transplantation (FMT) capsules or placebo as an adjunct to escitalopram (ChiCTR2300071421). Remission rates at week 8 did not differ significantly between groups, but FMT produced greater reductions in Hamilton Depression Rating Scale, 17-item version (HAMD-17) scores at weeks 2 and 8. FMT was well-tolerated with a safety profile comparable to placebo. Multi-omics analyses show durable donor microbial engraftment and enrichment of beneficial Lachnospiraceae and Oscillospiraceae taxa. Microbial remodeling is accompanied by an increase in serum bile acids that correlate with the alleviation of depressive symptoms. Mediation analysis supports a bile-acid-mediated suppression of inflammatory pathways linking microbial changes to antidepressant effects. Overall, FMT may provide a safe avenue to enhance escitalopram efficacy through microbiota-directed regulation of bile-acid metabolism and inflammation.
10 July 2026
Read appraisal →Journal of computer-aided molecular design
Two faces of drug repurposing data in machine learning-driven structure-based virtual screening supported by interaction fingerprints
Ensemble docking is a prominent source of protein-ligand complex structures, which could be conveniently analyzed with interaction fingerprints approach in a machine learning framework. Nevertheless, the chemical nature and provenance of the source data libraries used for model development may influence the predictive ability. We assessed the performance of SARS-CoV-2 main protease (Mpro) inhibitors classification by random forest models trained on different fingerprint implementations using three inhibitor libraries, comprising drug repurposing data or compounds rationally designed as Mpro inhibitors. Models trained on drug repurposing data showed a low prediction performance on their own, while infusion of these data into libraries with specific inhibitors greatly improved applicability domains of the models. Our results highlight the importance of balanced dataset preparation for machine learning applications in medicinal chemistry, especially when relied on drug repurposing experiments.
8 July 2026
Read appraisal →Journal of medical economics
Evaluation of nirmatrelvir/ritonavir treatment for COVID-19 on health-related outcomes: a global economic value systematic literature review.
AIMS: Nirmatrelvir/ritonavir (NMV/r)i is an antiviral drug indicated for the treatment of patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk of progressing to severe disease. We performed an updated economic systematic literature review (eSLR) of NMV/r to build upon evidence reported in our previous eSLR and additionally examine the health-related outcomes associated with NMV/r and any potential effect of long COVID. METHODS: A systematic search of Embase, PubMed, Cochrane, and EconLit and of conference and health technology assessment agency websites was performed to identify economic analyses published between January 2022 and October 2025. RESULTS: Of the 33 included economic evaluations, most were cost-utility analyses (n = 16) and used an analysis of a short-term decision tree with a long-term Markov model (n = 11). Several types of health-related endpoints were reported by studies, with most including hospital-related endpoints (n = 20), quality-adjusted life-years (QALYs) (n = 18), and death-related endpoints (n = 18). Positive health-related outcomes were associated with NMV/r treatment, including reductions in hospitalizations and deaths and an increase in QALYs. NMV/r treatment was also associated with a reduced number of patients with long COVID complications. LIMITATIONS: Most studies were conducted in high-income countries, were based on different COVID-19 variants, and were limited in data on the long COVID population. CONCLUSION: In addition to monetary benefits, NMV/r provides short-term and long-term health-related benefits to patients with mild to moderate COVID-19. This study provides further support for NMV/r as a cost-effective treatment option.
7 July 2026
Read appraisal →Molecular pharmaceutics
Computational Identification of Active Drug Metabolites for Human Protein Targets
Understanding drug metabolism helps mitigate toxicity risks and anticipate pharmacological effects beyond the parent compound. Here, we explore high-confidence in vitro human bioactivity annotations from the public domain associated with a curated data set of drug-metabolite pairs. Our findings show that 26% of all drug-metabolite-target combinations contain metabolites with retained or increased bioactivity relative to their parent drugs, showing a high proportion of active metabolites with potencies below 100 nM. Moreover, these active metabolites display similar predicted physicochemical and ADME properties to their parent drugs, indicating that their biological activity may be preserved in vivo. Two key features of the identified active metabolites are noted: (1) the metabolite is more likely to be formed via an O-demethylation or an N-demethylation at a tertiary nitrogen, and (2) these drug-metabolite pairs are frequently active against the membrane receptor target class. To support further research in this area, we make our data compilation, including pairs with identified active metabolites and recorded bioactivity data, openly available.
7 July 2026
Read appraisal →Molecular pharmaceutics
Platelets as Programmable Drug Depots: Toward Predictive and Mechanistic Drug Loading
Efficient drug delivery remains a major challenge in pharmaceutical science, with synthetic nanocarriers often facing limitations in real biological systems. While blood platelets have been explored as biomimetic carriers, their intrinsic capacity for molecular storage and stimulus-triggered release remains largely underutilized. Here, we propose that platelet granules can be viewed as programmable drug depots, whose loading can be rationally controlled using physicochemical principles and endogenous transport mechanisms. In contrast to empirical approaches, we outline a framework based on two complementary pathways: passive accumulation driven by ion trapping of weakly basic compounds in acidic granules, and active uptake mediated by vesicular transporters. Building on recent advances in structural biology and computational modeling, we further argue that drug loading into platelets can be predicted and optimized using molecular descriptors, docking approaches, and machine learning models to estimate transporter compatibility and accumulation efficiency. This perspective introduces a conceptual design loop linking prediction and molecular optimization─i.e., enabling both selection of suitable drug candidates and rational modification of their structures to enhance platelet compatibility. Together, these concepts position platelets not simply as biomimetic carriers but as model-guided and engineerable platforms for drug delivery, bridging biological systems with rational design strategies.
6 July 2026
Read appraisal →European journal of medicinal chemistry
Accurate and interpretable ADMET prediction: Integrating structural, geometric, and global molecular context representations
Predicting absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles early in drug discovery is essential to avoid late-stage failures. However, most current computational models depend on single-view molecular representations. This restricts them from capturing the complex interplay between 2D topology, 3D conformations, and specific functional groups that collectively drive structure-pharmacokinetic relationships. Here, we present LGSM, a comprehensive deep learning framework for integrative molecular property prediction. By fusing structural (2D topology), geometric (3D conformational descriptors), and sequence-derived semantic representations, LGSM provides accurate ADMET predictions. Specifically, a language model-based encoding of SMILES sequences is utilized to capture the global molecular context, seamlessly complementing local functional group characteristics. By fusing these different levels of information, our architecture accounts for both local chemical environments and broader spatial relationships. We evaluated this approach across four public ADMET datasets. To mimic real-world drug design scenarios where new chemotypes are constantly explored, we applied a strict scaffold split. Under these conditions, LGSM consistently outperformed standard computational baselines. Beyond predictive accuracy, we prioritized chemical interpretability. By combining the model's internal analysis with molecular docking, we show that LGSM successfully flags key substructures responsible for metabolic liabilities or transporter recognition. This transparency makes the framework a practical tool to guide rational lead optimization in medicinal chemistry.
6 July 2026
Read appraisal →International health
Antimicrobial stewardship interventions currently implemented at primary healthcare settings across low- and lower-middle-income countries (LLMICs)
BACKGROUND: Antimicrobial resistance (AMR) is a top global public health and development threat. Antimicrobial stewardship programs (AMSPs) are one of the most cost-effective interventions to optimize the use of antimicrobials. This study reviews AMSPs that have been implemented in low- and lower middle-income countries. METHODS: A systematic search was conducted on electronic databases including MEDLINE, PubMed, Embase, OVID, Web of Science and Cochrane Library on 18 July 2024 for published papers from 2014 to 2024 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Relevant published literature was then selected based on the established inclusion/exclusion criteria. Each article was screened by two independent reviewers. Data were extracted and synthesized in the review. RESULTS: Of the 425 articles screened, only 13 were eligible for review and included in this study. Two studies were multinationals. Five studies were randomized controlled trials. Among the three key focuses of AMSPs, most of the interventions focused on optimizing antibiotic use (n=8), followed by improving diagnostics and monitoring (n=3) and education and training (n=2). The most commonly reported barriers to implementing AMSPs was a lack of resources (n=9). Facilitators reported included knowledge of AMS (n=8), availability of educational and training resources (n=8), adequate funding (n=6), accountable and transparent procedures (n=5) and positive communication within healthcare facilities (n=4). CONCLUSIONS: All included studies show improvement in AMS through innovative programs. However, only a few have been adopted nationwide and influence policy formulation in the country. We recommend adoption of effective AMSPs into the national strategic planning and implementation across primary health settings.
5 July 2026
Read appraisal →Journal of neurology
The dual role of mTOR in multiple sclerosis pathophysiology: a systematic review
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelination, neuroinflammation, and progressive neurodegeneration. The mechanistic target of rapamycin (mTOR) pathway plays a key role in regulating immune responses, cell metabolism, autophagy, and repair processes. Although the role of mTOR in neurodegeneration has been explored in previous reviews, a systematic assessment of its function in MS across different models is still lacking. This systematic review aimed to examine the role of mTOR signaling in the pathophysiology of MS. Following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, we screened preclinical and clinical studies using two databases and assessed the risk of bias specific to the study types. A total of 189 records were identified, of which 90 met the inclusion criteria for qualitative analysis. Studies using in vitro and in vivo (mainly rodent models, both sexes) models of MS, as well as MS patient tissue or data, consistently demonstrated that mTOR is involved in the MS-related processes neuroinflammation, myelination, autophagy, gliosis, mitochondrial dysfunction, and oxidative stress. mTOR inhibition reduces pro-inflammatory signaling and may enhance autophagy, offering neuroprotection. In contrast, activation of mTOR promotes remyelination by enhancing oligodendrocyte differentiation and maturation. These remyelinating effects may be masked in inflammatory environments, because activation of mTOR supports immune cell expansion and glial reactivity, inducing inflammation and oxidative stress. Overall, our findings underscore a dual role of mTOR in MS pathology, with important implications for disease stage and timing of intervention. Although mTOR is mechanistically important in MS, its therapeutic modulation is unlikely to be readily clinically translatable without a substantial risk of unintended and context-dependent effects.
5 July 2026
Read appraisal →PloS one
Developing a natural language processing system using transformer-based models for adverse drug event detection in electronic health records
OBJECTIVE: To develop a transformer-based natural language processing (NLP) system for detecting adverse drug events (ADEs) from clinical notes in electronic health records (EHRs). MATERIALS AND METHODS: We fine-tuned BERT Short-Formers and Clinical-Longformer using the processed dataset from the 2018 National NLP Clinical Challenges (n2c2) shared task Track 2. Two data processing methods, window-based and split-based approaches, were compared to identify the optimal processing method. Model generalizability was evaluated on a dataset extracted from Vanderbilt University Medical Center (VUMC) EHRs. RESULTS: On the n2c2 dataset, the best 5-fold cross-validation AUPRC, micro F1, and macro F1 scores were 0.840 (Clinical-Longformer, 4-chunk split), 0.965 (BioBERT, 15-word window), and 0.852 (Clinical-Longformer, 10-chunk split). On the VUMC dataset, the best AUPRC, micro F1, and macro F1 scores were 0.536 (Clinical-Longformer, 6-chunk split), 0.966 (BERT-base-uncased, 6-chunk split), and 0.762 (Clinical-Longformer, 4-chunk split). DISCUSSION: Transformer-based models demonstrated strong performance for ADE detection, with split-based processing generally outperforming window-based methods. Clinical-Longformer combined with a practical split-based approach showed promise for real-world implementation. Beyond token limits, chunk size substantially influenced model performance, even when text length remained within limits. CONCLUSION: Our findings provide practical guidance for developing transformer-based ADE detection systems from clinical notes. The selection of both text preprocessing strategies and model architectures should be guided by note characteristics and practical considerations such as annotation burden.
2 July 2026
Read appraisal →Advanced drug delivery reviews
Artificial intelligence and machine learning in smart vaginal formulation development
Vaginal drug delivery in women's health remains underutilized and insufficiently studied, largely due to the complexity and dynamic nature of the vaginal microenvironment. Variations in vaginal pH, hormonal levels, and microbiota composition introduce significant biological variability, complicating formulation design and contributing to inconsistent therapeutic outcomes and poor patient adherence. Conventional vaginal formulations often fail to account for these individual differences, highlighting the need for more adaptive and predictive approaches. Emerging advances in artificial intelligence (AI) and machine learning (ML) offer promising strategies to address these challenges by enabling multi-parameter, data-driven formulation development that explicitly considers biological variability. Despite their transformative potential, the application of AI and ML in vaginal drug delivery remains limited. This review addresses this gap by examining the emerging role of AI/ML in the design, optimization, and development of next-generation vaginal formulations, including mucoadhesive, mucus-penetrating, bio-responsive, and controlled-release systems. Key factors influencing formulation performance, such as vaginal microbiota composition, are discussed, and ethical, regulatory, and technical challenges relevant to integrating AI/ML into vaginal drug delivery are also considered. Although research is in its early stages, existing studies indicate that AI and ML integration can enhance predictability, efficiency, and reproducibility in vaginal formulation development. Finally, we highlight the potential of developing personalized medicines through the integration of AI/ML and digital health monitoring devices to create patient-centered vaginal drug delivery systems, thereby advancing therapeutic outcomes and transforming women's health.
1 July 2026
Read appraisal →CPT: pharmacometrics & systems pharmacology
A Narrative Review of Artificial Intelligence for Drug Repurposing: Lessons From COVID-19 and Oncology (2020-2025)
Drug repurposing presents a cost-effective and time-efficient strategy to identify new therapeutic applications for existing drugs. Recent advances in artificial intelligence, including machine learning, deep learning, knowledge graphs, and natural language processing, have revolutionized this field by enabling automated discovery of drug-disease associations. This review examines the role of artificial intelligence in drug repurposing, drawing insights from two critical case areas: Coronavirus disease 2019 and oncology. We explore current trends, methodological frameworks, and technological innovations in artificial intelligence-driven drug repurposing, as well as challenges and emerging future directions. The findings of this paper underscore the transformative potential of artificial intelligence in biomedical research and justify its continued integration in pharmaceutical pipelines.
1 July 2026
Read appraisal →Journal of integrative medicine
Deep learning in traditional Chinese medicine
As an alternative medicine approach, traditional Chinese medicine (TCM) is mainly built on an ancient understanding of the world. In order to translate the promises of TCM into modern therapies, rigorous scientific techniques are applied, which generates big data from experiments, clinical practices and medical literature. Recently, deep learning (DL) has attracted the attention of TCM researchers due to its application in data mining. In this review, we summarized recent examples of DL application in the study of TCM, including medical image processing, medicinal substances investigation, data fusion and natural language processing. We find that DL methods have considerable potential to extract valuable information from TCM data, but high-quality TCM data are still needed for further development of DL techniques. Please cite this article as: Liu LP, Yang C, Cen SX, Suo TC. Deep learning in traditional Chinese medicine. J Integr Med. 2026; 24(4):471-480.
1 July 2026
Read appraisal →European journal of hospital pharmacy : science and practice
Unit dose drug dispensing systems in hospitals: a systematic review of medication error reduction and cost-effectiveness
BACKGROUND: Medical errors pose significant risks to patient safety and public health. Automated unit dose drug dispensing systems (UDDSs) have emerged as valuable tools to reduce medication errors while optimising economic and logistical resources. OBJECTIVES: This systematic review aims to evaluate studies specifically focused on the impact of automated UDDSs in reducing medication errors and streamlining processes. METHODS: A literature search was performed on PubMed, Scopus, and Web of Science, focusing on peer-reviewed articles published between 2019 and 2024. The search, concluded on 24 September 2024, included studies conducted in inpatient hospital settings that assessed automated UDDS effects on medication errors, therapy management and inventory control. Outcomes examined included effects on patient safety, cost-effectiveness and inventory management. Results were synthesised qualitatively. RESULTS: From 3346 references, four studies met the inclusion criteria: a cost-effectiveness analysis, an uncontrolled before-and-after study, and two observational studies. UDDS improved medication processes, reducing drug-related problems, medication handling and dispensing time by 50% per patient per day. Integrated with barcode scanning, UDDS lowered medication administration errors (MAEs) from 19.5% to 15.8% and harmful MAEs from 3.0% to 0.3%. Overall, medication errors dropped by 45-70%, enhancing safety and reducing manual handling risks. UDDS demonstrated cost-effectiveness by significantly reducing MAEs. The study estimated a reduction in MAEs, with a cost-effectiveness ratio of €17.69 per avoided MAE. For potentially harmful MAEs, the cost-effectiveness ratio was estimated at €30.23 per avoided error. These findings suggest substantial long-term savings potential, though the exact magnitude may vary depending on hospital size and implementation specifics CONCLUSIONS: Automated UDDSs improve patient safety by significantly reducing medication errors and delivering cost savings through better inventory management. Challenges such as high initial costs and workflow adjustments can be mitigated through gradual implementation and staff training. Further integration with other healthcare technologies, such as barcoding, real-time tracking, artificial intelligence (AI)-driven error prevention tools and fully automated restocking systems could enhance UDDS benefits and further support hospital processes.
25 June 2026
Read appraisal →Journal of medical economics
From options to decisions: an innovative model for treatment sequencing in relapsing-remitting multiple sclerosis
AIMS: With the expanding range of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS), clinicians face increasing complexity in defining optimal treatment sequences and timing of therapy switches. In this study, we adapted an earlier computer-assisted model to optimize therapeutic decisions and identify preferred treatment pathways, based on expert opinion and observations from clinical practice in Spain. MATERIALS AND METHODS: The original model was updated to integrate magnetic resonance imaging (MRI) activity data and define reaching an Expanded Disability Status Scale (EDSS) score of 3 - indicating moderate disability without ambulation impairment - as a criterion for switching treatment. Matrices were designed to model options when switching DMTs, triggered by either a lack of effectiveness or safety concerns. Change in DMT was based on a set of composite criteria (encompassing contributions from relapses, disability worsening, MRI activity, costs, and quality of life) according to the disease activity level. A maximum of three DMTs could be administered within the 8-year time horizon evaluated. RESULTS: The revised model identified high efficacy treatment, in particular cladribine tablets as the preferred initial DMT for patients with RRMS with mild or moderate disease activity. Of these patients with mild and moderate disease activity, most were switched to ofatumumab (79.4%) and ocrelizumab (75.9%), respectively, when disease progression occurred. Patients with high disease activity mostly received natalizumab if they were John Cunningham virus (JCV)-negative, or ocrelizumab if they were JCV-positive. LIMITATIONS: The model is informed by a Spain-based healthcare expert panel and has been evaluated using a simulated cohort of 10,000 patients with RRMS. CONCLUSION: This computational model helps to inform clinicians towards making optimal treatment decisions for RRMS, and identified high-efficacy DMTs as the preferred model-based option for all levels of disease activity, supporting early and effective control of disease activity in real-world clinical practice.
25 June 2026
Read appraisal →PloS one
A multi-modal co-attention model for accurate drug-target interaction prediction
Accurate prediction of drug-target interactions (DTIs) plays a crucial role in modern drug discovery and repositioning. Despite recent advances in deep learning, existing methods often fail to effectively integrate heterogeneous data, such as molecular structures and protein sequences, into a unified representation. To address this limitation, we propose MMCA (Multi-Modal Co-Attention), a novel deep learning framework that introduces a multi-modal co-attention mechanism to dynamically align and fuse graph-based drug features with sequence-based protein embeddings. Our model leverages parallel encoding pathways to capture both structural and semantic information, followed by a context-aware fusion module that adaptively weighs cross-modal dependencies. Evaluation on three benchmark datasets-BioSNAP, BindingDB, and Human STRING-demonstrates that MMCA outperforms state-of-the-art methods in terms of AUC, AUPR, and F1-score, achieving up to 98.4% AUC. Ablation studies confirm the significance of our co-attention fusion mechanism in enhancing both accuracy and robustness. Case studies of high-confidence predictions reveal biologically plausible drug-protein interactions, supporting MMCA's potential for prioritizing candidates for experimental validation. By enabling end-to-end multi-modal reasoning, MMCA provides a powerful framework for advancing DTI prediction systems and offers broad applicability for various bioinformatics tasks. The source code of MMCA is publicly available at https://github.com/Join-xiaobai/MMCA.
25 June 2026
Read appraisal →BMJ open
Development of phenotype algorithms for the detection of adverse events in electronic health record data: a multicentre study
OBJECTIVES: To develop phenotype algorithms for the detection of adverse events (AEs) or AE-proxies in electronic health records (EHRs), accounting for varying data availability. DESIGN: Multicentre study conducted as part of the Use Case POLAR_MI (POLypharmacy, drug interActions, Risks) of the German Medical Informatics Initiative (MII). SETTING: Germany. PARTICIPANTS: Multidisciplinary teams from 10 German university sites within the MII. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Literature- and consensus-based development and operationalisation of AE algorithms using structured EHR data, including a standardised, multicentre expert review process. Data categories used: International Classification of Diseases, 10th Revision (ICD-10) codes for diagnoses; Anatomical Therapeutic Chemical (ATC) codes and 'Pharmazentralnummern' (PZN; German eight-digit identification code for pharmaceutical products) for medications (used in the treatment of AEs); Logical Observation Identifiers Names and Codes (LOINC) for laboratory values and medical findings; and 'Operationen- und Prozedurenschlüssel' (OPS; German procedure classification) codes for medical and surgical procedures. RESULTS: We developed 82 algorithms for 48 AEs. Algorithms for the same AE varied by data categories or code selections. At the AE level, 31 AEs were covered exclusively by newly developed algorithms, and 17 AEs by at least one modified algorithm.Overall, 52 algorithms were based on a single data category, while 30 required multiple categories. ICD-10 codes were most commonly used (n=65 AE algorithms), followed by LOINC (n=27), ATC codes (n=18), OPS codes (n=11) and PZN (n=2). All phenotype algorithms were semantically modelled and can be executed using the publicly available Terminology- and Ontology-based Phenotyping (TOP) Framework, which supports export in various formats. CONCLUSION: We present a peer-reviewed set of algorithms for a large number of AEs, which can be implemented in structured routine electronic data sources and (pending validation studies) may support pharmacoepidemiologic research. The algorithms will be implementable across all 39 participating sites of the German MII. As a next step, we will empirically validate the algorithms against all information (including free text) contained in EHRs. TRIAL REGISTRATION: Not applicable.
24 June 2026
Read appraisal →Rheumatology international
Pruritus associated with systemic sclerosis: a systematic review of treatment-based clinical trials
This paper aims to examine the latest research on treatments for itch (pruritus) in people with systemic sclerosis (SSc), identify areas where information is lacking, and propose suggestions for future studies.A comprehensive literature search was performed in PubMed and Scopus in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies evaluating therapeutic interventions for pruritus in SSc. Eligible studies included randomized controlled trials, cohort studies, and case series comprising a minimum of three patients. Data extraction encompassed study design, patient demographics, pruritus assessment instruments including validated and non-validated measures, and clinical outcomes. Studies were excluded if they concerned localized scleroderma, irrelevant populations, case reports, systematic reviews, lacking relevant outcome data, or incomplete trials. Ten studies met criteria, evaluating immunomodulatory agents, mast cell stabilizers, opioid receptor antagonist, and lysophosphatidic acid receptor antagonists. Pruritus assessment varied and was often secondary to fibrosis outcomes. Oral lenabasum improved pruritus in a phase II trial; low-dose opioid receptor modulators and rituximab also showed qualitative improvement. Pruritus is a frequently overlooked yet clinically significant symptom in systemic sclerosis (SSc) that negatively impacts patients' quality of life. Existing evidence regarding effective therapeutic options remains limited. Future research should prioritize pruritus as a predefined outcome and utilize validated assessment instruments to inform treatment strategies and enhance patient quality of life.
23 June 2026
Read appraisal →Journal of chemical information and modeling
GraFSyn: An Interpretable Deep Learning Framework for Anticancer Drug Synergy via Graphlet Fingerprints
Predicting drug synergy is important for accelerating the discovery of effective anticancer combination therapies. Synergy intrinsically depends on the precise interactions of key chemical substructures within specific cellular environments. However, current molecular graph-based computational methods typically rely on implicit atom-level feature aggregation, which may obscure the topological representation of critical chemical substructures and limit structural traceability. Therefore, we present Graphlet Fingerprint-based Synergy prediction (GraFSyn), a deep learning framework for anticancer drug synergy prediction that uses graphlet fingerprints to encode drugs as explicit connected substructure units, preserving predefined chemical substructures and their topological identity. We further introduce a Dynamic Multi-Scale Convolution (DMSC) module to learn informative representations from high-dimensional and sparse graphlet features. The framework also includes an interaction module to capture context-dependent interactions between drug substructures and cell line gene expression. On the Merck and AstraZeneca benchmark data sets, GraFSyn achieved ROC-AUC/PR-AUC values of 0.972/0.912 and 0.823/0.906, respectively, outperforming representative baseline methods. In addition, attributed signals can be mapped back to specific pharmacophoric regions, supporting substructure-level analysis of synergistic interactions. In general, GraFSyn provides an accurate and structurally traceable approach for anticancer drug combination screening.
23 June 2026
Read appraisal →Journal of chemical information and modeling
Generative Artificial Intelligence Optimization of Albumin Binders: Coumarin and Fatty Acid Derivatives
Previously, we reported a dual combination based on 4-hydroxycoumarin and dodecanedioic acid that could synergistically bind to human serum albumin (HSA). However, optimizing this combination remains challenging and could often be guided by empirical selection and extensive experimental screening, which may limit the chemical diversity and suboptimal affinity. In this study, we established a systematic artificial intelligence framework that integrates computational optimization with wet-lab synthesis and experimental validation, enabling improvement of the dual combination while preserving the core chemotypes. We first trained a machine learning classifier on curated HSA binding data and used it as an external scoring function to guide reinforcement learning-driven scaffold decoration with LibINVENT, enabling goal-directed generation of coumarin derivatives and fatty acid derivatives. Candidate molecules were prioritized through multiparameter filtering and diversity-aware selection, followed by synthesis and experimental validation using surface plasmon resonance. The optimized representatives show nanomolar HSA binding and enhanced affinity compared to the original ligands. Molecular docking and molecular dynamics simulations further provide a mechanistic rationale for the affinity improvements by revealing additional stabilizing interactions and more favorable binding energetics at the corresponding HSA sites. Besides, the optimized coumarin derivative (CD1) is a warfarin-derived coumarin analogue, yet it did not show detectable anticoagulant activity in an acute clotting time assay, whereas warfarin did. Overall, this work demonstrates a practical AI-guided route to expand chemical diversity and improve affinity for a synergistic HSA binding combination.
23 June 2026
Read appraisal →Journal of chemical information and modeling
A Reproducible Hierarchical Virtual Screening Framework Integrating Scaffold-Aware Machine Learning, Ensemble Docking, and Molecular Dynamics: Application to IDO1
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme implicated in cancer immune escape and remains an attractive therapeutic target despite recent clinical setbacks. We report a fully reproducible hierarchical virtual screening framework integrating scaffold-aware machine learning, ensemble docking, consensus scoring, and molecular dynamics simulations for robust prioritization of IDO1 inhibitors. A curated ChEMBL data set of IDO1 inhibitors was subjected to strict standardization, duplicate removal, and activity binarization at pChEMBL ≥6. Models were trained using scaffold-based splitting and nested cross-validation to prevent chemical series leakage. An ensemble of Random Forest, XGBoost and SVM classifiers achieved balanced predictive performance (ROC-AUC ≈0.88-0.89) with applicability domain filtering to ensure reliability. Prospective screening of FDA-approved drugs yielded 39 compounds within the applicability domain predicted as active. These were further evaluated through ensemble docking against multiple IDO1 crystal structures using GNINA with CNN rescoring. Consensus strategies were systematically benchmarked, demonstrating that best-Z-score aggregation outperformed mean, rank-based, and weighted methods in enrichment factor (EF) metrics. Two top-ranked candidates were subjected to 300 ns molecular dynamics simulations, revealing stable binding modes and persistent interactions with key catalytic residues. This study demonstrates that hierarchical integration of scaffold-aware machine learning with structure-based ensemble strategies enhances robustness and reduces false positives in virtual screening campaigns. The proposed workflow is generalizable and supports reproducible candidate prioritization in computational drug discovery. The complete implementation, including data processing, model training, and analysis steps, is provided as a fully executable Jupyter notebook available at https://github.com/rocco-b/IDO1-inhibitors-ML-and-docking-data.
23 June 2026
Read appraisal →Science advances
Discovery of TYR inhibitors from de novo molecular generation to dual-track lead optimization: 'Competition' between AI and chemists.
This study introduces a unified framework combining artificial intelligence (AI)-directed de novo molecular generation with dual-track lead optimization-comprising expert-guided strategies and AI-driven pathways-to discover tyrosinase (TYR) inhibitors for hyperpigmentation disorders. Using a reinforcement learning (RL)-based generative model, the lead compound AI10 was identified. Subsequent optimization followed two parallel routes. The expert-guided approach yielded AI10-m15 as the most potent TYR inhibitor, with notable antipigmentation activity and excellent cellular safety profiles. In contrast, the AI-driven pathway explored broader chemical spaces, generating unconventional chemotypes, exemplified by the potent TYR inhibitor AI10-a2, highlighting AI's capacity to uncover nonintuitive activity cliffs despite greater output variability. Systematic comparison revealed that the AI model offers exploratory diversity, whereas expert-guided optimization provides predictable improvements in activity and developability. In summary, starting from an AI-generated lead and subsequently integrating both expert-guided and AI-driven structural optimization strategies, these findings further underscore that combining AI technologies with experts' medicinal chemistry insights can substantially accelerate the discovery of viable candidate compounds.
21 June 2026
Read appraisal →Journal of medical Internet research
Extracting and Classifying Drug Discontinuations From Estonian Electronic Health Records: Development and Validation Study
BACKGROUND: Drug adherence is crucial for chronic disease management, yet treatment discontinuation remains common due to factors such as side effects, inefficacy, or cost. These reasons are often recorded only in free-text clinical notes, making large-scale analysis difficult. While large language models (LLMs) can interpret such unstructured data more effectively than traditional natural language processing methods, few studies have systematically categorized reasons for discontinuation or identified whether the decision was initiated by the patient or the clinician, especially in low-resource languages such as Estonian. OBJECTIVE: This study aimed to assess the ability of LLMs to extract and classify reasons for drug discontinuation and identify who initiated it using Estonian electronic health records and characterize the observed discontinuation patterns and initiators for statins and antidiabetic medications. METHODS: We combined prescription data with free-text anamneses from a 10% sample of the Estonian population (2012-2019). LLMs (Llama 3.1-70B and GPT-4o) were applied to extract discontinuation phrases and reasons, classify them into a clinician-developed taxonomy, and identify who discontinued the treatment. Performance was evaluated on 100 randomly chosen cases per drug group. RESULTS: Extraction yielded 625 antidiabetic drug and 233 statin discontinuation cases. Validation confirmed a precision of 0.93 to 0.98 for extracting phrases and 0.95 to 0.96 for extracting reasons. Classification of discontinuation reasons achieved weighted F1-scores of 0.81 to 0.84, whereas classification of who initiated discontinuation achieved weighted F1-scores of 0.64 to 0.78. Adverse reactions were the most frequent reason overall, accounting for 70% (163/233) of statin discontinuations and 44.8% (280/625) of antidiabetic drug discontinuations. Regarding antidiabetic drugs, treatment inefficacy and contraindications were more common. Patients more often stopped due to adverse reactions or nonmedical reasons, whereas physicians more often initiated discontinuation for contraindications. CONCLUSIONS: LLMs can accurately extract and classify medication discontinuation reasons and show variable performance in identifying discontinuation initiators in Estonian clinical narratives. Both local and proprietary models showed promising results, enabling scalable analyses that complement structured health records. This demonstrates the potential of LLMs to unlock information from clinical notes, turning this underused electronic health record component into a valuable resource for monitoring treatment patterns and detecting adverse event signals.
19 June 2026
Read appraisal →The American journal of cardiology
Efficacy and Safety of Olezarsen for the Management of Dyslipidemia: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials
This updated systematic review and meta-analysis evaluated the efficacy and safety of olezarsen in patients with dyslipidemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing olezarsen with placebo. Seven trials (n = 2,121) were included. Olezarsen significantly reduced triglycerides (mean difference [MD] -59.20 mg/dL), very-low-density lipoprotein cholesterol (MD -52.68 mg/dL), apolipoprotein B (MD -10.74 mg/dL), non-HDL cholesterol (MD -17.06 mg/dL), and apolipoprotein C-III (MD -64.16 mg/dL), and increased HDL cholesterol (MD 30.97 mg/dL), with no significant effect on LDL cholesterol. Injection site reactions (risk ratio [RR] 3.93) and platelet counts <140,000/µL (RR 4.76) were increased, whereas serious adverse events and significant liver enzyme elevations were comparable to placebo. Certainty of evidence ranged from moderate to low. In conclusion, olezarsen produces substantial improvements in triglyceride-rich lipoproteins with an acceptable safety profile; long-term cardiovascular outcome trials are warranted.
16 June 2026
Read appraisal →European journal of pharmacology
Inhibition of the serotonin transporter and risk of heart valve disease: A systematic review and meta-analysis
BACKGROUND: The serotonin transporter (SERT) plays an essential role in regulating a wide range of physiological and psychological processes, including neurotransmitter homeostasis, circadian rhythm, sleep regulation, platelet function, immune modulation, mood and emotions. Although SERT was initially studied in the context of neurological and psychiatric disorders, growing evidence highlights how its off-target exogenous inhibition, and the resulting dysregulation of serotonin signaling, can promote valvular interstitial cell proliferation, extracellular matrix remodeling, and fibrosis, thereby contributing to the pathophysiology of heart valve disease (HVD). Despite the increasing interest in the role of SERT in valve biology, mechanistic studies remain limited, and a deeper understanding of the implications of commonly used SERT-targeting drugs in the progression of HVD is still needed. METHODS: In this review, we examine the impact of drug-induced SERT inhibition on HVD, integrating findings from cellular studies, animal models, and clinical data to better understand the risks associated with chronic use of SERT inhibitors. To strengthen the clinical relevance of our review, we also performed a meta-analysis of published clinical studies on SERT-modulating drugs, which revealed a significant association between the use of these medications and increased HVD risk (OR = 2.76). CONCLUSIONS: Our analysis supports the implementation of clinical screening for high-risk patients, such as those with diabetes, hypertension, or pre-existing valvular abnormalities, prior to serotonergic drug recommendations. Ultimately, a deeper understanding of the role of serotonin and SERT in valvular pathophysiology may guide safer prescribing practices and facilitate the development of novel therapeutics for managing or preventing the progression of HVD.
16 June 2026
Read appraisal →The American journal of cardiology
Sacubitril/Valsartan and Prevention of Chemotherapy-Induced Cardiac Dysfunction: Meta-analysis of Randomized Trials
Chemotherapy-related cardiac dysfunction (CTRCD) is a major limitation of cardiotoxic cancer therapies. Although global longitudinal strain (GLS) allows early detection of myocardial injury, preventive strategies remain scarce. Angiotensin receptor-neprilysin inhibitors (ARNIs) may offer cardioprotection, but current evidence is limited. We conducted a systematic review and meta-analysis of randomized controlled trials evaluating Sacubitril/Valsartan versus control in patients undergoing chemotherapy. PubMed, Embase, and Cochrane databases were searched. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were computed for binary and continuous outcomes. Four randomized controlled trials comprising 412 participants were included; 42.7% received ARNI therapy, with follow-up ranging from 6 to 18 months. Compared with control, ARNI significantly preserved left ventricular systolic function (MD 1.47%, 95% CI 0.59-2.34) and attenuated GLS deterioration (MD -0.93%, 95% CI -1.49 to -0.38). However, ARNI did not significantly reduce the incidence of CTRCD (RR 0.40, 95% CI 0.08-1.97) or all-cause mortality (RR 0.63, 95% CI 0.08-5.01). ARNI increased the risk of hypotension but had no significant effects on NT-proBNP or dyspnea. In conclusion, ARNI therapy improves GLS and left ventricular ejection fraction during chemotherapy but has not yet demonstrated reductions in CTRCD or mortality. Hypotension remains a key safety consideration.
16 June 2026
Read appraisal →Journal of affective disorders
Multiple peripheral inflammatory markers in adolescents with major depressive disorder treated with repeated esketamine infusions: results from a randomized controlled trial
OBJECTIVE: While inflammatory dysregulation is well-documented in major depressive disorder (MDD), its response to esketamine treatment in adolescents remains poorly understood. We aimed to examine the effects of esketamine on the inflammatory cytokines in adolescent MDD. METHODS: This randomized, double-blind trial assigned 49 adolescents with MDD to receive three infusions of esketamine or midazolam over five days between December 2020 and April 2022. Suicidal ideation (measured by Columbia Suicide Severity Rating Scale, C-SSRS), depressive symptoms (measured by Montgomery-Åsberg Depression Rating Scale, MADRS) and plasma levels of 10 inflammatory markers were assessed at baseline, Day 6, and Day 12. RESULTS: Linear mixed model revealed significant time effects for all markers, but no significant drug main effect was observed. In esketamine group, alterations in IL-8 were associated with the reduction of C-SSRS Intensity at Day 6 (r = 0.444, p = 0.026), and alterations in IFN-γ were correlated with the reduction of MADRS (r = 0.399, p = 0.048) and C-SSRS Intensity (r = 0.427, p = 0.033) at Day 12. Baseline C4 negatively related to the reductions of MADRS and C-SSRS Ideation at Day 6 and 12 (all p < 0.005). CONCLUSIONS: Our study found no significant drug main effects for inflammatory markers, with most changes representing time effects observed in both groups. Exploratory results indicate that IL-8, IFN-γ, and C4 may warrant further investigation as potential biomarkers of esketamine response in adolescent MDD.
15 June 2026
Read appraisal →Signal transduction and targeted therapy
Liposomal doxorubicin plus nab-paclitaxel with/without chemoradiotherapy in head and neck adenoid cystic carcinoma: single-arm phase II study
Given no standard therapies, this single-arm, open-label, multicenter phase II study was conducted in unresectable locally advanced or recurrent/metastatic adenoid cystic carcinoma of the head and neck (LA or R/M ACCHN). Patients received chemotherapeutic nanomedicines (20 mg/m2 liposomal doxorubicin plus 120 mg/m2 nab-paclitaxel on days 1 and 8) for three 21-day cycles. Subsequently, patients eligible for radiotherapy received concurrent chemoradiotherapy (cCRT; helical tomotherapy or intensity-modulated radiotherapy and nab-paclitaxel), whereas those ineligible for radiotherapy continued 2-3 cycles of original chemotherapy. Between May 27, 2021, and November 13, 2024, 31 enrolled patients were evaluable for efficacy and safety. The primary endpoint objective response rate (ORR) was 90.3% (95% CI, 74.2-98.0%), with 15 (48.4%) complete responses and 13 (41.9%) partial responses, meeting the prespecified primary endpoint. The median duration of response was 18.5 (95% CI, 0-45.8) months. With a median follow-up of 15.7 months by data cutoff (June 25, 2025), the median progression-free survival (PFS) was 25.7 (95% CI, 6.5-44.8) months; the 1-year PFS was 77.1%. The median overall survival (OS) was not reached (NR), with a 1-year OS of 90.0%. Patients who received cCRT had a prolonged PFS (NR vs. 12.8 months) and OS (NR vs. 21.2 months) compared to those who did not. Grade 3 treatment-related adverse events (TRAEs) occurred in 8 (25.8%) patients. No ≥grade 4 TRAEs or treatment-related deaths occurred. This study demonstrated tumor responses among the highest reported to date, with a manageable safety profile in unresectable LA or R/M ACCHN. Chemotherapeutic nanomedicines, especially sequential cCRT for appropriate patients, may represent an effective and safe option.
14 June 2026
Read appraisal →The pharmacogenomics journal
Development and validation of an open data model for pharmacogenetics to enable semantic interoperability in clinical practice
Pharmacogenetics uses genetic testing to improve the safety and effectiveness of prescribed medicines, yet implementation at scale remains limited due to the absence of interoperable health IT solutions that integrate results into prescribing workflows. This study aimed to develop and validate open data standards for pharmacogenetic results to enable interoperability across healthcare systems. A baseline data model was constructed using the open standard openEHR by synthesising literature, genomic sequencing outputs, and international data specifications, and refined through iterative workshops with the Global Alliance for Genomics and Health. The model underwent two rounds of structured peer review involving 24 experts from 10 countries. Mapping to HL7 FHIR was evaluated using both manual and automated approaches, including the FHIR-Connect tool. The resulting standardised pharmacogenetic data model separates test results from therapeutic implications and incorporates recognised terminologies such as SNOMED CT and HGNC. It achieved international consensus and is published on the openEHR Clinical Knowledge Manager platform. Mapping to HL7 FHIR demonstrated bidirectional information flow within healthcare systems, with automated mapping enabling scalable and reusable transformations. This work provides a framework for storing and exchanging pharmacogenetic test results, supporting semantic harmonisation, interoperability, and integration with clinical decision support systems. Open data standards for pharmacogenetic test results therefore offer a foundation for scalable implementation of pharmacogenetics in routine clinical practice.
14 June 2026
Read appraisal →Lancet (London, England)
Atrasentan in patients with IgA nephropathy (ALIGN): final 2·5-year results from a randomised, double-blind, placebo-controlled, phase 3 trial
BACKGROUND: Atrasentan, a selective endothelin A receptor antagonist, reduced proteinuria in the prespecified interim analysis (week 36) of the ALIGN trial in adults with IgA nephropathy. We assessed whether atrasentan slowed estimated glomerular filtration rate (eGFR) decline after 2·5 years' treatment. METHODS: We performed a randomised, double-blind, placebo-controlled, phase 3 trial (133 sites, 20 countries). Adults with biopsy-proven IgA nephropathy, eGFR of at least 30 mL/min per 1·73 m2, and urinary protein excretion of at least 1·0 g/day while receiving renin-angiotensin system inhibition were enrolled (main stratum). An exploratory stratum enrolled participants also receiving an SGLT2 inhibitor. Participants were randomly assigned (1:1) to oral atrasentan 0·75 mg once daily or placebo for 132 weeks, followed by a 4-week off-treatment follow-up. The key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum, assessed in all randomised patients (excluding data after intercurrent events, defined as initiation of restricted or alternative IgA nephropathy medications or kidney replacement therapy). Safety was assessed in all randomised patients who received at least one dose of study treatment. ALIGN is registered with ClinicalTrials.gov, NCT04573478; the double-blind section is complete, and the open-label extension is ongoing. FINDINGS: Between March 15, 2021, and April 28, 2023, 404 participants were randomly assigned (main stratum: 340; SGLT2 inhibitor stratum: 64). In the main stratum, change from baseline in eGFR at week 136 was -7·5 mL/min per 1·73 m2 (95% CI -9·2 to -5·8) with atrasentan and -9·9 mL/min per 1·73 m2 (-11·7 to -8·1) with placebo (between-group difference 2·4 mL/min per 1·73 m2; 95% CI -0·1 to 4·8; p=0·057). The between-group difference in eGFR change from baseline at end of treatment (week 132) was 2·6 mL/min per 1·73 m2 (95% CI 0·1-5·0), and the difference in total eGFR slope (baseline to week 136) was 1·4 mL/min per 1·73 m2 per year (95% CI 0·5-2·3). In the SGLT2 inhibitor stratum, the difference in eGFR change from baseline at week 136 between atrasentan and placebo was 9·1 mL/min per 1·73 m2 (95% CI 3·0-15·2). Treatment-emergent adverse events were well balanced between atrasentan and placebo, with no new safety signals. In the main stratum, fluid retention adverse events occurred in 24 (14%) of 169 patients receiving atrasentan and 20 (12%) of 170 receiving placebo. INTERPRETATION: Atrasentan reduced proteinuria and preserved kidney function after 2·5 years. This effect was present with or without concomitant SGLT2 inhibitor use. Atrasentan was well tolerated. FUNDING: Novartis.
14 June 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial
BACKGROUND: Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. METHODS: In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA1c) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m2. Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA1c concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed. FINDINGS: Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48·8 years (SD 12·1), mean HbA1c concentration was 7·9% (SD 1·1), mean duration of diabetes was 2·5 years (SD 4·4), and mean BMI was 35·8 kg/m2 (SD 7·0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA1c concentration was -1·69% (SE 0·11) with retatrutide 4 mg, -1·86% (0·10) with 9 mg, and -1·94% (0·08) with 12 mg, versus -0·81% (0·12) with placebo, resulting in estimated treatment differences versus placebo of -0·88% (95% CI -1·18 to -0·59) with retatrutide 4 mg, -1·04% (-1·32 to -0·76) with 9 mg, and -1·12% (-1·39 to -0·85) with 12 mg (all p<0·0001). The mean percentage change from baseline in bodyweight was -11·5% (SE 0·7) with retatrutide 4 mg, -13·9% (0·8) with 9 mg, and -15·3% (0·8) with 12 mg, versus -2·6% (0·5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug. INTERPRETATION: Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. FUNDING: Eli Lilly and Company.
13 June 2026
Read appraisal →Journal of medicinal chemistry
Integrating AI in Medicinal Chemistry for Accelerated Drug Discovery: A Comprehensive SAR (CSAR) Optimization Strategy and Discovery of Potent ALDH3A1 Inhibitors
Developing potent, selective small-molecule inhibitors remains a major challenge in drug discovery. ALDH3A1, a detoxifying aldehyde dehydrogenase isoform implicated in cancer and neurodegeneration, is a promising yet underexplored therapeutic target. To accelerate inhibitor optimization, we developed an AI-guided, reaction-based hit-to-lead workflow combining sequential reaction enumeration, pharmacophore-informed docking, and predictive modeling to support scalable SAR expansion. Applied to ALDH3A1, two rounds of enumeration using Enamine building blocks generated about 250,000 virtual analogues. Combined deep learning and docking-based triage prioritized 150 compounds for synthesis, leading to a roughly 1,000-fold improvement in biochemical potency from 1.41 μM to 1 nM for NCATS-SM0707, together with 4 nM cellular activity for NCATS-SM0708. Crucially, this methodology can be expanded by applying various chemical reactions at different positions. This study highlights CSAR as a scalable, generalizable complementary strategy to accelerate hit optimization through reaction-based enumeration and AI-guided prioritization of larger synthetically accessible chemical space.
13 June 2026
Read appraisal →Journal of medicinal chemistry
MEG-mod: A Multiview Enhanced Graph Neural Network for Knockdown Efficiency Prediction of Chemically Modified siRNA
Chemical modification is essential for improving the stability and knockdown efficiency of siRNAs. However, the combinatorial complexity of modification types and positions makes rational design difficult. Here, we propose MEG-mod, a deep learning framework for predicting the knockdown efficiency of chemically modified siRNAs. By integrating a literature-reading agent, manual curation, and public database resources, we construct an expanded data set. MEG-mod jointly models sequence context, physicochemical properties, chemical modification features, and duplex structural relationships. A structure-aware Transformer-based graph neural network captures base-pairing and adjacency dependencies within double-stranded siRNAs, while a modification-base fusion module models context-dependent modification effects. MEG-mod outperforms existing methods, achieving a pearson correlation coefficient of 0.9171. The attention mechanism enables interpretable analysis of key modification positions and modification types, and provides recommendations consistent with reported experimental designs. MEG-mod is available as a public web server (https://lmmd.ecust.edu.cn/megmod/), providing a practical tool for prediction and candidate prioritization of chemically modified siRNAs.
13 June 2026
Read appraisal →Journal of medicinal chemistry
Developing Predictive Models by Sharing Predictions - An Investigation of a Federated Learning Approach for ADMET Predictions
Machine learning models for ADMET prediction benefit from large, diverse data sets, yet such data are typically siloed across organizations. Federated learning (FL) enables collaborative modeling while preserving data privacy. Here, we investigate a student-teacher model (STM) framework in which organizations train internal models on proprietary data and share predictions on a public data set to generate pseudolabels for a centralized student model. As a proof of concept, 11 pharmaceutical companies contributed predictions for rat steady-state volume of distribution, yielding a pseudolabeled data set of ∼133,000 compounds. The resulting student model achieved performance comparable to individual teacher models on an external test set (RMSE ≈ 0.51 vs 0.47-0.61). Compared with FL approaches such as MELLODY and Effiris, STM offers a simpler workflow that avoids direct data sharing or iterative collaboration, providing a practical and scalable framework for secure cross-company model development.
13 June 2026
Read appraisal →Blood
Fixed-duration VenO vs FCR/BR in fit patients with untreated CLL: primary analysis of the phase 3 CRISTALLO trial
The phase 3 CRISTALLO trial compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia (CLL), using undetectable minimal residual disease (uMRD) as the sole primary end point. Previously untreated patients with a cumulative illness rating scale score ≤6 and creatinine clearance ≥70 mL/min without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary end point was uMRD (<10-4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary end points included uMRD (<10-4) in PB and bone marrow (BM) at end of treatment (EOT) and progression-free survival (PFS). uMRD at deeper cutoffs were explored. At data cutoff (19 March 2024), 80 patients received VenO, and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary end point was met: 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD (<10-4) in PB at month 15 (P = .0004). uMRD (<10-4) in PB and BM at EOT was also higher with VenO vs FCR/BR. Short follow-up precluded evaluation of PFS at the first planned interim analysis; however, fewer patients progressed/died with VenO vs FCR/BR (7 vs 13). At month 15, 65.0% (VenO) and 25.6% (FCR/BR) achieved uMRD (<10-6) in PB. The overall safety profile was consistent with the known safety profile of each drug. No patient in the VenO arm was deemed high risk for tumor lysis syndrome (TLS) after obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies. This trial was registered at www.clinicaltrials.gov as NCT04285567.
13 June 2026
Read appraisal →BMJ open gastroenterology
Safety and efficacy of advanced combination therapies for treating inflammatory bowel disease in adults: a systematic review and meta-analysis
OBJECTIVES: To systematically synthesise available evidence on the safety of advanced combination therapy (ACT) in adults with inflammatory bowel disease (IBD), with secondary exploratory evaluation of efficacy outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Searches of Embase (via Ovid), MEDLINE and PubMed were initially undertaken on 9 May 2025 and updated on 8 April 2026. Additional studies were identified through hand-searching and reference list screening. Eligible publications were restricted to those published between 1 January 2015 and 31 March 2026. ELIGIBILITY CRITERIA: We included randomised controlled trials as well as observational and descriptive studies. Conference abstracts, reviews, editorials and commentaries were excluded. Inclusion was restricted to publications in English. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened studies, extracted data and assessed risk of bias using Joanna Briggs Institute tools and Cochrane RoB-1. Pooled proportions of total adverse events (TAEs), serious adverse events (SAEs) and treatment discontinuations were calculated using random-effects meta-analysis. Subgroup analyses were conducted by drug class. Where meta-analysis was not appropriate, findings were narratively synthesised. RESULTS: Fifty-two studies (n=2022 participants) were included. The most frequent combinations were anti-TNFa plus integrin inhibitors and interleukin (IL) 23 plus integrin inhibitors. Pooled analyses demonstrated low rates of SAEs (eg, anti-TNFa plus integrin inhibitors: 2.7%, 95% CI 0.22% to 6.86%) and discontinuations (6.38%, 95% CI 2.36% to 11.58%), although heterogeneity was substantial and certainty of evidence was very low, with some analyses based on small sample sizes. CONCLUSION: ACT may be associated with low rates of SAEs in selected patients with refractory IBD; however, the evidence is limited by small sample sizes, heterogeneity and predominantly observational designs. Robust conclusions regarding safety and efficacy cannot be made due to very low GRADE certainty. PROSPERO REGISTRATION NUMBER: CRD420251025883.
13 June 2026
Read appraisal →Human vaccines & immunotherapeutics
Safety and immunogenicity of a booster dose of COVAC-2, a Sepivac SWE™ adjuvanted SARS-CoV-2 recombinant protein vaccine in previously vaccinated healthy adults; a randomized controlled multicentre trial.
This Phase 1 clinical trial evaluated the safety and immunogenicity of COVAC-2, a recombinant protein subunit vaccine as a heterologous booster in adults previously immunized with authorized COVID-19 vaccines (NCT05226702). COVAC-2 contains the SARS-CoV-2 S1 spike protein subunit adjuvanted with Sepivac SWE™, an open-access oil-in-water adjuvant. Sixty participants were randomized to receive a single intramuscular dose of COVAC-2 (10 µg or 25 µg) or placebo, with follow-up through Day 180. The vaccine was well tolerated, with most adverse events being mild or moderate; no serious adverse events were attributed to vaccination. Immunogenicity assessments included spike-binding antibody ELISA, pseudovirus neutralization assays (PNA), ELISpot, and flow cytometry. The 25 µg dose elicited the strongest humoral and cellular responses, with peak antibody titers observed 14 d after COVAC-2 vaccination. While titers waned, they were sustained above baseline through Day 180. ELISpot and flow cytometry revealed elevated IFN-γ and IL-2 responses indicating antigen-specific T-cell activation. Minimal IL-4 and IL-13 responses were demonstrated by flow cytometry. These findings support the safety and immunogenicity of COVAC-2 as a heterologous booster, particularly at the 25 µg dose level. The favorable safety profile, induction of immune responses, and thermal stability of the vaccine formulation suggest its potential utility in global vaccination strategies, especially in low- and middle-income countries. COVAC-2 may offer a scalable and accessible platform for enhancing protection against COVID-19.Clinicaltrials.gov: NCT05226702 - Registered 22 Jul 2022.
13 June 2026
Read appraisal →Journal of ethnopharmacology
Revealing the temporal metabolic trajectory and potential pharmacodynamic substances of Da-Cheng-Qi Decoction in treating patients with acute pancreatitis: A serum metabolomics-based study
ETHNOPHARMACOLOGICAL RELEVANCE: Acute Pancreatitis (AP) is a pancreatic inflammatory disease lacking specific therapeutics. Da-Cheng-Qi Decoction (DCQD) has been proven to alleviate the severity and mortality of AP. However, its underlying mechanisms remain to be fully elucidated. AIM OF THE STUDY: This study aimed to explore DCQD's dynamic metabolic regulatory effects on AP patients and potential pharmacodynamic substances via serum metabolomics and serum pharmacochemistry analysis, with validation in animal models. MATERIALS AND METHODS: AP patients were randomized into conventional therapy (Con) and Con + DCQD groups. Fasting venous blood samples were collected at four time points (admission, 24 h/96 h post-admission, pre-discharge) for biochemical assays and UHPLC-Q-Exactive-Orbitrap-MS analysis. Metabolomics was used to screen AP-related biomarkers, evaluate the two regimens' reversal effects, and compare inter-group differences in metabolic recovery trajectories. Prototypes and metabolites of DCQD were identified, with potential pharmacodynamic substances screened via correlation analysis with AP biomarkers. L-arginine-induced SAP mouse model was used for validation. RESULTS: Serum amylase normalization and C-reactive protein decline were accelerated in Con + DCQD group. Both regimens reversed AP-related energy, amino acid, and lipid metabolic disorders. Adjuvant DCQD therapy accelerated inflammation alleviation and energy homeostasis restoration in early stage, and improved lipid metabolism more comprehensively in middle-to-late stage, with efficacy validated in SAP mice. Forty-eight and 35 blood-migrated components were identified in patients and mice, respectively, with 8 key pharmacodynamic substances screened. CONCLUSIONS: Integrating serum metabolomics and multi-time-point monitoring, this study delineated AP's metabolic recovery trajectory and clarified DCQD's efficacy and dynamic metabolic regulation, providing guidance for its clinical application.
12 June 2026
Read appraisal →Journal of ethnopharmacology
Insight of traditional Chinese medicine in treating pulmonary hypertension: Achievements from 2021 to 2025.
ETHNOPHARMACOLOGICAL RELEVANCE: Pulmonary hypertension (PH) significantly impairs patients' quality of life and imposes a substantial economic burden. Despite advances in pharmacotherapy, PH remains a life-threatening pulmonary vascular disease. Traditional Chinese Medicine (TCM), with its multi-target and multi-pathway mechanisms, has shown therapeutic potential for PH management. AIMS OF THE REVIEW: This review systematically summarizes TCM formulas, extracts, and active components, along with their pharmacological mechanisms, for the treatment of PH, and highlights the advantages of TCM in managing PH. MATERIALS AND METHODS: A systematic review of the literature on TCM for PH was conducted. The search included scientific publications from January 2021 to August 2025. Relevant articles were identified through comprehensive searches of PubMed, Web of Science, ScienceDirect, and Google Scholar. The search strategy combined keywords including "pulmonary hypertension", "pulmonary arterial hypertension", "Traditional Chinese Medicine", "Chinese herbal medicine", "herb", "formula", "extract", "active component", and "active ingredient". Retrieved publications were screened and analyzed using pre-defined inclusion and exclusion criteria to ensure relevance and methodological quality. RESULTS: This review synthesizes findings on TCM-based theory, experimental models, TCM formulas (both classical and novel), extracts (including ethanol/aqueous extracts, volatile oils, total flavonoids, saponins, and alkaloids), and active components (terpenoids, flavonoids, glycosides, and alkaloids) for the treatment of PH. Predominant models include monocrotaline-induced pulmonary arterial hypertension (PAH) in vivo and hypoxia-induced in vitro models using pulmonary artery smooth muscle cells (PASMCs). Mechanistic studies indicate that TCM target multiple signaling pathways, including NF-κB to alleviate inflammation, PI3K-AKT-mTOR signaling to mitigate oxidative stress, modulation of K+/Ca2+ channels to attenuate pulmonary vascular remodeling, the HIF-2α-Arg-NO signaling pathway to protect endothelial function, inhibition of the TGF-β1/Smad pathway to suppress endothelial-to-mesenchymal transition, and regulation of JAK2-STAT3 and p53-p21 pathways to inhibit abnormal proliferation, migration, apoptosis resistance, and phenotypic transformation. CONCLUSION: TCM, including formulas, extracts, and components exhibit significant therapeutic potential for PH, positioning TCM as a promising complementary strategy for managing this disease.
12 June 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
HER2CLIMB-05: A Phase III Study of Tucatinib Versus Placebo in Combination With Trastuzumab and Pertuzumab as First-Line Maintenance Therapy for HER2+ Metastatic Breast Cancer
PURPOSE: The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC). METHODS: Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. RESULTS: Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor-positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. CONCLUSION: Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.
12 June 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Neoadjuvant Taxane Plus Trastuzumab and Pertuzumab With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The Randomized Noninferiority Phase III neoCARHP Trial
PURPOSE: The neoCARHP aimed to investigate the efficacy and safety of investigator-selected taxane (docetaxel, paclitaxel, or nab-paclitaxel) plus trastuzumab and pertuzumab, with carboplatin (TCbHP) or without carboplatin (THP), in stage II and III human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: The neoCARHP was a multicenter, randomized, phase III, noninferiority study. Eligible patients were women age 18 years or older with previously untreated, stage II and III, HER2-positive invasive breast cancer. Patients were randomly assigned (1:1) to receive six 3-week cycles of TCbHP or THP. The primary end point was pathologic complete response (pCR) rate in the breast and axilla (ypT0/is ypN0) in the modified intention-to-treat (mITT) population (all randomly assigned patients receiving at least one dose of study treatment). Safety was evaluated in all patients who received any study treatment. RESULTS: Between April 30, 2021, and August 27, 2024, 774 patients were randomly assigned and 766 were included in the mITT population (382 in THP and 384 in TCbHP). pCR was achieved in 245 (64.1% [95% CI, 59.1 to 69.0]) patients in the THP group and 253 (65.9% [60.9-70.6]) in the TCbHP group (absolute difference, -1.8% [95% CI, -8.5 to 5.0]; odds ratio, 0.93 [95% CI, 0.69 to 1.25]; Pnoninferiority = .0089). The THP group had fewer grade 3 and 4 adverse events (20.7% v 34.6%) and serious adverse events (1.3% v 4.7%) than the TCbHP group. The most common grade 3 and 4 adverse events with THP were neutropenia (6.8% v 16.4% with TCbHP), leukopenia (5.5% v 14.8%), and diarrhea (2.6% v 4.2%). No treatment-associated deaths occurred. CONCLUSION: THP provided noninferior pCR rates and improved tolerability compared with TCbHP. Omitting carboplatin may be applicable in HER2-positive breast cancer.
12 June 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Amivantamab Monotherapy in Chemorefractory RAS/BRAF Wild-Type Metastatic Colorectal Cancer: Results From OrigAMI-1, an Open-Label, Phase Ib/II Study
PURPOSE: Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, is approved in non-small cell lung cancer (NSCLC). Effective treatments are limited for chemorefractory metastatic colorectal cancer (mCRC). METHODS: OrigAMI-1 (ClinicalTrials.gov identifier: NCT05379595) is a phase Ib/II study evaluating amivantamab monotherapy in chemorefractory (2-3 prior lines) mCRC. Participants had centrally confirmed RAS/BRAF/EGFR ectodomain wild-type status, without ERBB2/HER2 amplification. Participants with left-sided mCRC without (cohort A) or with (cohort B) prior anti-EGFR antibody treatment, or right-sided mCRC (cohort C) regardless of prior anti-EGFR treatment, received intravenous amivantamab 1,050 mg (1,400 mg for ≥80 kg) once every 2 weeks. The primary end point was objective response rate (ORR) per RECIST v1.1. RESULTS: By October 31, 2024, 94 participants received amivantamab monotherapy (median follow-up, 11.9 months). The median age was 60 years, and 65% of participants were male, with a median of 2 prior lines (94%, prior bevacizumab). In left-sided cohorts, the ORR was 29% (5 of 17) in cohort A and 19% (10 of 54) in cohort B; the median duration of response (DoR) was 9.0 months and 6.1 months, and the median progression-free survival (PFS) was 5.7 months and 4.6 months, respectively. In the right-sided cohort, the ORR was 22% (10 of 23; 43% had prior anti-EGFR), the median DoR was 9.8 months, and the median PFS was 3.7 months. Most frequent treatment-related grade ≥3 adverse events (AEs) were rash (7%), dermatitis acneiform (4%), and hypoalbuminemia (4%). One participant discontinued amivantamab because of a treatment-related AE. CONCLUSION: Amivantamab monotherapy demonstrated promising, durable antitumor activity in chemorefractory mCRC, regardless of prior anti-EGFR therapy and the primary tumor location. The amivantamab safety profile in mCRC is consistent with experience in NSCLC. Amivantamab plus chemotherapy is currently being explored in two phase III studies in first-line and second-line mCRCs.
11 June 2026
Read appraisal →International journal of biometeorology
Impact of balneotherapy on drug consumption: a systematic review and an economic evaluation of drug deprescribing
Some previous studies have suggested that balneotherapy could be associated with a decrease in drug consumption. No study has investigated pharmacoeconomic consequences in terms of monetary savings. The present study was performed to evaluate potential savings (according to societal perspective) associated with decreased drug consumption resulting from spa treatments using randomized clinical trials (RCT) identified after a systematic review. Among 48 RCT, 8 trials investigating rheumatological diseases (low back or shoulder pain, osteoarthritis, ankylosing spondylitis, fibromyalgia), were included in the economic evaluation of direct costs (€) using 2024 data of drug reimbursements according to French health insurance data. Savings calculated related to non-steroidal anti-inflammatory drugs (NSAIDs') decrease were between €0.05 million and €1.03 million at 6 months (mean value: €504.900) for the 441,776 patients who underwent rheumatology-oriented spa treatment in France in 2024 versus controls. For analgesics, values ranged from €0.73 million to around €2.31 million (mean value: €1,547.400). Despite several limitations that could not be overlooked (heterogeneity of studied populations, interventions, duration, outcome measures), the study showsfor the first timethat decreased drug consumption resulting from balneotherapy is associated with important savings regarding NSAIDs and, to a greater extent, analgesics. Balneotherapy is a unique opportunity for deprescribing, enabling both significant monetary savings for national health insurance, complementary health insurances and patients, while preventing adverse drug reactions or decreasing physiotherapy sessions or hospitalizations.
11 June 2026
Read appraisal →Journal of controlled release : official journal of the Controlled Release Society
Toward animal-free approaches in subcutaneous drug delivery: A pain management case study.
Subcutaneous (s.c.) administration offers practical advantages for long-acting drug delivery, yet its complex tissue environment, lack of standardized models, and limited regulatory guidance pose challenges for predicting pharmacokinetics (PK). Here, we present a complementary set of experimental and computational approaches to reduce reliance on animal testing while maintaining translational relevance. Ex vivo skin models captured the influence of tissue variability, while 3D-printed constructs and molded agarose hydrogels enabled standardized, reproducible in vitro drug release studies. In parallel, machine learning models trained on curated rodent datasets predicted key PK parameters with strong agreement to in vivo data, providing an alternative that bypasses additional animal experiments and resource-intensive assays. Finally, a liposomal carprofen formulation case study demonstrated the translational potential of these methods in veterinary applications. Together, these strategies illustrate routes toward animal-free drug development: simplified experimental systems that mimic s.c. release and computational models that predict systemic PK. By combining them conceptually, we outline a framework that advances the 3Rs principles while supporting mechanistic and predictive understanding of s.c. drug delivery.
10 June 2026
Read appraisal →Blood advances
A phase 1/2 study of duvelisib plus venetoclax in patients with relapsed/refractory CLL/SLL or Richter transformation
In this phase 1/2 study we evaluated duvelisib plus venetoclax in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Richter transformation (RT). Venetoclax was added after 1 week of duvelisib. After 1 year of therapy, patients with a complete response (CR) and undetectable minimal residual disease (uMRD) could discontinue therapy; patients with detectable MRD continued venetoclax monotherapy until 2 separate occasions of uMRD. Thirty five patients with CLL/SLL and 9 with RT enrolled. Among patients with CLL, 77% had unmutated immunoglobulin heavy chain variable region, 46% had TP53 aberrancy, and patients had a median of 2 prior therapies, including 60% with prior Bruton tyrosine kinase inhibitor. In phase 1 the maximum tolerated dose was not reached, and the recommended phase 2 dose was 25mg twice daily duvelisib plus 400mg daily venetoclax. 91% of patients experienced ≥grade 3 neutropenia, with febrile neutropenia in 6%. Common nonhematologic toxicities were diarrhea (63%, 14% ≥grade 3) and elevated aspartate aminotransferase (51%, 9% ≥grade 3). The best CR and overall response rates were 60% and 91%, respectively. At cycle 13, peripheral blood and bone marrow uMRD at 10-4 were 43% and 40%, respectively. The median progression-free survival (PFS) for patients with CLL/SLL was 46 months, and the 3-year PFS was 67% (95% confidence interval, 0.51-0.86). Four patients with RS achieved a response (3 CRs). Overall, duvelisib plus venetoclax was active in R/R CLL/SLL and RT, although serious adverse events occurred, including immune-mediated toxicities. This trial was registered at www.clinicaltrials.gov as NCT03534323.
9 June 2026
Read appraisal →Blood advances
Final phase 2 study results of acalabrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia
Acalabrutinib is a selective, covalent Bruton tyrosine kinase inhibitor approved for marketing in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report final, long-term phase 1/2 study results in 99 patients with treatment-naive (TN) and 134 with relapsed/refractory (R/R) CLL/SLL. At final data cutoff, 71% and 31% of patients in the TN and R/R cohorts, respectively, remained on acalabrutinib treatment (median follow-up of 73.7 and 52.6 months). Among the events of clinical interest (any grade) in the TN and R/R cohorts, atrial fibrillation was reported in 6.1% and 9.0%, hypertension in 29.3% and 23.1%, other malignancies (excluding nonmelanoma skin cancer) in 14.1% and 17.2%, and major bleeding in 8.1% and 8.2% of patients, respectively. The incidence of the most common adverse events decreased over time. Overall response rates were 97.0% and 94.8% in the TN and R/R cohorts, respectively, with similar response findings among patients with standard and high-risk genomic features. In the TN cohort, median progression-free survival (PFS) was not reached and the 72-month PFS rate was 86.7% (95% confidence interval [CI], 77.0-92.5). For the R/R cohort, median PFS was 66.1 months (range, 0.4-87.8) and the 72-month PFS rate was 45.1% (95% CI, 35.6-54.1). This final analysis extends the duration of benefit observed with acalabrutinib, demonstrates that no new safety signals are apparent with longer follow-up, and confirms the safety and tolerability of acalabrutinib monotherapy for patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.
9 June 2026
Read appraisal →Blood advances
Ropeginterferon alfa-2b for prefibrotic myelofibrosis and lower-risk myelofibrosis requiring cytoreduction
There is currently no consensus on the optimal treatment of early myelofibrosis (MF). Ropeginterferon alfa-2b (ropeg) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms. We conducted a phase 2 study in patients with prefibrotic primary MF (pre-PMF) and Dynamic International Prognostic Scoring System low-/intermediate-1-risk fibrotic PMF or secondary MF (SMF) who required cytoreduction. Ongoing treatment with hydroxyurea was substituted with ropeg (week 0, 250 μg; week 2, 350 μg; week 4 onward, 500 μg every 2 weeks). The primary end points were safety and clinicohematologic complete response (CHCR). Seventy-one patients (40 men and 31 women) with a median age of 60 years (range, 31-86) were enrolled and followed up for a median of 119 weeks (range, 10-131). At weeks 24, 48, and 104, CHCR was achieved in 63.8% (pre-PMF, 74%; fibrotic PMF, 20%; fibrotic SMF, 42.9%), 63.5% (pre-PMF, 69.6%; fibrotic PMF, 25%; SMF, 53.9%), and 70% of patients (pre-PMF, 78.4%; fibrotic PMF, 33.3%; SMF, 50%), respectively. Thrombo-hemorrhagic events were not observed after stopping hydroxyurea. At weeks 24, 48, and 104, reduction in JAK2V617F variant allele frequency (VAF) was observed in 53.1%, 70%, and 67.6% of patients, and reduction in CALR mutant VAF was observed in 52.6%, 42.9%, and 40% of patients, respectively. In 50 evaluable cases at week 104, 13 patients (26%) had reduced bone marrow reticulin fibrosis. There were 3 treatment discontinuations (4.2%) due to adverse events. In conclusion, ropeg was safe and induced CHCR associated with significant molecular responses in patients with early MF. This trial was registered at www.clinicaltrials.gov as NCT04988815.
9 June 2026
Read appraisal →Neurology
Vamorolone Safety, Pharmacokinetics, and Exploratory Efficacy in Duchenne Muscular Dystrophy: A Phase II, Nonrandomized, Multiple-Dose Study in 2-<4-Year-Old Boys
BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative corticosteroid (CS) approved by the US Food and Drug Administration in 2023 for treating Duchenne muscular dystrophy (DMD). This study evaluated the safety, tolerability, and pharmacokinetics (PK) of vamorolone in young boys with DMD; exploratory objectives included efficacy and patient-reported outcomes. METHODS: A 12-week, phase II, open-label, multiple-dose study (VBP15-006) enrolled CS-naive boys with DMD aged 2-<4 years in Canada. Participants received 2 or 6 mg/kg/d oral vamorolone. An ongoing expanded access protocol (EAP) provided longer-term data. Primary end points were the occurrence of treatment-emergent adverse events (TEAEs) and changes from baseline to week 12 in height, weight, and body mass index (BMI); other end points included PK and effects of vamorolone on muscle function. RESULTS: Twenty boys (mean age [SD] 3.4 [0.39] years) with similar baseline characteristics were enrolled; all completed VBP15-006 and 19 continued to receive vamorolone through EAP Canada. TEAEs were mostly mild, with no deaths, serious TEAEs, or TEAEs leading to drug discontinuation during VBP15-006. TEAEs were more frequent with 6 mg/kg/d vamorolone than with 2 mg/kg/d, with gastrointestinal disorders and infections/infestations, respectively, most reported. Vamorolone use was associated with morning serum cortisol reductions in all patients, more pronounced with 6 mg/kg/d. Stable growth trajectories were observed at both doses throughout VBP15-006 and the EAP Canada follow-up period, with a total median (Q1; Q3) exposure to vamorolone of 2 years (1.7; 2.3). By EAP Canada last visit, 8/19 patients had weight and BMI z-scores changes >0.5, suggestive of excessive weight gain over time. Vamorolone displayed a dose-dependent PK profile with rapid absorption and no accumulation. Dose-dependent improvements in motor function (measured by Bayley-III gross motor scaled score) were observed. Glucose metabolism and bone turnover biomarkers remained stable. Ease of administration was rated favorably. DISCUSSION: Vamorolone was well tolerated in 2-<4-year-old boys with DMD, with no new safety concerns identified. A dose-dependent PK profile was observed, consistent with previous studies. Exploratory evidence suggested dose-dependent improvements in gross motor function. These findings are consistent with potential therapeutic benefit of vamorolone for young boys with DMD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT05185622 (VBP15-006; clinicaltrials.gov/study/NCT05185622), NCT03863119 (EAP; clinicaltrials.gov/study/NCT03863119). First submitted November 9, 2021. First patient enrolled: March 21, 2022. CLASSIFICATION OF EVIDENCE: The VBP15-006 study provides Class IV evidence that in boys with DMD aged 2-<4 years, 12-week treatment with vamorolone was not associated with serious adverse events or changes in weight, height, or BMI. Gastrointestinal events and infections were the most reported TEAEs.
9 June 2026
Read appraisal →Blood advances
Phase 1 study of zanubrutinib plus lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma
Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose-escalation/-expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily plus lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary end points were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 previous therapies, 83% had stage III/IV disease, and ∼67% had non-geminal center B-cell-like or activated B-cell-like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were decreased neutrophil count (58%) and decreased white blood cell count (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% confidence interval [CI], 2.9-11.1); the 12-month event-free rate was 34% (95% CI, 21-48). Zanubrutinib plus lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as NCT04436107.
9 June 2026
Read appraisal →Neurosurgical review
Rho-associated kinase inhibitors in cerebral cavernous malformations: a preclinical systematic review
Cerebral cavernous malformations (CCMs) are vascular abnormalities characterized by clusters of dilated capillaries. They are most associated with loss-of-function mutations in three genes (Ccm1, Ccm2, and Pdcd10/Ccm3). In capillary endothelial cells, mutations activate the Rho-associated coiled-coil-containing protein kinase (ROCK), leading to non-heme iron deposition and lesion formation, thereby contributing to CCM pathophysiology. To address this, ROCK inhibitors are being explored as potential stabilizing therapies in CCM. By reviewing the existing literature, this study aims to provide a descriptive evaluation of their effects on non-heme iron deposition and lesion formation in murine models. This systematic review followed the PRISMA 2020 guideline and was registered in PROSPERO (CRD420251048073). PubMed, Embase, Web of Science, and Scopus were searched from inception to 2 February 2026. Eligible studies included in vivo murine CCM models with mutations in the Ccm1, Ccm2, and Pdcd10/Ccm3 genes. Studies had to evaluate direct ROCK inhibitors, such as fasudil and BA-1049, or indirect modulators of the RhoA/ROCK pathway, such as statins, regardless of dosage, route, or duration, and provide molecular evidence of RhoA/ROCK pathway modulation. The primary outcome was lesion burden, and the secondary outcomes included non-heme iron deposition and ROCK activity. Systematic searches identified 389 records, of which 4 studies were included, demonstrating that fasudil, a ROCK inhibitor, consistently reduced non-heme iron deposition and lesion burden in preclinical CCM models in mice. In Ccm1+/-Msh2-/- mice, fasudil reduced non-heme iron deposition and stage 2 lesions; in Ccm2+/-Msh2-/- mice, fasudil reduced non-heme iron deposition and lesion burden. One study demonstrated that BA-1049 caused a dose-dependent reduction in non-heme iron deposition and lesion burden. Studies have shown that ROCK pathway modulation reduces non-heme iron deposition and lesion burden. Further clinical investigations involving patients with CCM are essential to verify whether these experimental benefits can be reproduced in clinical settings.
9 June 2026
Read appraisal →Bioorganic chemistry
In silico discovery and biological evaluation of a novel selective HDAC8 inhibitor featuring 1H-pyrazolo[3,4-b]pyridine scaffold
Histone deacetylase 8 (HDAC8), a pivotal epigenetic regulator orchestrating chromatin remodeling and transcriptional control, has emerged as a compelling anticancer target owing to its frequent dysregulation in malignancies. The development of isoform-selective inhibitors, however, confronts substantial challenges because of the pronounced structural conservation across HDAC isoforms. This study developed a high-efficiency drug screening pipeline primarily leveraging artificial learning (AI) models and molecular simulation techniques, and further evaluated the biological activity of computationally prioritized compounds through enzymatic inhibition assays and cellular experiments. The structurally novel compound Cmpd.16 was successfully identified, exhibiting promising inhibitory activity against HDAC8 (IC50 = 0.16 ± 0.01 μM) and moderately inhibited HCT116 cell proliferation mainly through the induction of apoptosis and G2/M phase cell cycle arrest. Subsequently, molecular dynamics simulations were employed to investigate the binding conformation of Cmpd.16 within the active pocket, and the key residues identified through free energy decomposition further elucidated the drug-target binding mode. Collectively, Cmpd.16, featuring 1H-pyrazolo[3,4-b]pyridine scaffold, was discovered via an efficient screening workflow, offering valuable insights to guide the rational design of HDAC8-targeted agents.
7 June 2026
Read appraisal →Bioorganic chemistry
Multi-relational knowledge graph for drug-drug interaction prediction via dual aggregation and collaborative optimization
Identifying potential drug-drug interactions is crucial in clinical care and new drug development, as mutual interference between drugs can lead to adverse reactions. Recently, computational methods have been widely employed for predicting DDIs. However, these approaches often encounter high computational complexity during the process of node feature representation and frequently overlook the interactivity and polysemy of entities. Effectively handling heterogeneous information remains a significant challenge. To cope with these limitations, we propose a dual aggregation and collaborative optimization learning framework，named MRACO，for DDIs prediction based on a multi-relational knowledge graph. MRACO utilizes structural information from these graphs, efficiently learning interactivity information across various relationship types. Additionally, MRACO employs dual aggregation operations to explicitly encode and aggregate multi-type information, capturing diverse semantic relationships of drug nodes. Moreover, MRACO simplifies complex computational processes by utilizing the collaborative loss optimization function, eliminating redundant information and enhancing model robustness. By integrating deep-level interactive information, MRACO leverages rich contextual data from knowledge graphs, enhancing prediction stability. Experiments demonstrate the effective of MRACO feature extraction capabilities in multi-relational networks, highlighting its understanding of the underlying mechanisms of DDIs.
7 June 2026
Read appraisal →European journal of medicinal chemistry
Machine learning-based prediction of drug lactation risk: Bridging molecular features and breastfeeding safety
BACKGROUND: Breastfeeding medication safety assessment presents critical challenges due to limited clinical evidence and ethical constraints on lactation studies. While existing computational models focus on predicting pharmacokinetic surrogates such as milk-to-plasma ratios, these endpoints lack direct clinical actionability for therapeutic decision-making. METHODS: We developed LRCpredictor, a computational framework for predicting drug lactation risk based on Dr. Thomas W. Hale's evidence-based Lactation Risk Categories (LRC) system. A dataset of 391 drugs (179 high-risk L4/L5, 212 low-risk L1/L2) was characterized using three complementary molecular representations. Systematic feature engineering with four selection algorithms identified optimal feature subsets. Five ensemble machine learning algorithms were evaluated through cross-validation and independent testing. Multi-level SHAP analysis and structural alert mining were employed to elucidate molecular determinants of lactation risk. RESULTS: The optimal Gradient Boosting Decision Tree (GBDT) model using 35 selected features achieved robust cross-validated performance (AUC = 0.80, MCC = 0.52) and demonstrated notably superior discrimination for extreme risk categories (L1 vs. L5: AUC = 0.85, MCC = 0.62). Analysis revealed lactation risk is governed by the complex interplay of electronic properties, structural topology, electrotopological characteristics, polarizability and drug-likeness attributes. Matched molecular pair analysis demonstrated how specific structural modifications translate into interpretable risk changes. We further identified 18 structural alerts, including five exclusive to high-risk drugs, enabling rapid toxicophore recognition during risk assessment and drug design. CONCLUSIONS: LRCpredictor provides the first interpretable framework for clinically actionable lactation risk prediction with mechanistic molecular insights. The freely accessible web platform (https://lrcpredictor.streamlit.app/) with integrated visual explanations supports evidence-based decision-making for healthcare providers and drug design optimization.
7 June 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of a bodyweight-adjusted higher dose of ocrelizumab in relapsing (MUSETTE) and primary progressive (GAVOTTE) multiple sclerosis: two multicentre, randomised, double-blind, parallel-group phase 3b trials.
BACKGROUND: Ocrelizumab is a humanised anti-CD20 monoclonal antibody approved for people with relapsing (RMS) or primary progressive multiple sclerosis (PPMS). In a post-hoc analysis of phase 3 trials in RMS and PPMS using a 600 mg dose, higher exposure to ocrelizumab was associated with greater B-cell depletion and lower risk of confirmed disability progression. Here, we prospectively assessed the efficacy and safety of a high dose of ocrelizumab in patients with RMS or PPMS. METHODS: Two multicentre, double-blind, phase 3 controlled trials were conducted to compare high-dose ocrelizumab with the approved 600 mg dose of the drug in patients with RMS (MUSETTE) and PPMS (GAVOTTE) aged 18-56 years. MUSETTE involved 122 centres in 21 countries and GAVOTTE involved 149 centres in 22 countries. Participants were randomly assigned 2:1, with a permuted-block randomisation method, to high-dose ocrelizumab (1200 mg or 1800 mg for baseline body weight <75 kg or ≥75 kg, respectively) or 600 mg ocrelizumab. Patients, investigators, and the sponsor were blinded to treatment allocation. Patients received ocrelizumab infusions every 24 weeks for a minimum 120 weeks and until a prespecified minimum number of confirmed disability events (MUSETTE, 205; GAVOTTE, 357) had occurred. In both trials, the primary endpoint was time to onset of 12-week composite confirmed disability progression (cCDP), assessed by prespecified increases in Expanded Disability Status Scale, Timed 25-Foot Walk Test, or 9-Hole Peg Test scores. Efficacy endpoints were evaluated in all randomised participants and safety endpoints were evaluated in participants who received at least one ocrelizumab infusion. These studies are registered with ClinicalTrials.gov: MUSETTE, NCT04544436; GAVOTTE, NCT04548999. FINDINGS: Participants in MUSETTE were enrolled between Nov 26, 2020, and Aug 30, 2022; participants in GAVOTTE were enrolled between Dec 3, 2020, and May 15, 2023. In MUSETTE, 860 patients were randomly assigned (high-dose ocrelizumab, n=577; 600 mg ocrelizumab, n=283) and had median overall treatment duration of 184·4 weeks. In GAVOTTE, 753 patients were randomly assigned (high-dose ocrelizumab, n=500; 600 mg ocrelizumab, n=253) and had median overall treatment duration of 174·1 weeks. In MUSETTE, the percentage of patients with 12-week cCDP was 34% (198 of 577) with high-dose ocrelizumab versus 37% (104 of 283) with 600 mg ocrelizumab (hazard ratio [HR] 0·93 [95% CI 0·73-1·18]; p=0·53). In GAVOTTE, the percentage of patients with 12-week cCDP was 47% (235 of 500) with high-dose ocrelizumab versus 49% (124 of 253) with 600 mg ocrelizumab (HR 0·95 [95% CI 0·76-1·18]; p=0·64). Safety profiles were similar for the high-dose ocrelizumab and 600 mg ocrelizumab; in MUSETTE, rates of adverse events (552 [96%] of 577 and 267 [94%] of 283), serious adverse events (77 [13%] of 577 and 34 [12%] of 283), and fatalities (four [1%] of 577 and one [<1%] of 283) were comparable, as were rates of adverse events (447 [90%] of 499 and 230 [91%] of 254), serious adverse events (61 [12%] of 499 and 29 [11%] of 254), and fatalities (two [<1%] of 499 and three [1%] of 254) in GAVOTTE. INTERPRETATION: In both studies, high-dose ocrelizumab did not further improve control of disability progression in either RMS or PPMS, and no new safety concerns were identified. FUNDING: F Hoffmann-La Roche.
1 June 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study
BACKGROUND: Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication. METHODS: This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America. Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached. Participants, investigators, and clinical assessors were masked to group assignment. The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned). Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received. The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting. FINDINGS: Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blind treatment (prasinezumab, n=277; placebo, n=273). The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio 0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group. The incidence of one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]). INTERPRETATION: Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310). FUNDING: F Hoffmann-La Roche.
1 June 2026
Read appraisal →Journal of medical Internet research
From Virtual Molecules to Clinical Trials: How AI Is Reshaping Preclinical Drug Discovery
Pharmaceutical development is typically a long and arduous process, but advances in artificial intelligence may help streamline each stage of this pipeline. In this News and Perspectives article, JMIR Correspondent Benedette Cuffari reports on recent innovations and their potential implications for drug discovery.
1 June 2026
Read appraisal →The AAPS journal
New Frontiers of Drug Development Through the Use of New Approach Methodologies
On November 2025, AAPS PharmSci 360 convened a symposium that included experts in the application of various types of New Approach Methodologies (NAMs). They shared their experiences and insights on topics that included microphysiological systems (MPS), the use of 3D organoids, and in silico tools. MPS systems were explored from the perspective of their testing and qualification through an academia-industry-government tissue chip testing consortium whose mission is to perform context-of-use-based testing of MPS and conduct comparative evaluations to support the use of MPS systems in safety assessments. 3D organoids were described and insights shared on how and when they may provide an appropriate tool for evaluating drug safety and effectiveness, and their use in supporting personalized medicine. Regarding in silico tools, examples were provided to describe their growing utility in predicting drug toxicity, population variability, and its potential benefits over traditional evidence-based toxicology. These tools include in silico models (e.g., physiologically based pharmacokinetic models), Artificial Intelligence (AI), and Machine Learning (ML) which, unlike other aspects of model informed drug development, reduce reliance on predefined models and allows for the integration of diverse sources of data. Computationally, these tools can generate predictions in hours where it would otherwise have taken weeks or months (and extensive experimentation). Within this meeting report, we highlight the key issues discussed during that symposium and share additional aspects to consider when developing a NAMs-based roadmap for specific contexts of use.
1 June 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis, including older patients and those with more advanced disease (ORATORIO-HAND): a multicentre, double-blind, randomised, placebo-controlled, phase 3b study
BACKGROUND: The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly regarding hand function preservation. METHODS: ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries. Patients with PPMS aged 18-65 years and Expanded Disability Status Scale (EDSS) score of 3·0-8·0 were randomly assigned 1:1 to intravenous ocrelizumab 600 mg or placebo every 6 months for 144 weeks or until a prespecified number of progression events occurred. Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab. Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments. MRI scans were evaluated by a masked central reader, and laboratory parameters that could reveal treatment allocation were masked to site personnel until the primary analysis. Two coprimary estimands were defined, with the endpoint of time to onset of 12-week composite confirmed disability progression (12W-cCDP) in 9-Hole Peg Test or EDSS evaluated in all randomly assigned patients, and the same endpoint evaluated in a subset of patients with MRI activity at baseline. This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting. FINDINGS: Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]). The proportion of patients with 12W-cCDP was 165 (33%) of 505 with ocrelizumab and 205 (40%) of 508 with placebo (hazard ratio, 95% CI 0·70 0·57-0·86; relative risk reduction=30%; p=0·0007). In the MRI-active subgroup, a significant risk reduction was also observed in 12W-cCDP (risk reduction=55%; p<0·0001). The overall safety profile was similar in both groups. More infections (245 [48%] of 506 vs 226 [45%] of 506) were observed with ocrelizumab, but not after COVID-19 was excluded (38% vs 37%). Rates of serious adverse events and serious infections were similar between groups. INTERPRETATION: Ocrelizumab was superior to placebo in delaying disability progression, with stronger effect on hand function, in a broad PPMS population including older patients and those with more advanced disease, while maintaining a manageable safety profile. FUNDING: F Hoffmann-La Roche.
31 May 2026
Read appraisal →Cancer chemotherapy and pharmacology
A randomized, open-label, two-way crossover clinical trial to evaluate the food effect on pharmacokinetics and safety of DHP107 in patients with advanced solid tumors: the FEEL study
PURPOSE: The phase 1, randomized, open-label, two-way crossover FEEL study assessed the effect of food on the pharmacokinetics of DHP107, an oral paclitaxel with a novel lipid formulation designed to be systemically absorbed without Cremophor EL, in patients with advanced solid tumors. METHODS: Patients were randomized 1:1 to DHP107 (200 mg/m2 orally twice daily on Days 1, 8, 15 every 28 days for two cycles) treatment sequences: fasted-fed (first DHP107 dose administered after overnight fast; n = 13) and fed-fasted (first DHP107 dose administered after a high-fat meal; n = 12). The primary objective was to evaluate the effect of food on DHP107 pharmacokinetics. The secondary objective was DHP107 safety; efficacy was also assessed (both in all patients regardless of dosing sequence). RESULTS: Mean systemic exposures were similar for paclitaxel and its metabolites under fed and fasted conditions. Geometric mean ratios (fed:fasted) for paclitaxel were: maximum concentration (Cmax), 101.00% (95% CI 91.93-110.95%); area under the curve (AUC0-72), 102.92% (95% CI 95.04-111.45%); and AUC0-inf 104.76% (95% CI 96.44-113.80%), meeting criteria for no food effect. Common adverse events across the study period included diarrhea (fasted-fed 61.5%; fed-fasted 41.7%), vomiting (fasted-fed 30.8%; fed-fasted 8.3%), and neutropenia (fasted-fed 23.1%; fed-fasted 16.7%). Two fed-fasted patients (16.7%) had partial responses and six had stable disease (50.0%); seven fasted-fed patients had stable disease (53.8%). CONCLUSION: This study suggests that the pharmacokinetics of DHP107 are unaffected by food and DHP107 can be taken with or without food. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04675528; 107CS-7.
31 May 2026
Read appraisal →PLoS medicine
Characterization of the VHH-Fc construct rimteravimab in healthy adults and patients hospitalized for mild-to-moderate COVID-19: Two Phase 1 randomized clinical trials
BACKGROUND: Variable Heavy domain of Heavy chains (VHH) are innovative tools to target unique epitopes, yet few have been developed as heavy chain-only antibodies for clinical use. Rimteravimab (referred to here as XVR011) is a humanized antibody developed for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19), consisting of two identical VHHs targeting the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, with a human immunoglobulin (Ig) G1 fragment constant of antibody (Fc), silenced for Fc effector functions. We conducted two Phase 1 studies in healthy volunteers or hospitalized COVID-19 patients to evaluate its safety, tolerability, pharmacokinetics and immunogenicity. METHODS AND FINDINGS: A randomized, double-blinded, single-center, placebo-controlled, single ascending dose study was performed in healthy volunteers (Phase 1a, EXEVIR0102, EudraCT 2021-003707-17), in parallel to an open-label, multi-center, single ascending dose study in patients hospitalized for mild to moderate COVID-19 (Phase 1b, EXEVIR0101, EudraCT 2020-005299-36, NCT04884295). Participants received a single intravenous infusion of 250, 500 or 1,000 mg of XVR011. The primary objective for both trials was the safety and tolerability of XVR011. Pharmacokinetics were evaluated as a secondary objective in Phase 1a and as an exploratory objective in Phase 1b. Efficacy (evaluated as respiratory parameters and COVID-19 clinical status) and antiviral activity in patients were evaluated as a secondary objective in Phase 1b. Immunogenicity was evaluated as an exploratory objective. Part 2 of the EXEVIR0101 study (initially a phase 1b/2 study) was not conducted due to the loss of XVR011 potency against SARS-CoV-2 Omicron BA.2. Demographics, safety, efficacy, and immunogenicity were analyzed using descriptive statistics, while pharmacokinetics were analyzed with noncompartmental pharmacokinetics (PK) modeling. In the Phase 1a study, there were no infusion-related reactions, serious treatment-emergent adverse events (TEAEs) or TEAEs grade ≥3. 22/30 volunteers (73.3%) reported 53 TEAEs (49 Grade 1, 4 Grade 2) with none being related to XVR011. The most common TEAE was headache (n = 8, 26.7%) in various treatment groups. In the Phase 1b study, 27 hospitalized patients were enrolled, and followed up to 30 days. Seven patients (25.9%) reported a total of 15 TEAEs, the majority (80%) being mild to moderate (Grade 1-2). There were no treatment-related serious TEAEs. All TEAEs resolved by the end of the study. Peak exposure (maximal concentration, Cmax) and systemic exposure (area under the curve, AUC0-t, and AUC0-inf) for XVR011 increased dose-proportionally. Geomean half-life ranged from 15.4 to 17.0 days in Phase 1a, while individual half-life ranged from 11.4 to 15.6 days in Phase 1b. SARS-CoV-2 viral load, as detected in nasopharyngeal samples by reverse transcription and quantitative polymerase chain reaction (RT-qPCR), decreased similarly in all cohorts compared to baseline. No treatment-induced anti-drug antibodies (ADA) were detected in Phase 1a. In Phase 1b, higher XVR011 concentrations increased the likelihood of ADA formation, without impacting pharmacokinetics and pharmacodynamics. No obvious dose-response in COVID-19 clinical status or respiratory parameters was observed. Technological limitations included study size, absence of placebo for the Phase 1b, absence of repeated dosing, evolving SARS-CoV-2 variants and standard-of-care. CONCLUSIONS: XVR011 displayed a favourable safety, tolerability, pharmacokinetics, and immunogenicity profile, both in healthy volunteers and in patients hospitalized for mild to moderate COVID-19. These data pave the way for the design and clinical development of VHH-Fc constructs.
31 May 2026
Read appraisal →Journal of computer-aided molecular design
Target-aware molecule SMILES generation using a large language model with retrieval-augmented generation, multi-turn memory, and a predictive model
Given the vastness of chemical space and the cost and time requirements of high-throughput screening, resource-efficient computational strategies are needed to prioritize candidate drug molecules. Here, we evaluated whether an open-weight large language model (LLM) augmented with retrieval-augmented generation (RAG), multi-turn memory, and a pretrained drug-target interaction predictor can generate target-aware molecules without task-specific retraining. Protein-ligand-pKi examples retrieved from BindingDB, Davis, and KIBA were used as contextual guidance, while DeepPurpose provided the optimization signal during iterative SMILES refinement. Our approach produced a statistically significant increase in predicted pKi across successive multi-turn memory iterations, indicating that retrieval- and memory-guided refinement may improve target-conditioned molecular generation. The proposed framework also showed favorable molecular generation characteristics, with novelty reaching 100%, diversity up to 0.882, and uniqueness up to 1.0, suggesting that retrieval did not reduce the process to simple reproduction of known ligands but instead supported exploration of new regions of chemical space. In addition, the approach yielded supportive docking results consistent with the generation of chemically relevant candidate ligands. However, the increase in predicted affinity was accompanied by trade-offs in molecular quality, including reduced validity and drug-likeness in later iterations. Taken together, these findings suggest that this framework provides a flexible and comparatively resource-efficient strategy for target-aware de novo molecular design, while further multi-objective optimization and independent validation remain necessary.
31 May 2026
Read appraisal →Medicine
Triple oral therapy combining metformin, SGLT-2 and DPP-4 inhibitors versus dual therapy in type 2 diabetes mellitus: A systematic review and meta-analysis
BACKGROUND: Triple oral therapy combining metformin, sodium-glucose cotransporter 2 inhibitor, and a dipeptidyl peptidase-4 inhibitor has been proposed as a synergistic approach to intensify glycemic control in patients with type 2 diabetes mellitus. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of triple therapy compared to dual therapy (metformin plus either sodium-glucose cotransporter 2 or dipeptidyl peptidase-4 inhibitor). METHODS: Following preferred reporting items for systematic review and meta-analysis guidelines, we searched PubMed, Embase, Scopus, and Web of Science through January 2026. Studies included randomized controlled trials comparing triple versus dual therapy in adults with type 2 diabetes mellitus. Outcomes included hemoglobin A1c (HbA1c), fasting plasma glucose, body weight, achievement of HbA1c < 7%, and adverse events (AEs). Pooled standardized mean differences (SMDs) and risk ratios (RRs) were calculated using random-effects models. RESULTS: Eight studies encompassing 2606 participants were included. Findings indicate triple therapy significantly reduced HbA1c levels compared to dual therapy, with a SMD of - 0.54 (95% confidence interval [CI]: -0.92 to -0.16; P = .005). Triple therapy resulted in greater reduction in fasting plasma glucose, with an SMD of -0.30 (95% CI: -0.62 to 0.01; P = .06). Patients on triple therapy were more likely to achieve HbA1c levels below 7% (RR: 2.02; 95% CI: 1.55-2.63; P < .0001). Weight reduction was modest, with an SMD: -0.14 (95% CI: -0.22 to -0.07; P = .0002). No significant differences were found in total AEs (RR = 0.97; P = .69) or hypoglycemia (RR = 1.32; P = .32), although there was higher discontinuation due to AEs (RR = 2.62; P = .03). CONCLUSION: Triple therapy offers superior glycemic control over dual therapy without major safety trade-offs, though tolerability may affect long-term adherence.
31 May 2026
Read appraisal →Purinergic signalling
Turning failure into success: how artificial intelligence can help personalize therapies and re-use patient data.
Despite robust preclinical evidence, many clinical trials, including several that targeted the purinergic system, fail to demonstrate efficacy in humans. Failure may stem from inability to accurately identify patient subgroups responding similarly to treatments. Here, we explore the potential of artificial intelligence to revolutionize how we group and classify patients in clinical studies. We introduce a new framework using Large Language Models-generated embeddings of detailed patient data, to create a semantic-aware latent space, enabling us to identify truly meaningful patients' clusters. Large Language Models can provide explainable groupings, giving clear reasons why certain patients respond similarly to treatments. We present an example of successful application of this approach through the re-analysis of the AMARANTH clinical trial (NCT02245737, involving ~ 2200 patients and completed in 2018) testing Lanabecestat, a BACE1 inhibitor decreasing β-amyloid production in Alzheimer's disease, for which traditional analysis reported no efficacy. As in the original trial, our simulation showed no overall benefit. However, re-analysis per patients' clusters and subjects' re-stratification by semantic similarities (shared symptom profiles, progression patterns) identified a patients' subgroup in one of the clusters showing Lanabecestat-associated slower disease worsening, thus succeeding where the full trial had failed. By making a new therapy available to at least a subset of patients with a defined disease, this new approach may help maximize the return on drug development and reduce the burden on healthcare. Moreover, it will significantly improve the precision, efficiency and interpretability of clinical trials, paving the way for a new era of personalized medical treatments.
31 May 2026
Read appraisal →Medicine
The clinical efficacy of Astragalus-containing Chinese patent medicines in the effective treatment of heart failure: A systematic review and network meta-analysis
BACKGROUND: The incidence of cardiovascular diseases, particularly heart failure, has been rising year by year. Traditional Chinese medicines containing Astragalus have been widely used in clinical research. However, there is no definitive research on the efficacy of proprietary Chinese medicines containing Astragalus. A network meta-analysis was conducted to investigate the efficacy and safety of oral traditional Chinese medicines containing Astragalus for the treatment of heart failure. METHODS: This study searched 6 databases for clinical randomized controlled trials involving the use of traditional Chinese herbal medicines containing Astragalus alone or in combination with other drugs, with a search period from the establishment of the databases to May 27, 2025. Using the Cochrane Quality Assessment Manual, we conducted a bias analysis of the included studies, and the extracted data were analyzed using network meta-analysis in Stata 18. RESULTS: A total of 18 studies were included, involving 1584 patients with heart failure, with 16 types of traditional Chinese medicines containing Astragalus. The network meta-analysis via Surface Under the Cumulative Ranking Curve analysis indicated that: Compared to using Western medicine (WM) alone, Astragalus Granule + WM ranked best for improving overall clinical efficacy rate; Qiangxin Capsule + WM was optimal for improving six-minute walk test; Astragalus Granule + WM showed the best efficacy for reducing B-type natriuretic peptide levels; Yanxing Decoction + WM ranked first for lowering N-terminal pro-B-type natriuretic peptide levels; Xinlishen Compound + WM was the optimal combination for improving left ventricular ejection fraction; Qili Qiangxin Capsule + WM performed best for reducing left ventricular end-diastolic diameter; Yangxin Tongmai II Prescription + WM exhibited the highest efficacy for decreasing Minnesota Heart Failure Quality of Life Questionnaire scores. CONCLUSIONS: Adding oral traditional Chinese medicine containing Astragalus to WM treatment can further improve the clinical efficacy of heart failure. However, due to the limited number and quality of the included studies in this research, the above conclusions still require further validation through well-designed randomized double-blind controlled trials.
31 May 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials
BACKGROUND: Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease. METHODS: evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome. FINDINGS: Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group). INTERPRETATION: Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications. FUNDING: Novo Nordisk.
31 May 2026
Read appraisal →Journal of medical Internet research
How Machine Learning Can Help Close Evidence Gaps for Drug Safety in Pregnant Women
Women, especially pregnant women, have historically been excluded from clinical research. In this News and Perspectives article, JMIR Correspondent Michelle Falci reports on how advances in data analytics may help bridge evidence gaps.
29 May 2026
Read appraisal →Polish archives of internal medicine
Biologic and targeted synthetic treatment of SAPHO syndrome: systematic literature review
INTRODUCTION: SAPHO syndrome is a rare autoimmune / autoinflammatory disorder with no approved therapies or standardized management guidelines. Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are increasingly used off‑label. OBJECTIVES: This review aimed to systematically evaluate the evidence for the efficacy of b/tsDMARDs in SAPHO. PATIENTS AND METHODS: A PRISMA‑guided search of PubMed database was conducted through March 31, 2025. Studies of any design reporting outcomes of b/tsDMARDs in patients with SAPHO fulfilling the modified Kahn criteria were included. Exclusion criteria were non‑English language, inaccessible full text, and insufficient treatment details. Data on patient characteristics, drug class, follow‑up duration, and treatment response were extracted. As all the included studies were case reports or case series, the risk of bias was not assessed. Treatment responses were summarized using descriptive statistics. RESULTS: Of 1610 screened records, 106 studies comprising 385 instances of b/tsDMARD use met the inclusion criteria; no randomized controlled trials were identified. Tumor necrosis factor inhibitors (TNFis) were used in 203 patients, with complete skeletal and skin responses in 81% and 72%, respectively. The use of Janus kinase inhibitors (JAKis) in 77 patients was associated with complete response rates of 89% (skeletal) and 94% (skin). Other b/tsDMARD classes-including interleukin 17 (IL‑17), IL‑23, IL‑1, and IL‑6 inhibitors, as well as phosphodiesterase‑4 inhibitors-demonstrated variable and generally lower efficacy. CONCLUSIONS: Evidence for b/tsDMARD efficacy in SAPHO remains limited to low‑quality, uncontrolled studies with substantial heterogeneity and probable publication bias. TNFis and JAKis are among the most consistently effective therapies reported in the available literature, but high‑quality research, including randomized trials or prospective registries, is urgently needed to inform evidence‑based management.
29 May 2026
Read appraisal →The New England journal of medicine
Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer
BACKGROUND: Zanidatamab, a dual human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody, plus chemotherapy both with and without tislelizumab (anti-programmed death 1), showed encouraging efficacy and safety as first-line therapy in phase 2 studies involving patients with HER2-positive gastroesophageal adenocarcinoma. METHODS: In an open-label, phase 3 trial, we randomly assigned, in a 1:1:1 ratio, patients with previously untreated, centrally confirmed HER2-positive advanced gastroesophageal adenocarcinoma to receive zanidatamab and tislelizumab plus chemotherapy, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy. The two primary end points were progression-free survival and overall survival. RESULTS: At a median follow-up of 25.9 months, progression-free survival was longer with zanidatamab-tislelizumab-chemotherapy (median among 302 patients, 12.4 months) and zanidatamab-chemotherapy (median among 304 patients, 12.4 months) than with trastuzumab-chemotherapy (median among 308 patients, 8.1 months) (hazard ratio for progression or death with zanidatamab-tislelizumab-chemotherapy, 0.63 [95% confidence interval {CI}, 0.51 to 0.78]; hazard ratio with zanidatamab-chemotherapy, 0.65 [95% CI, 0.52 to 0.81]; P<0.001 for both comparisons). Overall survival was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab-chemotherapy (median, 26.4 vs. 19.2 months; hazard ratio for death, 0.72; 95% CI, 0.57 to 0.90; P = 0.004). At this interim analysis, overall survival did not differ significantly between zanidatamab-chemotherapy (median, 24.4 months) and trastuzumab-chemotherapy (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P = 0.06). The incidence of grade 3 or higher adverse events was 83.3% with zanidatamab-tislelizumab-chemotherapy, 73.8% with zanidatamab-chemotherapy, and 74.5% with trastuzumab-chemotherapy; diarrhea was the most common such event, in 24.8%, 20.0%, and 12.9% of patients, respectively. CONCLUSIONS: Zanidatamab plus chemotherapy, both with and without tislelizumab, led to longer progression-free survival than trastuzumab plus chemotherapy among patients with HER2-positive advanced gastroesophageal adenocarcinoma. At this interim analysis, overall survival was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab-chemotherapy; further analyses are planned to assess zanidatamab-chemotherapy. Diarrhea was a common adverse event. (Funded by Jazz Pharmaceuticals and others; HERIZON-GEA-01 ClinicalTrials.gov number, NCT05152147.).
29 May 2026
Read appraisal →Neurology
Efficacy of Levetiracetam in Patients With Pediatric Epilepsy: A Systematic Review and Meta-Analysis
BACKGROUND AND OBJECTIVES: Levetiracetam (LEV) is widely used in pediatric epilepsies because of its favorable pharmacokinetics, ease of administration, and perceived tolerability. However, its comparative efficacy relative to established antiseizure medications (ASMs) in children remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate LEV efficacy in pediatric epilepsies and compare outcomes vs placebo and active comparators. METHODS: We systematically searched PubMed/MEDLINE and Embase (2000-6 August 2025) for RCTs enrolling patients 16 years or younger with epilepsy and reporting seizure freedom and/or ≥50% responder rate. Trials including both pediatric and adult patients were eligible if pediatric participants were represented. Comparisons included LEV vs placebo or active ASMs as monotherapy or adjunctive therapy. Primary outcomes were seizure freedom and responder rate at the trial's primary endpoint or, if not specified, longest reported follow-up. We assessed risk of bias using Cochrane Risk of Bias 2. We pooled risk differences (RDs) with 95% CIs using random-effects models, stratified by comparator and epilepsy subtype. RESULTS: We included 25 RCTs (4,070 participants): 23 contributed to pooled meta-analyses. Across 25 trials, the mean age ranged from 0.4 to 39.3 years, reflecting pediatric-only and mixed-age RCTs; 43.8% were female. In placebo/no-therapy-controlled trials (mainly add-on studies), LEV was associated with higher seizure freedom (RD 11.0%; 95% CI 5.3%-16.7%) and responder rates (RD 24.3%; 95% CI 19.1%-29.4%). In active-comparator-controlled trials (mainly monotherapy head-to-head studies), LEV showed no overall advantage vs active comparators for seizure freedom (RD -2.4%; 95% CI -5.6% to 0.7%) or responder rate (RD -7.4%; 95% CI -23.0% to 8.1%). Fourteen trials were at high risk of bias. Sensitivity analyses confirmed benefit vs placebo but showed significant disadvantage vs active comparators in low risk-of-bias trials. Findings in pediatric-only trials (16 RCTs; 1,380 participants) were consistent with the overall results. DISCUSSION: LEV confers benefit vs placebo, mostly as adjunctive therapy, but does not consistently outperform established ASMs in pediatric epilepsies and may be inferior in some subgroups when higher-quality evidence is considered. Limitations include substantial heterogeneity, frequent high risk of bias, variable follow-up durations, publication bias, and limited pediatric-only comparative data.
28 May 2026
Read appraisal →Blood advances
Refining busulfan exposure enhances pediatric ALL HSCT outcomes: insights from the International FORUM study
The optimal busulfan exposure window in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) remains to be defined. We identify this window for patients receiving busulfan within the prospective international, randomized controlled phase 3 ALLSCTped 2012 FORUM trial. We included 145 participants receiving fludarabine-busulfan-thiotepa conditioning, with available busulfan plasma levels. Busulfan exposure was estimated using a validated pediatric population pharmacokinetic model. Primary outcomes were event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS). Patients were aged between 0.5 and 19.5 years, with a median follow-up of 5.0 years. The optimal busulfan exposure was defined as area under busulfan concentration curve (cAUC) of 73.3 to 98.0 mg.h/L based on EFS and GRFS. Patients with nonoptimal exposure had lower EFS (hazard ratio [HR], 1.93; p = 0.008) and GRFS (HR, 2.01; p = 0.002). Underexposure (cAUC <73.3 mg.h/L) was associated with higher relapse rates (HR, 1.93; p = 0.019), and overexposure (cAUC >98.0 mg.h/L) with an increased risk of treatment-related toxicities and graft-versus-host disease. Patients with optimal busulfan exposure showed no differences in EFS, GRFS, overall survival, or relapse with post hoc matched total-body irradiation (TBI) recipients (n = 51 in each group). This study identifies a favorable busulfan exposure window for pediatric patients with ALL undergoing HSCT from an HLA-matched donor. Therapeutic drug monitoring for optimized personalized busulfan dosing improves HSCT outcomes and might be validated for use as an alternative to irradiation. This trial was registered at EudraCT as 2012-003032-22 and on www.ClinicalTrials.gov as NCT01949129.
28 May 2026
Read appraisal →BMC nephrology
Roxadustat for CKD-related anemia in patients undergoing peritoneal dialysis: a systematic review and meta-analysis
BACKGROUND: CKD-related anemia remains a major complication in patients receiving peritoneal dialysis (PD), with limited treatment options beyond erythropoiesis-stimulating agents. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, has shown promise in correcting CKD-related anemia and modulating iron and metabolic parameters. However, its evidence in PD remains limited. METHODS: We conducted a systematic search of PubMed, Scopus, and Web of Science from inception to July 20, 2025. We included studies reporting the efficacy and safety of roxadustat in PD. Statistical analysis was performed using Review Manager (RevMan 5.4 for Windows) and R Studio. RESULTS: Eight studies were included in the meta-analysis (n = 607). Roxadustat significantly increased hemoglobin at all time points (MD 0.35 g/dL, 95% CI 0.28-0.41; p < 0.00001), serum iron (MD 0.95 µmol/L, 95% CI 0.02-1.89; p = 0.05), and total iron-binding capacity (MD 6.25 µmol/L, 95% CI 3.95-8.55; p < 0.00001), and reduced hepcidin (MD - 12.28 ng/mL, 95% CI - 21.06 to - 3.50; p = 0.006). No significant effects were observed for ferritin (p = 0.49), transferrin saturation (p = 0.45), cholesterol (p = 0.07), LDL (p = 0.14), HDL (p = 0.27), triglycerides (p = 0.26), CRP (p = 0.75), systolic blood pressure (p = 0.10), or diastolic blood pressure (p = 0.08). Heterogeneity was low to moderate for most outcomes. CONCLUSION: Roxadustat is effective in improving hemoglobin and iron metabolism in patients with PD, while exerting neutral effects on lipids, inflammation, and blood pressure. These findings support its role as a promising therapy for CKD-related anemia in PD. CLINICAL TRIAL NUMBER: Not applicable.
28 May 2026
Read appraisal →European journal of clinical pharmacology
Efficacy and safety of Ongericimab in patients with hypercholesterolemia: a systematic review and meta-analysis
BACKGROUND: Hypercholesterolemia represents abnormally elevated cholesterol levels and constitutes a major modifiable risk factor for cardiovascular diseases (CVDs). Low-density lipoprotein cholesterol (LDL-C) reduction remains the primary therapeutic target. However, many high-risk patients fail to achieve recommended LDL-C targets with conventional lipid-lowering therapies. Ongericimab is a new humanized recombinant monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). We aimed to evaluate the efficacy and safety of Ongericimab compared to placebo in patients with hypercholesterolemia. METHODS: Following PRISMA guidelines, we searched PubMed, Scopus, Cochrane Library, Web of Science and Google Scholar through February 2025 for randomized controlled trials (RCTs) comparing Ongericimab versus placebo. Outcomes were pooled as mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CIs) using random-effects models. RESULTS: Five RCTs comprising 1421 patients were included. Ongericimab significantly reduced LDL-C across all dosing regimens: 150 mg every 2 weeks (MD -69.48%, 95% CI: -73.02 to -65.94), 300 mg every 4 weeks (MD -61.82%, 95% CI: -66.66 to -56.98), and 450 mg every 4 weeks (MD -73.11%, 95% CI: -89.56 to -56.65); all p < 0.00001. Significant reductions were also observed in lipoprotein(a) (MD range: -44.81% to -50.06%), apolipoprotein B, non-HDL cholesterol, triglycerides, and total cholesterol, along with significant increases in HDL cholesterol and apolipoprotein A1. Adverse event rates were comparable between groups, with a pooled reduction OR of 0.85 (95% CI: 0.73-0.99) for overall treatment-emergent adverse events, favoring Ongericimab. CONCLUSION: This meta-analysis demonstrates that Ongericimab is effective and safe for improving lipid parameters in patients with hypercholesterolemia and dyslipidemia. These findings support Ongericimab as a valuable therapeutic option for patients requiring additional LDL-C reduction beyond conventional therapy. Further long-term studies are recommended to confirm cardiovascular outcomes.
28 May 2026
Read appraisal →Journal of chemical information and modeling
Integrating QSAR-Machine Learning, Biochemical Assays, and Molecular Dynamics for the Discovery of JAK2 Inhibitors in Cervical Cancer
Cervical cancer remains a major global health challenge, where dysregulated JAK2 signaling constitutes a key molecular driver. Nevertheless, selective small-molecule JAK2 inhibitors for HPV-positive cervical cancer are still limited. Here, we integrated biochemical assays, QSAR-machine learning, and molecular dynamics simulations to identify potent JAK2 inhibitors. A series of naphthalene-based derivatives, including hydroxynaphthalenamide and phosphorylated dihydronaphthylamide analogs, were evaluated for cytotoxicity in HeLa cells and JAK2 kinase inhibition. Several compounds exhibited selective cytotoxicity with minimal activity toward normal fibroblasts, among which 2q and 2s showed low-nanomolar JAK2 inhibition and strong apoptosis induction through suppression of the JAK2/STAT3/STAT5 pro-tumorigenic signaling pathway. To accelerate hit identification, a QSAR-machine learning (QSAR-ML) framework was employed to prioritize 13 newly designed derivatives. Among three ensemble boosting models, the Categorical Boosting (CB) model demonstrated the strongest predictive capability, achieving a high R2 of 0.955 for the training set and a low RMSE of 0.156 for the test set. This model successfully identified five active candidates with strong prediction-experiment agreement (MAPE = 2.6-14.4%), with D4 and D13 meeting drug-likeness criteria and displaying potent nanomolar JAK2 inhibition. Finally, 1-μs molecular dynamics simulations revealed that hydrophobic contacts and hydrogen bonding cooperatively stabilize these inhibitors within the JAK2 ATP-binding pocket. Collectively, these findings establish a QSAR-ML-guided strategy for accelerating JAK2 inhibitor discovery and highlight naphthalene-based scaffolds as promising leads for targeted cervical cancer therapy.
27 May 2026
Read appraisal →ChemMedChem
A 24-Day MicroCycle Journey to Interleukin-17 Inhibitors: From Library Design to Central Core Prioritization and Capping Group Identification
We herein report an application of the MicroCycle platform, which leverages advanced machine learning models, automation, and miniaturization of processes to accelerate the exploration of chemical space through libraries. This approach was applied to a novel thiazole-based series targeting interleukin-17, enabling rapid prioritization of central cores and identification of compelling new capping groups, thereby guiding further optimization efforts.
27 May 2026
Read appraisal →The Cochrane database of systematic reviews
Steroid avoidance or withdrawal for kidney transplant recipients.
RATIONALE: Steroid-sparing strategies aim to reduce the adverse effects associated with steroid use. The main concern has been a potential increase in the risk of rejection, as reported in previous systematic reviews. In recent years, improvements in immunosuppressive regimens and a significant decline in the incidence of acute rejection have renewed interest in steroid-sparing strategies. More contemporary trials suggest that reducing steroid exposure might be safe. This is an updated review, previously published in 2009 and 2016. OBJECTIVES: To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register, CENTRAL, MEDLINE, Embase and two trials registers up to 29 April 2025. ELIGIBILITY CRITERIA: All randomised and quasi-randomised controlled trials that evaluated steroid avoidance or withdrawal after kidney transplantation. OUTCOMES: Critical outcomes were all-cause death, graft loss and biopsy-proven acute rejection. Important outcomes were post-transplant diabetes mellitus, cardiovascular events, infection, malignancy, and kidney function measures. RISK OF BIAS: Risk of bias was assessed with the Cochrane RoB 1 tool. SYNTHESIS METHODS: Assessment of risk of bias and data extraction were performed independently by at least two authors, and disagreements were resolved through discussion. Statistical analyses were performed using the random-effects model, and dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs) with 95% confidence intervals (CIs). The certainty of the evidence was assessed using the GRADE approach. INCLUDED STUDIES: This updated review includes 53 studies (261 reports, 8317 randomised kidney transplant recipients). Of these, three studies were conducted in children (204 randomised participants). SYNTHESIS OF RESULTS: The overall certainty of the evidence of the included studies was low, ranging from moderate to very low. Factors downgraded on GRADE were primarily risk of bias and imprecision. Over 50% of the included studies did not adequately report random sequence generation or allocation concealment. Only five of 53 studies blinded participants and investigators. Incomplete outcome data was judged to be low in 26 studies, and 41 were free of selective reporting. Studies in adult kidney transplant recipients Steroid avoidance versus steroid maintenance The evidence is very uncertain about the effect of steroid avoidance on all-cause death up to one year (RR 0.84, 95% CI 0.51 to 1.39; 13 studies, 2126 participants; very-low-certainty evidence). Steroid avoidance may reduce death by one to five years (RR 0.61, 95% CI 0.39 to 0.96; 9 studies, 1607 participants; low-certainty evidence), and has little to no effect on graft loss censored for death up to one year (RR 0.95, 95% CI 0.62 to 1.46; moderate-certainty evidence). Steroid avoidance may increase the risk of biopsy-proven acute rejection up to one year (RR 1.58, 95% CI 1.11 to 2.25; 10 studies, 1845 participants; low-certainty evidence), although subgroup analysis showed no increase in risk when steroid avoidance was used in combination with tacrolimus, an antimetabolite and induction therapy. Steroid avoidance may reduce the risk of post-transplant diabetes mellitus up to five years (RR 0.70, 95% CI 0.59 to 0.84; 13 studies, 2390 participants; low-certainty evidence), but may have little to no effect on cardiovascular events (RR 0.73, 95% CI 0.46 to 1.18; 6 studies, 1417 participants; low-certainty evidence), infection (all) (RR 0.96, 95% CI 0.87 to 1.05; 11 studies, 2426 participants; low-certainty evidence), and probably has little to no effect on cytomegalovirus (CMV) infection (RR 1.01, 95% CI 0.80 to 1.27; 9 studies, 2155 participants; moderate-certainty evidence). Steroid withdrawal versus steroid maintenance Compared to steroid maintenance, steroid withdrawal may have little to no effect on all-cause death up to one year (RR 0.69, 95% CI 0.35 to 1.37; 9 studies, 1884 participants; low-certainty evidence) or one to five years (RR 1.17, 95% CI 0.67 to 2.03; 8 studies, 1189 participants; low-certainty evidence), and probably has little to no effect on graft loss censored for death up to one year (RR 1.19, 95% CI 0.72 to 1.96; 8 studies, 1854 participants; moderate-certainty evidence). Steroid withdrawal may have little to no effect on biopsy-proven acute rejection up to one year (RR 1.41, 95% CI 0.89 to 2.23; 5 studies, 1406 participants; low-certainty evidence). Steroid withdrawal probably has little to no effect on post-transplant diabetes mellitus up to five years (RR 0.82, 95% CI 0.55 to 1.21; 8 studies, 1647 participants; moderate-certainty evidence), and may have little to no effect on cardiovascular events up to five years (RR 0.91, 95% CI 0.42 to 1.97; 3 studies, 712 participants; low-certainty evidence) or infection (all) up to five years (RR 1.06, 95% CI 0.83 to 1.36; 6 studies, 1924 participants; low-certainty evidence). Steroid withdrawal probably has little to no effect on CMV infection up to five years (RR 1.10, 95% CI 0.85 to 1.43; 7 studies, 1956 participants; moderate-certainty evidence). Steroid avoidance versus steroid withdrawal The evidence is very uncertain regarding the effects of steroid avoidance compared with steroid withdrawal (4 studies, 466 randomised participants). Studies in paediatric kidney transplant recipients The evidence is very uncertain regarding the effects of steroid-sparing regimens in paediatric kidney transplant recipients (3 studies, 204 randomised participants). AUTHORS' CONCLUSIONS: There was no evidence to suggest a difference in patient death or graft loss up to one year after transplantation with steroid avoidance or withdrawal compared to maintenance, but steroid avoidance may reduce patient death at five years in adult kidney transplant recipients. Steroid avoidance may increase the risk of biopsy-proven acute rejection, but the risk may be similar when steroid avoidance is paired with tacrolimus, antimetabolite and induction therapy. The risk of biopsy-proven acute rejection in steroid withdrawal regimens may be similar to steroid maintenance regimens. We found no evidence to suggest differences in cardiovascular events or infection, but steroid avoidance compared to steroid maintenance may reduce the risk of post-transplant diabetes mellitus. FUNDING: LO is supported by a Río Hortega predoctoral fellowship from the Instituto de Salud Carlos III. REGISTRATION: Protocol and previous versions available via https://doi.org/10.1002/14651858.CD005632, https://doi.org/10.1002/14651858.CD005632.pub2, and https://doi.org/10.1002/14651858.CD005632.pub3.
27 May 2026
Read appraisal →Clinical and experimental dermatology
An open-label phase II study of bitopertin in adults and adolescents with erythropoietic protoporphyria or X-linked protoporphyria
BACKGROUND: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare genetic disorders characterized by accumulation of protoporphyrin IX (PPIX), painful phototoxic reactions and hepatobiliary disease. No disease-modifying therapies are approved for these conditions. OBJECTIVES: To evaluate the safety and efficacy of bitopertin in adults and adolescents with EPP or XLP. METHODS: BEACON (ACTRN12622000799752) was a phase II, randomized, open-label, parallel-arm study in adult and adolescent participants with EPP or XLP. Participants received an oral, once-daily administration of bitopertin 20 mg or 60 mg for 24 weeks. RESULTS: Twenty-six participants were randomized to 20 mg (n = 14) or 60 mg (n = 12) of bitopertin. The study met its primary efficacy endpoint. Treatment with bitopertin resulted in significant, dose-dependent reductions in PPIX levels compared with baseline at both the 20-mg and 60-mg dose levels (mean -31.7%, SE 7.0; P < 0.001 vs. baseline and mean -57.7%, SE 7.4; P < 0.001 vs. baseline, respectively). Similar efficacy was observed across the adult and adolescent populations. No serious adverse events were reported. Dizziness was the most common adverse event reported with bitopertin, in 9 (64%) and 8 (67%) participants completing the study in the 20-mg and 60-mg dose groups, respectively. CONCLUSIONS: By reducing whole-blood PPIX levels, bitopertin targets the underlying pathophysiology of EPP, resulting in consistent improvements in multiple measures of light tolerance and quality of life. Bitopertin was well tolerated, and most adverse events were mild or moderate in severity.
27 May 2026
Read appraisal →Clinical and experimental dermatology
Novel and existing therapeutic interventions in psychogenic pruritus.
Psychogenic pruritus (PP) is a chronic itch disorder associated with psychological conditions lacking any dermatological or systemic cause. Diagnosis relies on excluding other aetiologies and identifying psychological stressors. Treatments include dermatological and psychiatric interventions such as topical steroids, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antihistamines, antipsychotics and psychotherapy. However, efficacy remains inconsistent, necessitating a systematic review of current and emerging pharmacological options. This study reviews pharmacological treatments for PP published in the past decade, evaluating efficacy and therapeutic potential. A systematic literature search was conducted using PubMed, Embase and Google Scholar (November 2014 to November 2024) following the PRISMA guidelines (PROSPERO: 1000201). In total, 1034 articles were screened by two independent reviewers. Inclusion criteria focused on human studies evaluating pharmacological treatments for PP. Seven studies met the inclusion criteria. Levels of evidence were assessed using the Joanna Briggs Institute critical appraisal checklist. SSRIs, particularly escitalopram, showed symptom improvement in case reports. Naltrexone (an opioid antagonist) led to complete itch resolution in a patient refractory to SSRIs. Gabapentin reduced pruritus severity. A neurokinin-1 receptor (NK-1R) antagonist (serlopitant) demonstrated significant efficacy in a phase II trial. Biologics such as dupilumab showed promise in chronic pruritus. Targeted therapies, including SSRIs, naltrexone, opioid pathway modulators, NK-1R antagonists and biologics, show promise in the clinical management of PP, but further research through randomized controlled trials is necessary to establish their efficacy and optimize treatment strategies.
27 May 2026
Read appraisal →Clinical and experimental dermatology
Topical statins in the treatment of porokeratosis: a systematic review
Porokeratosis is a chronic disorder of keratinization associated with significant morbidity and no spontaneous resolution. Currently, there are no therapies approved by the US Food and Drug Administration (FDA). However, the off-label use of topical statins - targeting the mevalonate pathway - has shown promise as a novel therapeutic strategy. This systematic review aims to evaluate the efficacy and safety of topical statins in the treatment of porokeratosis. We conducted a systematic review of the PubMed, Semantic Scholar and Cochrane databases from 1 January 2015 to 15 February 2025, identifying clinical studies evaluating topical statin therapy (atorvastatin, fluvastatin, lovastatin, rosuvastatin or simvastatin) in patients with any subtype of porokeratosis. Twenty-four studies encompassing 95 patients met the inclusion criteria. Most publications (88%) were case reports. The majority of patients (79%) received compounded topical lovastatin 2% or simvastatin 2%, typically in combination with cholesterol 2%. Clinical improvement - defined as partial resolution of symptoms or reduction in lesion size - was observed in 92% of patients (87 of 95), with onset of response reported as early as 4 weeks. Adverse events were reported in 15% of patients, primarily mild, localized dermatological reactions. Two patients discontinued treatment due to side effects. Topical statins appear to provide preliminary evidence of some clinical benefits in porokeratosis by inhibiting the mevalonate pathway, supporting a promising and plausible mechanism-based approach. However, the use of off-label compounded formulations introduces variability in efficacy and safety due to lack of quality control. The absence of FDA-approved therapies for porokeratosis represents an ongoing unmet therapeutic need warranting further investigation in prospective, controlled studies. Together, these preliminary case reports indicating clinical benefit encourage the development of an FDA-approved, Good Manufacturing Practice-quality topical statin formulation that is carefully evaluated in rigorous, well-designed clinical trials that demonstrate safety and substantial evidence of effectiveness.
27 May 2026
Read appraisal →Journal of computer-aided molecular design
ADMET-vault: an interactive framework for real-time ADMET prediction and molecular optimization
Drug discovery pipelines face persistent challenges, as candidates that show promising results in early laboratory studies are found ineffective in clinical trials-often because their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles were not well understood early enough. In this study, an interactive machine-learning based platform, ADMET-Vault, is presented, which brings ADMET prediction directly into the molecular design process, allowing researchers to assess and optimize drug candidates during the molecule design phase itself. ADMET-Vault integrates multiple molecular representations including physicochemical descriptors, molecular fingerprints, and graph neural network embeddings. The platform evaluated 12 benchmark datasets from Therapeutics Data Commons using scaffold-based validation. ADMET-Vault demonstrated consistent predictive performance across multiple ADMET endpoints. Strong results were observed for clearance related properties, intestinal absorption, hepatotoxicity, and aqueous solubility. Moreover, regression showed mean absolute error value that ranged from 0.28 (Caco-2 permeability, expressed as log cm/s) to 7.68 (plasma protein binding rate, expressed as % bound), with Spearman's rank correlation coefficients between 0.44 and 0.66. Classification tasks showed area under the receiver operating characteristic curve values ranged between 0.87 and 0.99. ADMET-Vault's main contribution is not just in its predictive accuracy. It combines reliable machine learning models with a live molecular editor. This allows researchers to see how a structural change impacts drug-like properties instantly. This interactive design-predict-optimize loop fills a long-standing gap in early-stage drug discovery workflows.
27 May 2026
Read appraisal →Blood advances
Phase 1b study of ABBV-744, a novel, selective BET inhibitor, as monotherapy for patients with myelofibrosis
Janus kinase inhibitors (JAKi) are standard of care for patients with myelofibrosis (MF) but can be associated with treatment-limiting cytopenias and do not modify underlying disease. Novel treatments targeting other clinically relevant pathways are needed. Inhibitors of bromodomain (BD) and extraterminal domain (BET) proteins are a promising class of drugs that have demonstrated the ability to modulate key pathways involved in inflammation, fibrosis, and apoptosis. ABBV-744 is a novel small molecule that targets the BDII of BET proteins and has previously been shown to be well tolerated when administered daily at doses of 120 and 180 mg to patients with acute myeloid leukemia. We report the outcomes of a multicenter, open-label phase 1b study of ABBV-744 in patients with MF who received ≥1 previous lines of therapy, including a JAKi. The primary objective was safety, including dose-limiting toxicities (DLTs). Secondary end points included a reduction in spleen volume of ≥35% (SVR35), ≥50% reduction in total symptom score (TSS50), objective response rate, and pharmacokinetics. All 21 patients experienced at least 1 treatment-emergent adverse event, and 11 patients experienced a DLT. The most common events leading to DLTs were thrombocytopenia (33%) and anemia (24%). SVR35 was attained in 24% of patients at week 12 and 33% at week 24. TSS50 was reported for 29% of patients at 12 weeks and 19% at week 24. These outcomes are noteworthy in this heavily pretreated population considering the advanced disease state and limited treatment options for this patient population. This trial was registered at www.clinicaltrials.gov as NCT04454658.
27 May 2026
Read appraisal →Zeitschrift fur Naturforschung. C, Journal of biosciences
Exploring the potency of 6-bromo-3-methylquinoline analogues as prostaglandin F2α inhibitors
Prostaglandin F2α (PGF2α) is associated with preterm labor and preterm birth. PGF2α inhibitors have thus proven to be a promising target in the development of lead compounds to prevent preterm birth. In this work, Quantitative Structural Activity Relationship (QSAR) was implemented on a dataset of 77 compounds of 6-bromo-3-methylquinoline analogues using statistical approach and random selection in the QSARINS software. The Genetic Algorithm-Multiple Linear Regression (GA-MLR) approach was used to predict the best model (R 2 = 0.8943 and Q 2 LOO = 0.8836). The inclusion of descriptors FNSA-2 and WV.mass resulted in a well-fitted and highly predictable model. Artificial neural network (ANN) analysis was also carried out to validate the model effectiveness. Twenty eight new molecules with better predicted biological activity (pIC50) were designed. The binding energy from the docking study of seven compounds have shown higher binding activity than P10 into prostaglandin F synthase protein (PDB ID: 2F38). The stability of protein-ligand complex was further validated by 100 ns molecular dynamics simulation and MM-PBSA binding free energy. DFT and ADME-toxicity analysis also confirmed their drug-likeness properties. Collectively, our findings highlight novel quinoline derivatives as promising lead candidates, warranting further validation through collaborative in vitro and in vivo studies.
27 May 2026
Read appraisal →Journal of perinatal medicine
Oral adjuvants supplemented to phototherapy as a therapeutic strategy for neonatal hyperbilirubinemia: a systematic review
INTRODUCTION: Neonatal jaundice is a common condition characterized by elevated serum bilirubin levels. Although usually benign, inadequate management may result in severe complications such as bilirubin encephalopathy and kernicterus. Phototherapy is the standard treatment; however, concerns regarding potential short- and long-term adverse effects have motivated the investigation of oral adjuvants as complementary therapies to accelerate bilirubin clearance and reduce phototherapy exposure. CONTENT: This systematic review followed PRISMA guidelines and was registered in PROSPERO (CRD420251071886). Randomized controlled trials published between 2010 and 2025 were included, evaluating full-term neonates (35-42 weeks, 2-4 kg) without Rh incompatibility. Searches were conducted in PubMed, Cochrane Central, Embase, and Web of Science. Of 193 identified records, 18 RCTs met eligibility criteria. The oral adjuvants assessed included probiotics, phenobarbital, ursodeoxycholic acid (UDCA), oral calcium, zinc sulfate, fenofibrate, and clofibrate. Lactobacillus reuteri demonstrated greater 24-hour reductions in total serum bilirubin (TSB) compared to controls, whereas Bifidobacterium strains primarily reduced phototherapy duration. Phenobarbital did not outperform phototherapy alone and was associated with longer hospitalization. UDCA showed substantial bilirubin reductions, although findings were heterogeneous. Zinc supplementation did not demonstrate consistent significant benefit. Fenofibrate produced statistically significant decreases in TSB across trials and showed the most consistent efficacy. Clofibrate also reduced bilirubin levels but with methodological variability and limited comparative data. SUMMARY: Oral adjuvants combined with phototherapy may enhance bilirubin reduction in term neonates, particularly fenofibrate. OUTLOOK: However, heterogeneity and potential bias limit definitive conclusions, emphasizing the need for large, multicenter randomized trials.
27 May 2026
Read appraisal →Journal of computer-aided molecular design
In silico discovery of novel small-molecule PD-L1 inhibitors through a multi-stage computational workflow integrating machine learning and molecular dynamics
Cancer immunotherapy targeting the PD-1/PD-L1 pathway has transformed modern oncology; however, developing small-molecule inhibitors as viable alternatives to monoclonal antibodies remains a major challenge. In this study, an integrated computational framework is established in which machine learning, molecular docking, molecular dynamics simulations, and binding free-energy calculations are combined to enable the discovery and optimization of novel PD-L1 inhibitors. A validated ML-QSAR model was constructed using the XGBoost algorithm (R2_train = 0.925, R2_test = 0.743) on a dataset of 74 known inhibitors with consistent assay conditions. Through virtual screening of FDA-approved drugs, Pralatrexate was subsequently identified as a promising repurposing candidate, demonstrating a higher predicted binding affinity than the reference inhibitors. Structure-based modification of Pralatrexate yielded the derivative D1, which exhibited improved computational binding properties across all evaluation methods. Molecular dynamics simulations indicated that the D1-PD-L1 complex achieved greater stability than both the free protein and the reference complex, with reduced RMSD fluctuations and preserved key interactions with tyrosine residues Tyr56(A/B). MM-GBSA calculations further confirmed D1's superior binding affinity (-86.21 kcal/mol vs. - 73.65 kcal/mol for the reference), and predicted IC50 values suggested enhanced inhibitory potential. This multi-stage computational workflow effectively integrates machine learning predictions with atomic-level binding analyses, providing a robust platform for accelerated drug discovery. The optimized derivative D1 thus represents a promising candidate for experimental validation and further development as a potential cancer immunotherapeutic agent.
26 May 2026
Read appraisal →Journal of perinatal medicine
Plant-based antioxidant strategies with potential for preeclampsia prevention: clinical and mechanistic insights
BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality, driven by oxidative stress, endothelial dysfunction, and systemic inflammation. Current preventive strategies, such as low-dose aspirin, offer modest benefit, highlighting the need for alternative approaches. Medicinal plants with antioxidant and anti-inflammatory properties, long used in maternal health traditions, may provide biological pathways relevant to preeclampsia prevention. SUMMARY: This review synthesizes human clinical and mechanistic evidence on four medicinal plants with documented antioxidant activity - Curcuma longa, Moringa oleifera, Orthosiphon aristatus, and Centella asiatica. These botanicals demonstrate potential mechanisms of action including redox modulation, preservation of endothelial function, and suppression of pro-inflammatory pathways, all of which are implicated in preeclampsia pathophysiology. CONTENT: A PRISMA-guided systematic search of PubMed, Scopus, Web of Science, and the Cochrane Library (2000-2025) identified human studies evaluating these plants' effects on oxidative stress and vascular health. Evidence was synthesized narratively due to heterogeneous study designs and outcomes. Most studies were small, often not pregnancy-specific, and used non-standardized botanical formulations. OUTLOOK: These medicinal plants offer biologically plausible pathways to reduce preeclampsia risk. However, pregnancy-focused randomized trials, dose optimization, pharmacokinetic profiling, and safety evaluations are essential before clinical integration into maternal care.
26 May 2026
Read appraisal →Blood advances
A phase 1 trial of romidepsin, azacitidine, dexamethasone, and lenalidomide in relapsed or refractory T-cell lymphoma
Targeted therapies can induce responses in patients with relapsed/refractory T-cell lymphoma (R/R TCL) but are not curative. Genetic mutations associated with epigenetic and transcriptional dysregulation are common in many TCL subtypes, and drugs that modulate the epigenome and that target transcriptional regulators have synergistic activity in TCL. We hypothesized that fixed duration treatment with multiagent combinations of these drugs could produce deep responses leading to durable remissions. In a phase 1 trial, we tested escalating doses of lenalidomide added to romidepsin, azacitidine, and dexamethasone (RAdR) for patients with R/R TCL. The primary objective was to identify the maximum tolerated dose (MTD) of lenalidomide that could safely be used in RAdR. Secondary end points included response rate, survival, and markers of immune activation. Twenty-six patients enrolled and 21 were evaluable for response. Adverse events were predominantly gastrointestinal and hematologic. Grade 3/4 thrombocytopenia and neutropenia occurred in 19% and 21% of cycles, respectively. The MTD of lenalidomide was 20 mg. Among 9 patients treated at the MTD the objective response rate was 89% and complete response rate 22%. At 1 year, the estimated rate of progression-free survival was 14% and overall survival was 66%. Cell line models of anaplastic large cell lymphoma were interrogated to explore the activity of drug combinations in responding genetic subtypes. RAdR demonstrated activity in patients with highly refractory TCL but did not induce durable responses. This novel combination effectively bridged some patients with refractory TCL to consolidation such as allogeneic transplantation. This trial was registered at www.ClinicalTrials.gov as NCT04447027.
26 May 2026
Read appraisal →Blood advances
Selinexor plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis: a multicenter, open-label, phase 1 study
The phase 1 portion of SENTRY/XPORT-MF-034 (NCT04562389) evaluated the exportin 1 inhibitor selinexor (40 mg/60 mg once weekly) plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (n = 24). Primary end points were maximum tolerated selinexor dose, recommended clinical trial dose, and safety. No dose-limiting toxicities were reported. Common adverse events were nausea, fatigue, anemia, thrombocytopenia, constipation, vomiting, and headache. Nausea was transient, mainly grade 1, and managed by prophylactic antiemetics. Four deaths occurred, all unrelated to study treatment. Selinexor 60 mg in combination with ruxolitinib was identified as the recommended phase 3 dose based on safety, efficacy, and exposure-response analyses. Overall safety profiles and grades of clinically significant adverse events were similar and generally manageable regardless of selinexor dose. A greater proportion of patients achieved spleen volume reduction of ≥35% (SVR35) and total symptom score reduction of ≥50% (TSS50) at week 24 in the selinexor 60-mg group (79% and 58%) than the 40-mg group (38% and 25%). Among evaluable patients who received suboptimal ruxolitinib ≤5 mg twice daily in the selinexor 60-mg group, SVR35 was observed in 100% (6/6) and TSS50 in 75% (3/4) of patients. The trial was registered at ClinicalTrials.gov as NCT04562389.
26 May 2026
Read appraisal →Blood advances
Phase 2 study of the lysine-specific demethylase 1 inhibitor bomedemstat for essential thrombocythemia
Novel treatments that can improve outcomes of essential thrombocythemia (ET) are needed. In a phase 2 trial, participants with ET who required cytoreduction and had inadequate response to, or were intolerant of, ≥1 standard therapy received bomedemstat at a starting dose of 0.6 mg/kg per day, titrated to achieve a target platelet count (200 × 109/L to 400 × 109/L). Primary end points were safety and response, defined as a platelet count of ≤400 × 109/L without new thromboembolic events. Of 73 who received bomedemstat, at 24 weeks, 49 of 64 evaluable participants (77%) achieved a response. Durable reductions in platelet count (≤400 × 109/L for ≥12 weeks) were observed in 52 of 72 participants (72%). Durable reduction in white blood cell count (<10 × 109/L for ≥12 weeks) was observed in 61 of 72 participants (85%); of 10 participants with elevated white blood cell count at baseline, 9 had normal white blood cell count (<10 × 109/L) at week 24. Hemoglobin levels remained stable. After 24 weeks of treatment, a decrease in variant allele frequency of CALR, JAK2, or MPL was observed in 39 of 46 (85%) evaluable participants. By week 24, 2 of 73 participants (3%) had experienced ≥1 thrombotic event, and 15 of 73 (21%) experienced ≥1 hemorrhagic event. During overall treatment period, grade 3 or 4 adverse events (AEs) occurred in 34 of 73 participants (47%). AEs led to temporary treatment interruption in 29 participants (40%) and permanent discontinuation in 11 (15%). No participants died due to AEs. Bomedemstat had clinically relevant activity and manageable safety in participants with ET. This trial was registered at www.clinicaltrials.gov as #NCT04254978.
26 May 2026
Read appraisal →European journal of pediatrics
Safety and efficacy of liposomal iron for iron deficiency anemia in pediatric population: A systematic review and meta-analysis of randomized controlled trials
Iron deficiency anemia (IDA) remains a public health problem in children. Conventional iron therapy is effective but often causes gastrointestinal adverse effects that reduce adherence. Liposomal iron has been developed to enhance absorption and improve tolerability. This systematic review and meta-analysis evaluated the efficacy and safety of liposomal iron compared with conventional iron formulations in pediatric patients with IDA. We searched PubMed, Scopus, Web of Science, and the Cochrane Library up to February 21, 2026 for randomized controlled trials (RCTs) comparing liposomal iron with conventional oral iron in children with IDA. Analyses were performed using R software with the meta package. Continuous outcomes were pooled as mean differences (MDs) and dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) using a random-effects model. Subgroup analyses according to follow-up duration. Four RCTs involving 454 children were included. At 6 months, liposomal iron produced a significantly greater increase in hemoglobin compared with conventional iron (MD 0.96 g/dL, 95% CI 0.09-1.82; P = 0.03), although heterogeneity was substantial (I2 = 92.9%). No significant differences were observed at earlier time points. Liposomal iron significantly reduced total iron-binding capacity (MD - 35.52 μg/dL; P < 0.0001) and increased mean corpuscular hemoglobin (MD 1.83 pg; P < 0.0001). Liposomal iron was associated with fewer adverse events (RR 0.29; P = 0.02) and lower risk of constipation (RR 0.56; P = 0.02).Conclusion: Liposomal iron offered better tolerability and was non-inferior to conventional iron for most hematologic outcomes. Evidence remains preliminary and larger RCTs are needed to confirm its efficacy in pediatric IDA.
26 May 2026
Read appraisal →European journal of clinical pharmacology
Ondansetron augmentation for obsessive-compulsive disorder: A systematic review and meta-analysis of randomized placebo-controlled trials
BACKGROUND: A substantial proportion of adults with obsessive-compulsive disorder (OCD) experience persistent symptoms despite optimized first-line treatment with exposure and response prevention and/or serotonin reuptake inhibitors (SRIs). Ondansetron, a selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist with plausible circuit-level relevance to cortico-striato-thalamo-cortical dysfunction, has been evaluated as an augmentation strategy. Still, evidence is dispersed across small randomized trials. METHODS: We conducted a PRISMA 2020-adherent systematic review and random-effects meta-analysis (PROSPERO: CRD420261302132). Embase (Ovid and Embase.com), MEDLINE, PubMed, and Scopus were searched from inception to 12 February 2026. Eligible studies were randomized, double-blind, placebo-controlled trials of oral ondansetron augmentation in adults (≥ 18 years) with OCD on stable background treatment. The primary outcome was change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score, pooled at prespecified acute windows (week 4, ~week 8 primary, week 12). Secondary outcomes included Y-BOCS obsession and compulsion subscales. Risk of bias was assessed using RoB 2. Random-effects models (DerSimonian-Laird) were used; Wan's method was applied when required. RESULTS: Five trials (total N = 289) were included. Ondansetron augmentation was associated with greater improvement in Y-BOCS total score versus placebo at week 4 (MD 2.63; 95% CI 0.87-4.39; I²=62%); heterogeneity resolved after excluding one influential study (MD 1.94; 0.37-3.51; I²=0%). At week 8 (four trials; N = 244), benefit was larger (MD 5.53; 3.45-7.60; I²=48%) and remained robust in sensitivity analysis (MD 6.76; 5.81-7.71; I²=0%). At week 12 (three trials; N = 200), effects persisted (MD 6.41; 4.28-8.53; I²=55%) with reduced heterogeneity after excluding one study (MD 5.06; 2.82-7.30; I²=0%). In two trials reporting subscales (N = 214), obsessions improved at weeks 4 and 8 (overall MD 2.67; 1.66-3.67; I²=0%), while compulsions showed a smaller, later signal (overall MD 1.02; 0.19-1.86; I²=0%). Safety reporting was variably detailed across trials; known QT-prolongation considerations remain relevant for off-label use. CONCLUSIONS: In randomized, placebo-controlled trials, ondansetron augmentation was associated with greater improvement in clinician-rated OCD severity than placebo over short-term follow-up, with signals emerging by week 4 and persisting through 8-12 weeks. However, these findings should be interpreted cautiously because the evidence base is small, geographically concentrated, and partly influenced by individual studies. The current evidence should therefore be considered preliminary and hypothesis-generating rather than definitive. Larger multicenter trials with standardized background SRI optimization, preregistered outcomes, and rigorous safety monitoring are required before routine clinical adoption can be considered.
25 May 2026
Read appraisal →European journal of clinical pharmacology
Dysesthesia associated with GLP-1 agonist therapies: data-mining analysis and literature review
PURPOSE: An increasing number of anecdotal reports on social media platforms and medical blogs describe dysesthesia, particularly burning skin sensations, in association with glucagon-like peptide-1 receptor (GLP-1R) agonists. We performed a pharmacovigilance data-mining analysis to characterise cases of dysesthesia related to GLP-1R. METHODS: We conducted a disproportionality analysis using VigiBase data on GLP-1R (Anatomical Therapeutic Chemical classification: ATC code A10BJ) and tirzepatide, focusing on the HLT (High Level Term) "Paraesthesia and dysesthesia", with the Information Component (IC). Additionally, we reviewed all narratives of dysesthesia cases in the French Pharmacovigilance database to extract clinical and pharmacological characteristics. A literature review complemented this analysis. RESULTS: Exenatide was significantly associated with hypoesthesia or oral paraesthesia, semaglutide and tirzepatide with hyperaesthesia, and semaglutide with dysesthesia and burning sensation. Dysesthesia appears to be dose-dependent, occurring more frequently at higher doses and with more potent GLP-1R, whether used for weight management or type 2 diabetes. Discontinuation was often performed, followed by spontaneous favourable outcomes, and cases of rechallenge were observed. Skin burning sensations represent a distinctive form of dysesthesia. CONCLUSION: Pharmacovigilance quantitative and qualitative data strengthens evidence for dysesthesias associated with GLP-1R agonists already observed in clinical trials of semaglutide, tirzepatide, and retatrutide.
25 May 2026
Read appraisal →Journal of gastrointestinal cancer
Optimal First-line Immune-related Therapy Selection for Advanced Gastric Cancer: A Systematic Review and Network Meta-analysis
PURPOSE: Although immune checkpoint inhibitors combined with chemotherapy improve survival in advanced gastric cancer (AGC), comparative evidence across first-line regimens remains insufficient. This study aimed to systematically evaluate their relative efficacy and safety. METHODS: PubMed, Embase, the Cochrane Library, Web of Science, and major conferences were searched up to February 28, 2025. Eligible RCTs comparing ICI-related regimens as first-line AGC treatment were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: Eleven RCTs involving 8,999 patients, six integrated strategies, and twelve specific regimens were included. Dual-target ICI-chemo and single ICI-chemo showed significant survival benefits over chemotherapy, whereas dual ICIs±chemo and single ICI alone did not. Dual-target ICI-chemo was associated with significantly better survival than both dual ICIs±chemo and single ICI±chemo. Among the specific regimens, cadon-chemo achieved the most favorable OS and PFS. No significant OS differences were observed among the single ICI-chemo regimens. In PD-L1-positive subgroups, both dual-target ICI-chemo and single ICI-chemo significantly improved survival compared with chemotherapy, with cadon-chemo being most effective in CPS ≥ 10 and CPS ≥ 1, and SHR1701-chemo in CPS ≥ 5. In the CPS < 5 subgroup, dual-target ICI-chemo significantly improved OS, while single ICI-chemo showed a trend toward benefit. However, no ICI-based strategy demonstrated benefit in CPS < 1. CONCLUSIONS: Dual-target ICI-chemo appears to be the most effective first-line strategy for AGC based on current indirect evidence, surpassing single ICI-chemo and dual ICI-based regimens. These findings support personalized therapy selection but await confirmation by head‑to‑head trials. Future studies should address CPS < 1 and explore optimized combinations to enhance outcomes.
25 May 2026
Read appraisal →Journal of ethnopharmacology
Comparative efficacy and safety of Chinese patent medicines in coronary heart disease patients after percutaneous coronary intervention: A systematic review and network meta-analysis
ETHNOPHARMACOLOGICAL RELEVANCE: Patients with coronary heart disease (CHD) remain at high risk of major adverse cardiovascular events (MACEs) after percutaneous coronary intervention (PCI). Chinese Patent Medicines (CPMs) have demonstrated therapeutic potential as adjunctive therapies, however, direct comparative evidence regarding their effectiveness is lacking. AIM OF THE STUDY: This network meta-analysis (NMA) aims to systematically evaluate and compare the clinical efficacy and safety of CPMs combined with conventional therapy (CT) in post-PCI management. MATERIALS AND METHODS: A systematic literature search was performed in PubMed, Web of Science, Embase, Cochrane Library, CNKI, CBM, VIP, and Wanfang databases up to December 24, 2024. Randomized controlled trials investigating CPMs in CHD patients following PCI were included. Methodological quality was assessed using the Cochrane Risk of Bias tool. Outcome measures included major adverse cardiovascular events (MACEs), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and nitric oxide (NO) levels. NMA was implemented using STATA 16.0 and R 4.1.2. Odds ratios and standardized mean differences with 95% confidence intervals were calculated for dichotomous and continuous outcomes, respectively. Model selection was guided by heterogeneity assessed using the I2 statistic. Intervention rankings were estimated using the surface under the cumulative ranking curve (SUCRA), with robustness and publication bias evaluated through sensitivity analyses and funnel plots. RESULTS: A total of 84 RCTs involving 10,524 patients and eight CPMs were included. For the primary outcome (MACEs), the SUCRA ranking indicated that Tongxinluo capsules combined with conventional therapy (TXLJN + CT) was the most effective intervention, followed by Shensong Yangxin capsules plus CT (SSYXJN + CT), Shexiang Baoxin pills plus CT (SXBXW + CT), Qili Qiangxin capsules plus CT (QLQXJN + CT), Qishen Yiqi dripping pills plus CT (QSYQDW + CT), Xinyu capsules plus CT (XYJN + CT), Fufang Danshen Dripping Pills plus CT (FFDSDW + CT), and Guanxin Shutong capsules plus CT (GXSTJN + CT), while CT alone ranked last. Correspondingly, the NMA demonstrated that TXLJN + CT was associated with the greatest reduction in LVEDD (SMD -1.01, 95% CI -1.35 to -0.66) and hs-CRP levels (SMD -2.50, 95% CI -3.33 to -1.68). The most significant improvement in LVEF (SMD 1.25, 95% CI 0.85 to 1.64) and NO levels (SMD 1.02, 95% CI 0.73 to 1.29) was observed with QSYQDW + CT. Meanwhile, SXBXW + CT showed the greatest efficacy in reducing NT-proBNP levels (SMD -3.43, 95% CI -4.68 to -2.18). CONCLUSION: CPMs combined with CT may provide clinical benefits in post-PCI management. According to SUCRA rankings, TXLJN + CT ranked first in reducing MACE and in lowering LVEDD and hs-CRP levels. QSYQDW + CT ranked first in improving LVEF and NO levels, while SXBXW + CT showed the highest ranking for reducing NT-proBNP levels. However, larger-scale, high-quality RCTs are needed to validate these findings.
25 May 2026
Read appraisal →Journal of ethnopharmacology
Therapeutic potential of pharmacological components of Salvia miltiorrhiza against atherosclerosis: A preclinical systematic review and meta-analysis
ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) severely threatens global health, while current therapies exhibit limitations. Recognized as a 'superior-grade' herb in the Shennong Ben Cao Jing, Salvia miltiorrhiza Bunge (Danshen) has been shown in modern studies to protect against cardiovascular diseases. AIM OF THE STUDY: The aim of this study was to investigate the therapeutic potential and protective mechanism of pharmacological components of Salvia miltiorrhiza against AS. MATERIALS AND METHODS: Relevant animal studies were collected from 8 databases, namely, PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang Data, VIP, and SinoMed. Risk of bias of the included studies was evaluated using the SYRCLE's tool. Statistical analysis was performed using R 4.2.0 and Python 3.14.2 software. Machine learning model was trained to predict optimal intervention parameters and was subsequently validated. RESULTS: A total of 64 studies were included. The pharmacological components of Salvia miltiorrhiza ameliorated atherosclerotic plaque formation and stability, and modulated various biomarkers, including lipid profiles, inflammatory cytokines, oxidative stress indicators, endothelial function markers, as well as matrix metalloproteinases. Machine learning identified an optimal Tanshinone IIA regimen against AS, which was defined as a single dose of 33.18 mg/kg dose over 84 days and demonstrated predictive robustness in validation. CONCLUSIONS: The pharmacological components of Salvia miltiorrhiza attenuate AS by regulating lipid metabolism, anti-inflammatory and antioxidant actions, improving endothelial function, modulating of vascular smooth muscle cells, remodeling extracellular matrix, and regulating programmed cell death. These findings provide translational insights that pave the way for subsequent preclinical and early-clinical studies, pending systematic validation through more rigorous research.
24 May 2026
Read appraisal →The AAPS journal
A Mechanistic Framework Integrating Renal QSP-PK-PD and Machine Learning for Baseline-Informed Stratification of Diuretic Resistance
Diuretic resistance represents a major source of heterogeneity in loop diuretic response and remains a key barrier to effective decongestion in heart failure. A key clinical challenge is the early identification of patients at high risk of an inadequate response to standard-dose furosemide in order to inform timely treatment intensification or alternative decongestive strategies. However, current approaches remain reactive and rely on post-treatment response, limiting prospective risk stratification and treatment decision-making. To address this problem, we integrated a mechanistic renal quantitative systems pharmacology (QSP) model with furosemide pharmacokinetics and pharmacodynamics to enable baseline-informed risk stratification of diuretic resistance. The model was calibrated using published clinical pharmacokinetic and renal response data and applied to generate a physiologically constrained virtual patient population capturing heterogeneity in renal function, tubular sodium handling, and neurohormonal activation. Machine learning methods were incorporated as complementary analytical tools to identify and validate baseline physiological determinants that define risk categories of diuretic response within the mechanistic simulation framework. Model-based analyses indicated that diuretic resistance arises from the combined effects of reduced filtration capacity, enhanced tubular sodium avidity, diminished pharmacodynamic sensitivity and sustained neurohormonal activation. Across analytical approaches, baseline fractional excretion of sodium and glomerular filtration rate emerged as integrative biomarkers that stratify patients into distinct risk categories of diuretic response, reflecting a mechanism-informed reduction of underlying physiological variability. These findings provide a mechanistically grounded framework for baseline-informed risk stratification and may inform earlier identification of patients at risk of inadequate response, supporting model-informed evaluation of treatment intensification or alternative decongestive strategies.
24 May 2026
Read appraisal →Lancet (London, England)
Safety and efficacy of astegolimab for COPD with frequent exacerbations regardless of baseline blood eosinophil counts (ALIENTO and ARNASA): randomised, double-blind, placebo-controlled, phase 2b and 3 trials
BACKGROUND: Interleukin-33 and its receptor, ST2, are implicated in neutrophilic and eosinophilic inflammation during chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to assess the efficacy and safety of astegolimab, an anti-ST2 human IgG2 monoclonal antibody, which were evaluated in two COPD pivotal trials. METHODS: In two randomised, double-blind, placebo-controlled trials (phase 2b ALIENTO and phase 3 ARNASA), current or former smokers with COPD and a history of frequent exacerbations, irrespective of baseline blood eosinophils, were randomly assigned (1:1:1; stratification by smoking status and region) to receive subcutaneous astegolimab 476 mg every 2 weeks, every 4 weeks, or placebo, alongside optimised inhaled maintenance therapy over 52 weeks. The primary endpoint (analysed in participants receiving one or more doses) was annualised rate of moderate or severe exacerbations. Missing data were considered similar to data from other participants in the same treatment group with the same baseline characteristics. The trials were registered with ClinicalTrials.gov (NCT05037929 and NCT05595642). FINDINGS: In ALIENTO, 1301 participants (astegolimab every 2 weeks, n=433; astegolimab every 4 weeks, n=437; and placebo, n=431) initiated treatment between Oct 5, 2021, and Feb 19, 2024. In ARNASA, 1375 participants (astegolimab every 2 weeks, n=459; astegolimab every 4 weeks, n=459; and placebo, n=457) initiated treatment between Jan 9, 2023, and June 25, 2024. Adjusted rate ratios versus placebo for the primary endpoint were 0·85 (95% CI 0·72-1·00; p=0·049) for astegolimab every 2 weeks and 0·93 (0·79-1·10; p=0·38) for astegolimab every 4 weeks in ALIENTO, and 0·85 (0·72-1·01; p=0·068) for astegolimab every 2 weeks and 0·82 (0·70-0·98; p=0·024) for astegolimab every 4 weeks in ARNASA. Adverse events were balanced between treatments, with most participants experiencing one or more adverse events (1093 [84·0%] of 1301 participants in ALIENTO and 1176 [85·5%] of 1375 in ARNASA). The most common non-COPD adverse event was nasopharyngitis in ALIENTO and upper respiratory chest infection in ARNASA. Deaths occurred in 40 (3·1%) of 1301 participants in ALIENTO and in 44 (3·2%) of 1375 participants in ARNASA, and were balanced across treatment groups. Across both trials, a total of three deaths (0·1%) were considered to be related to treatment by investigators. INTERPRETATION: In ALIENTO, astegolimab every 2 weeks was associated with a lower annual rate of exacerbations versus placebo in patients with COPD and a history of frequent exacerbations. In ARNASA, these findings did not meet statistical significance. Together, these findings suggest a role for targeting the ST2/IL-33 pathway to reduce the frequency of COPD exacerbations in patients with limited treatment options. FUNDING: Genentech, a member of the Roche Group, and F Hoffmann-La Roche.
23 May 2026
Read appraisal →BMJ open
Toolkit to prompt and support stopping antidepressants in general practice: an interview study exploring patient participants' experiences in the RELEASE trial.
OBJECTIVE: To explore patient experiences with the RELEASE (Redressing long-term antidepressant use) toolkit resources, including antidepressant hyperbolic tapering plans designed to minimise withdrawal symptoms as part of the RELEASE trial's implementation evaluation to understand what aspects of the toolkit work well and identify areas where refinement could enhance future implementation. The RELEASE intervention, a multistrategy intervention codesigned with general practitioners (GPs) and patients to prompt and support stopping long-term (>12 months) antidepressants, is being evaluated in an effectiveness-implementation hybrid type-1 cluster randomised controlled trial in general practice. STUDY DESIGN: One-to-one semistructured qualitative interviews using reflexive thematic analysis to identify patterns of shared meaning. SETTING: General practice, south-east Queensland, Australia. PARTICIPANTS: Adult participants (aged 18 years or older) taking an antidepressant long-term allocated to the intervention arm of the RELEASE trial. RESULTS: 31 participants with an average duration of antidepressant use of 16.5 years (range 1-30 years) were interviewed. Seven themes were identified. Across seven themes, participants described how the RELEASE toolkit resources prompted reflection on their antidepressant use, supported informed conversations with GPs, and offered tapering plans that were both structured enough to instil confidence and flexible enough to help participants feel in control of their tapering journey. They also identified barriers, including beliefs that very small tapering doses were unnecessary, difficulty accessing the mini-doses required for hyperbolic tapering and the challenge of managing withdrawal symptoms. For those who successfully stopped, the transition was associated with a renewed sense of autonomy. Participants also offered practical suggestions to strengthen the toolkit and its broader implementation. CONCLUSIONS: The RELEASE toolkit resources played a meaningful role in prompting and supporting informed shared decision-making and guiding attempts to stop antidepressants. Clearer messaging about the potential for withdrawal symptoms and access to mini-doses for tapering are needed to support patients to safely stop antidepressants. TRIAL REGISTRATION NUMBER: ACTRN12622001379707p; Pre-results.
23 May 2026
Read appraisal →BMC cancer
Efficacy and risk analysis of monotherapy and dual immunotherapy in dMMR/MSI-H metastatic colorectal cancer: a meta-analysis based on randomized controlled trials
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for metastatic colorectal cancer (mCRC) exhibiting DNA mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). However, the comparative efficacy and safety of monotherapy versus dual immunotherapy remain inadequately quantified. This meta-analysis aims to evaluate the benefits and risks of these strategies by quantitatively synthesizing data from randomized controlled trials (RCTs) to inform clinical decision-making. DESIGN: We systematically searched major databases (PubMed, Web of Science, Cochrane, Embase) from inception to September 2025 for relevant RCTs. Outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and adverse events. Statistical analyses were performed using RevMan 5.3 and Stata 18.0. RESULTS: Six RCTs (1,460 patients) were included. Pooled analysis showed that PD-1/PD-L1 monotherapy significantly improved ORR compared with chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04), based on two RCTs (n = 429), and demonstrated a significantly lower incidence of grade ≥ 3 adverse events (OR = 0.14, 95% CI: 0.08-0.23, P < 0.00001; 2 studies). Dual immunotherapy with nivolumab plus ipilimumab significantly improved ORR versus monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001), based on one RCT (n = 582), with a significantly increased toxicity risk (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002). For PFS, KEYNOTE-177 (HR = 0.59, 95% CI: 0.45-0.79) and CheckMate 8HW (HR = 0.62, 95% CI: 0.48-0.81) showed significant benefits, while SAMCO-PRODIGE 54 and CheckMate 9 × 8 did not demonstrate statistically significant PFS improvement. OS hazard ratios across four studies ranged from 0.74 to 1.03, with all 95% confidence intervals crossing 1.0, indicating no statistically significant survival benefit in any individual study. DOR was consistently longer with immunotherapy, with median not reached for pembrolizumab versus 10.6 months for chemotherapy in KEYNOTE-177. CONCLUSIONS: Effect estimates for PFS, OS, and DOR generally favored immunotherapy; however, confidence intervals were wide and statistical significance was not consistently observed across trials. PD-1/PD-L1 monotherapy demonstrated a favorable safety profile and a statistically significant improvement in ORR compared with chemotherapy (OR = 1.52, 95% CI: 1.02-2.27, P = 0.04). Dual immunotherapy significantly improved ORR compared with monotherapy (OR = 1.77, 95% CI: 1.25-2.49, P = 0.001), but this benefit was accompanied by significantly increased toxicity (OR = 1.73, 95% CI: 1.22-2.44, P = 0.002) and did not consistently translate into statistically significant PFS or OS benefits across trials. These findings highlight the need for personalized risk-benefit assessment. Future research should focus on biomarker-driven patient selection and strategies to overcome resistance.
23 May 2026
Read appraisal →PloS one
Effect of an herbal supplement on quality of life in participants with insomnia: A randomized placebo controlled cross-over pilot trial
BACKGROUND: Insomnia is a common sleep disorder linked to poor quality of life. Patients with insomnia frequently rely on herbal supplements to improve sleep and quality of life; however, most supplements do not undergo rigorous testing to determine their effectiveness. The primary objective of the pilot trial was to test the effectiveness of the herbal supplement on sleep and quality of life. METHODS: In a double-blind, randomized, placebo-controlled, crossover pilot trial, participants were assigned study drinks consisting of the herbal supplement containing extracts from chicory and green tea or placebo for 7 days. This was followed by a crossover to the other arm after 2 weeks of a washout period. Participants were healthy individuals of the age of 50 years or more with insomnia. Study measures included subjective assessments of sleep, daytime sleepiness, fatigue, and quality of life via questionnaires. Habitual sleep patterns and sleep architecture were objectively evaluated by a 7-day accelerometry and polysomnography. RESULTS: Ten participants (9 women; age 59 ± 6 y; BMI 30 ± 10 kg/m2) with insomnia severity index of 21 ± 4 and wake after sleep onset (WASO) of 75 ± 33 min were enrolled in the study. The impact of placebo and supplement was different for measures related to daytime sleepiness and physical fatigue but not quality of life. No within and between treatment differences were observed for any objective measures of habitual sleep patterns or sleep architecture. Within group analysis showed improvement in subjective sleep quality, daytime sleepiness, and general fatigue after 7-day consumption of the placebo drink, but not after consumption of herbal supplement. There were no adverse events related to study participation. CONCLUSION: Compared to placebo drink, daily consumption of the herbal supplement for 7 days did not improve any aspect of quality of life or sleep in our pilot study participants with insomnia. Well controlled clinical trials are needed to confirm the claims related to supplements.
22 May 2026
Read appraisal →Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Dolutegravir Reduces Human T-Cell Lymphotropic Virus Type 1 Proviral Load and Improves Neurological Outcomes in a Phase 2 Controlled Trial
BACKGROUND: No specific therapy is approved for human T-cell lymphotropic virus type 1 (HTLV-1) infection. We tested the effect of dolutegravir (DTG) on clinical outcomes and on HTLV-1 proviral load (PVL) in adults with HTLV-1 infection. METHODS: We conducted an open-label, randomized controlled phase 2 trial in Salvador, Brazil. Symptomatic adults with HTLV-1 infection were randomized 1:1 to DTG 50 mg once daily or vitamin C (VTC) 500 mg once daily for 48 weeks. We evaluated changes in gait performance (timed 10-meter walk test [T10MWT]). Key secondary endpoints included change in PVL and prespecified neurofunctional and urinary outcomes. Primary analyses emphasized intragroup and between-group comparisons; exploratory per-protocol analyses were performed for neurofunctional measures. Asymptomatic participants were included for PVL and immunological evaluations. RESULTS: Eighty-three participants (53 symptomatic) were randomized (DTG, n = 43; VTC, n = 40). At week 48, there was no between-group difference in T10MWT. However, DTG use significantly reduced PVL over 48 weeks compared with VTC (P < .001). Exploratory per-protocol analyses found significant improvements associated with DTG use in lower limb spasticity (P < .001), sensory function (light touch, P = .035; pinprick, P = .001), and median nocturia frequency (P = .012). Network analysis of cytokine expression showed a change in the DTG group from baseline to week 48, with loss of negative correlations and a more balanced pattern. DTG was well tolerated, with no unexpected safety signals. CONCLUSIONS: In this pilot randomized trial, DTG use was associated with significantly reduced PVL and improvement in neurofunctional and immunological characteristics of participants in exploratory analyses. These findings provide evidence supporting the use of integrase inhibitors for HTLV-1 infection. Clinical Trials Registration. Brazilian Clinical Trial Register (ReBEC), code RBR-5x7ccxp.
22 May 2026
Read appraisal →Postgraduate medical journal
Efficacy of tirzepatide in glycemic control and weight management in adults with type 2 diabetes: a systematic review and meta-analysis of real-world studies
A systematic review and meta-analysis of real-world studies on tirzepatide is essential to strengthen evidence of its effectiveness in improving glycated hemoglobin (HbA1c) and body weight in patients with type 2 diabetes. 13 real-world studies (N = 89 296; duration 3-18 months) with moderate to serious bias revealed a mean HbA1c reduction of 0.91% (95% confidence interval [CI]: -1.04 to -0.79), weight loss of 9.7 kg (95% CI: -14.05 to -5.35), and body mass index decrease of 2.09 kg/m2 (95% CI: -3.27 to -0.92). Overall, 64% of tirzepatide users reached HbA1c <7%. Furthermore, tirzepatide lowered HbA1c (mean difference [MD] -0.38%; 95% CI: -0.44 to -0.33) and body weight (MD -6.27 kg; 95% CI: -9.22 to -0.33) more than the control. 47%, 23%, 9%, and 4% of tirzepatide users lost ≥5%, ≥10%, ≥15%, and ≥ 20% of their baseline weight, respectively. Tirzepatide's effects on HbA1c and weight in observational studies support clinical trial findings.
22 May 2026
Read appraisal →Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Effects of Semaglutide on Cognitive Function in People With HIV: A Randomized, Controlled Trial
BACKGROUND: People with human immunodeficiency virus (HIV, PWH) are at higher risk for visceral adiposity, enhanced inflammation, and cognitive decline than controls who do not have HIV. We previously demonstrated that PWH with lipohypertrophy had a decrease in weight, visceral adipose tissue, and several inflammatory markers after receiving semaglutide, a glucagon-like peptide-1 receptor agonist. Our aim was to investigate the effect of semaglutide on cognitive function in PWH and the possible mediation of this effect by changes in adiposity or inflammation. METHODS: In this randomized, double-blind, placebo-controlled phase 2b clinical trial, PWH on antiretroviral therapy were randomized 1:1 to receive 32 weeks of subcutaneous semaglutide or placebo. The primary outcome was the change in cognitive function at 32 weeks. Secondary measures included changes in body composition and inflammatory markers. Causal mediation analysis assessed semaglutide's direct and indirect effects on Cognivue scores through changes in adiposity and inflammation. RESULTS: 108 participants were included (54 per arm); 65% were non-White, 40% were female, and median age was 53 years. Compared with placebo, PWH on semaglutide significantly increased visuospatial, naming/language, and delayed recall scores at 32 weeks (P = .01, .05, and .04, respectively). After adjusting for sex and absolute CD4 count, only visuospatial score remained statistically significant (P = .05). Semaglutide's total natural direct effect maintained a positive effect on the visuospatial score while accounting for potential changes in high-sensitivity C-reactive protein and soluble CD163 levels (P = .04). CONCLUSIONS: Semaglutide may have a beneficial impact on visuospatial cognitive function in PWH through its effect on inflammation. Clinical Trials Registration . NCT04019197.
22 May 2026
Read appraisal →Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Pharmacokinetics of Dexamethasone in Tuberculous Meningitis
BACKGROUND: Dexamethasone is recommended as adjunctive therapy for tuberculous meningitis (TBM). Co-administration with rifampicin is expected to reduce dexamethasone exposure in TBM, an effect that may be more pronounced with the higher rifampicin doses currently being evaluated in clinical trials. METHODS: This pharmacokinetic study was nested in a randomized controlled trial comparing the safety of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, versus standard-dose rifampicin (10 mg/kg) for adults with HIV-associated TBM. All participants received adjunctive oral dexamethasone every 12 hours starting at a dose of 0.4 mg/kg/day. Dexamethasone concentrations were measured on intensively sampled plasma on day 3 after study enrollment and analysed using nonlinear mixed-effects modeling. RESULTS: In total, 261 dexamethasone concentrations from 43 participants were available for model development. Eight (18%) participants were on efavirenz-based ART and five (11%) were on a lopinavir/ritonavir-based regimen. The median duration of rifampicin therapy at the time of pharmacokinetic sampling was 4 days (range: 0-7). Dexamethasone pharmacokinetics was best described by a one-compartment disposition model with first-order absorption and elimination. Typical oral clearance (CL/F) was 131 L/h, reduced to 11.5 L/h with concomitant lopinavir/ritonavir. High-dose rifampicin had no significant additional effect on dexamethasone pharmacokinetic parameters compared with the standard-dose. CONCLUSIONS: In adults with HIV-associated TBM, there was high dexamethasone clearance, likely related to a drug-drug interaction with rifampicin. High-dose rifampicin had no additional effect on dexamethasone exposure.
22 May 2026
Read appraisal →The Cochrane database of systematic reviews
Dose reduction and discontinuation of non-tumor necrosis factor (TNF) biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for people with rheumatoid arthritis in remission or low disease activity
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To determine the benefits and harms of dose reduction or discontinuation of non-TNF biologic or targeted synthetic DMARDs in people with rheumatoid arthritis who are in remission or have low disease activity.
21 May 2026
Read appraisal →European heart journal. Acute cardiovascular care
Guided de-escalation of antiplatelet treatment in patients at high atherothrombotic risk presenting with acute coronary syndrome: a post hoc analysis of the TROPICAL-ACS trial
AIMS: Platelet function testing (PFT)-guided de-escalation of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) has been shown to reduce bleeding risk without increasing ischaemic events. Patients with high atherothrombotic risk (ATR) remain a challenging subgroup for such strategies. This study evaluated the safety and efficacy of early PFT-guided DAPT de-escalation according to ATR status. METHODS AND RESULTS: In the TROPICAL-ACS trial, 2610 ACS patients were randomized to standard 12-month prasugrel therapy or PFT-guided DAPT de-escalation. For this post hoc analysis, patients were stratified by ATR. High ATR was defined as age ≥ 65 years, polyvascular disease, or ≥2 risk factors (diabetes, smoking, or renal dysfunction). Hazard ratios (HRs) for clinical endpoints were derived using multistate Cox regression. High-ATR patients (n = 990) had a higher incidence of the primary net clinical benefit endpoint-composite of cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium 2-5 bleeding-compared with low-ATR patients (n = 1620) (11.0% vs. 6.7%; HR 1.67, 95% confidence interval 1.28-2.18; P < 0.001). Platelet function testing-guided de-escalation showed no significant interaction by ATR status for the primary endpoint [high ATR: 10.5% vs. 11.5%, HR 0.90 (0.61-1.32), P = 0.586; low ATR: 5.6% vs. 7.7%, HR 0.71 (0.48-1.04), P = 0.082; Pinteraction = 0.394] or ischaemic events [high ATR: 3.7% vs. 4.4%, HR 0.83 (0.44-1.56); low ATR: 1.8% vs. 2.6%, HR 0.68 (0.35-1.34); Pinteraction = 0.666]. CONCLUSION: Early PFT-guided de-escalation from prasugrel to clopidogrel was safe across atherothrombotic risk categories, supporting individualized DAPT optimization in ACS patients with both low and high ischaemic risk.
21 May 2026
Read appraisal →Journal of the Egyptian National Cancer Institute
Preclinical efficacy of drug delivery systems in colon cancer therapy: a systematic review and meta-analysis of in vivo animal studies
BACKGROUND: Drug delivery systems (DDS) offer a promising strategy to enhance the therapeutic index of chemotherapeutic agents in colon cancer by improving tumor targeting, circulation time, and controlled drug release. Despite extensive preclinical research, a quantitative synthesis evaluating the efficacy of DDS and the influence of design parameters remains lacking. METHODS: We conducted a systematic review and meta-analysis of preclinical in vivo studies assessing DDS-based chemotherapy in murine models of colon cancer. A comprehensive search of PubMed, EMBASE, Scopus, Google Scholar, Cochrane CENTRAL, and ClinicalTrials.gov was performed through October 15, 2025. Outcomes included tumor growth inhibition, with subgroup analyses examining the effects of DDS platform, chemotherapeutic agent, targeting strategy, ligand type, and route of administration. RESULTS: Twenty-three studies comprising 25 experiments and 539 animals were included. Overall, DDS-based therapies significantly reduced tumor growth compared with controls ((WMD: - 557.7; 95% CI: - 716.8 to - 398.5; I²=88%; p < 0.001) and free-drug administration ((WMD: - 276.3; 95% CI: - 367.6 to - 185.1; I²=78%; p < 0.001). Both targeted and non-targeted DDS significantly reduced tumor growth compared with free drug treatment, while targeted DDS showed significantly greater efficacy than non-targeted systems (WMD: - 240.3; 95% CI: - 399.4 to - 81.25; I²=59%; p = 0.003). Although no statistically significant differences were observed between DDS platforms or chemotherapeutic agent subgroups, micelle-based systems and DDS formulations incorporating SN-38 or doxorubicin tended to show greater tumor growth reduction. Intravenous administration demonstrated significantly greater efficacy than intraperitoneal delivery, while hyaluronic acid- and aptamer-based targeting strategies achieved the largest tumor growth inhibition. Risk-of-bias assessment indicated moderate methodological quality, with variability in reporting of randomization, blinding, and sample size calculations. CONCLUSIONS: DDS-based chemotherapy consistently improves antitumor efficacy in preclinical colon cancer models, with targeting strategy, platform type, chemotherapeutic agent, and administration route influencing outcomes. These findings support the rational design of DDS platforms and underscore their translational potential. Rigorous preclinical study design and standardized reporting of efficacy and safety are essential to facilitate clinical translation.
21 May 2026
Read appraisal →BMC psychiatry
Olanzapine effectiveness on weight gain in anorexia nervosa patients: systematic review and meta-analysis
BACKGROUND: Anorexia nervosa (AN) is a complex psychiatric disorder marked by extreme caloric restriction, intense fear of weight gain, and distorted body image perception. Not only influence physical health, but it also creates serious psychological burdens. Treatment of AN is especially daunting due to its multi-dimensional nature. Recent research indicates that a pharmacological approach, such as the prescription of atypical antipsychotics like Olanzapine, may help treat both the nutritional deficiency and psychological distress related to the disorder. By allowing an individual gain weight and potentially reducing comorbid depression and anxiety, Olanzapine can be a valuable add-on to standard treatments. AIM: This study aims to investigate the effectiveness of Olanzapine in causing weight gain among anorexia nervosa patients. Based on comparisons of results in a number of clinical trials, the study aims at establishing the effect of Olanzapine on weight restoration and investigating any accompanying shift in the psychological state of the patients. METHOD: A comprehensive literature search was performed on Medline, ClinicalTrials.gov, Scopus, and the Cochrane Database of Systematic Reviews for all records from the earliest date available through to August 22, 2024. Randomized controlled trials of olanzapine treatment in anorexia nervosa were included. Studies were screened, and data were extracted. Risk of bias was assessed with the Cochrane risk-of-bias tool. Records for meta-analysis were combined in a random-effects model to calculate effect sizes, and heterogeneity was quantified with the I2 statistic. RESULT: 207 records were found, 159 of which were excluded after title and abstract screening. After full-text review, seven RCTs were found. These trials involving 152 patients assessed the impact of olanzapine on weight gain in anorexia nervosa. Meta-analysis of 4 studies (91 patients) showed a mean difference in BMI of 1.68 kg/m² (95% CI: 0.82, 4.18) in favor of olanzapine but not statistically significant (p = 0.19), with high heterogeneity (I² = 94%). Sensitivity analysis reduced the heterogeneity to 28% but not the effect size. CONCLUSION: Although olanzapine showed a numerically greater weight gain compared to control conditions, the pooled effect did not reach statistical significance and was associated with substantial heterogeneity. Therefore, current evidence remains inconclusive. Olanzapine may be considered in selected cases, particularly where psychological comorbidities are prominent, but larger and methodologically robust trials are needed before routine clinical use can be recommended. CLINICAL TRIAL NUMBER: Not Applicable.
21 May 2026
Read appraisal →The Journal of clinical endocrinology and metabolism
Sustained Action of Imapextide, A Glucagon-Like Peptide-1 Receptor Antagonist, in Healthy Volunteers
CONTEXT: After weight-loss surgery, some patients experience postbariatric hypoglycemia (PBH). Although PBH is customarily managed by dietary modifications with continuous glucose monitoring, advanced treatment options are needed. Imapextide is a sustained-action, selective, reversible glucagon-like peptide-1 (GLP-1) receptor antagonist designed for once-weekly administration for PBH treatment. OBJECTIVE: This work aimed to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses (SAD/MAD) of imapextide in healthy volunteers (HVs). METHODS: This 3-part, phase 1, double-blind study enrolled healthy adults. In the SAD/MAD parts, randomly assigned participants (3:1) received subcutaneous imapextide (SAD, 10-200 mg; MAD, 10-30 mg once weekly, 4 doses) or placebo. The primary end point was safety/tolerability (treatment-emergent adverse events [TEAEs]). PK (SAD/MAD; time-to-maximal concentration [tmax] and half-life [t1/2]) and PD (MAD; GLP-1 and glycemic parameters during a mixed meal tolerance test [MMTT]) were assessed. Imapextide drug-drug interactions (DDIs) of OATP1B1/OATP1B3 inhibition and accelerated gastric emptying were evaluated with coproporphyrin-I, rosuvastatin, and acetaminophen. RESULTS: Overall, 69 HVs were randomly assigned (32 SAD, 23 MAD, 14 DDIs). Imapextide TEAE rates ranged from 33.3% to 50.0% (SAD), 33.3% to 100% (MAD), and 14.3% (DDIs) across cohorts. The most common TEAEs included injection site erythema (SAD, MAD) and injection site swelling (MAD). Imapextide exposure was dose proportional (median tmax 24-48 hours; mean t1/2 ∼90 hours). During the MMTT, imapextide increased GLP-1 concentrations at early time points, while effects on other glycemic parameters were variable. Minimal nonclinically relevant DDIs occurred with rosuvastatin. Imapextide slightly accelerated gastric emptying. CONCLUSION: Imapextide was generally well tolerated in HVs. PK findings supported weekly dosing. PD showed consistent effects on GLP-1 levels, supporting a potential role for imapextide in modulating PBH pathophysiology.
21 May 2026
Read appraisal →The British journal of dermatology
Efficacy and safety of stapokibart in adolescents with moderate-to-severe atopic dermatitis: a multicentre randomized double-blind placebo-controlled phase III trial
BACKGROUND: Moderate-to-severe atopic dermatitis (AD) imposes a significant burden on adolescents and their families, leading to a substantial reduction in quality of life. Treatment options remain limited. Stapokibart, a novel humanized monoclonal antibody that targets interleukin-4Rα, has been approved in China for the treatment of adults with moderate-to-severe AD. OBJECTIVES: To evaluate the efficacy and safety of stapokibart in adolescents with moderate-to-severe AD. METHODS: In this randomized double-blind placebo-controlled phase III trial (NCT06277765), eligible patients were randomized (2 : 1) to stapokibart 300 mg (loading dose 600 mg) or placebo for 18 weeks. Patients with a baseline weight ≥ 60 kg received subcutaneous stapokibart or placebo every 2 weeks (Q2W), while those weighing 30 to < 60 kg received treatment every 3 weeks (Q3W). All patients were given moisturizers during the entire study period. Co-primary endpoints were the proportions of patients achieving a ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI 75) and an Investigator's Global Assessment (IGA) score of clear or almost clear (IGA 0 or 1) with ≥ 2-point reduction from baseline (IGA response) at week 18. Safety was also assessed. RESULTS: Of the 180 enrolled patients, 120 received stapokibart (Q2W, n = 54; Q3W, n = 66) and 60 received placebo (Q2W, n = 26; Q3W, n = 34). In total, 178 (98.9%) patients completed the double-blind treatment. At week 18, higher proportions of patients treated with stapokibart than those treated with placebo achieved EASI 75 [73.9% (n = 88/119) vs. 43% (n = 26/60); difference: 30.5% (95% confidence interval 15.3-44.3; P < 0.001)] and an IGA response [57.1% (n = 68/119) vs. 25% (n = 15/60); difference: 31.8% (95% confidence interval 16.6-44.4; P < 0.001)]. The proportion of patients achieving ≥ 4-point reductions in weekly average of daily Peak Pruritus Numerical Rating Scale score was also significantly higher in the stapokibart group than in the placebo group [36.1% (n = 43/119) vs. 15% (n = 9/60); difference: 21.1% (95% confidence interval 7.4-32.4; P = 0.004)]. The incidence of adverse events was similar between the stapokibart (62.5%; n = 75/120) and placebo (62%; n = 37/60) groups. No conjunctivitis was seen. CONCLUSIONS: Stapokibart has a high efficacy and favourable safety in adolescents with moderate-to-severe AD. An author video to accompany this article is available online. Atopic dermatitis is a long-term skin condition. It causes intense itching and painful patches of dry skin. It is more commonly known as eczema. Adolescents with moderate or severe eczema often need long-term treatment to control the symptoms. In China, a drug called ‘stapokibart’ has recently been approved to treat adults with moderate or severe eczema. This study was done in 32 hospitals in China. We included adolescents with moderate or severe eczema. We treated them with stapokibart or placebo (an inactive or ‘dummy’ medication) for 18 weeks. The patients received their treatment via an injection under their skin. Depending on their weight at the start of the study, patients received treatment every 2 or every 3 weeks. After 18 weeks, patients treated with stapokibart were less itchy and had more of an improvement in their skin than those treated with the placebo. Over half of the patients achieved clear (or almost clear) skin. Finally, we found that stapokibart was safe to take. Undesired results from taking the medication (called ‘adverse events’) were mild or moderate. Our results suggest that stapokibart is an effective and safe treatment option for adolescents with moderate or severe eczema.
20 May 2026
Read appraisal →Journal of the American Heart Association
Association of Edoxaban Pharmacokinetics With Bleeding in Older Patients With Atrial Fibrillation Treated With Low-Dose Edoxaban: A Post Hoc Analysis of a Randomized Controlled Trial
BACKGROUND: Edoxaban is a direct oral anticoagulant used for stroke prevention in patients with atrial fibrillation (AF) and treatment of venous thromboembolism. We examined the relationship between trough edoxaban concentrations (E-trough) and prothrombin time (PT) and major bleeding in very old Japanese patients with atrial fibrillation and high bleeding risk. METHODS: In this post hoc analysis of the multicenter, randomized, double-blind, placebo-controlled ELDERCARE-AF (Study of DU-176b Aged 80 Years or Older) trial, patients were randomly assigned 1:1 to edoxaban 15 mg or placebo once daily. After 8 weeks of treatment, E-trough was determined and the incidence of major bleeding examined in each quartile. The incidence of major bleeding by PT was also examined. RESULTS: Data were obtained from 427 patients. E-trough (ng/mL) was ≤9.24 in the first quartile (107 patients), >9.24 to ≤13.6 in the second (111 patients), >13.6 to ≤21.6 in the third (103 patients), and >21.6 in the fourth (106 patients). Older age, lower body weight, lower creatinine clearance, and the presence of congestive heart failure were independent predictors of higher E-trough. Higher E-trough was associated with greater incidence of major bleeding (0.8%, 1.9%, 3.4%, and 4.7%/year, respectively, P=0.0408). There was a significant positive correlation between E-trough and PT (r=0.426, P<0.0001). Significantly more major bleeding events occurred in the longer (>13 seconds) versus shorter (≤13 seconds) PT subgroups (4.61% versus 0.98%/year, P=0.0060). CONCLUSIONS: Several factors were associated with higher E-trough and increased risk of major bleeding events. PT >13 seconds may be a useful predictor of the development of major bleeding. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02801669.
20 May 2026
Read appraisal →JAMA
Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma: A Randomized Clinical Trial
IMPORTANCE: Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL. OBJECTIVE: To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled. INTERVENTIONS: Patients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability. RESULTS: Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care. CONCLUSIONS AND RELEVANCE: Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04231448.
20 May 2026
Read appraisal →The Journal of clinical endocrinology and metabolism
Efficacy and Safety of Once-Weekly Lonapegsomatropin in Adults With Growth Hormone Deficiency: foresiGHt Trial Results
CONTEXT: Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. OBJECTIVE: This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. METHODS: The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. RESULTS: At week 38, lonapegsomatropin significantly reduced trunk percent fat (-1.68% vs +0.37%; least squares [LS] mean difference -2.04%; P < .001), increased total body lean mass (+1.60 kg vs -0.11 kg; LS mean difference 1.70 kg; P < .0001), and reduced trunk fat mass (-0.48 kg vs +0.22 kg; LS mean difference -0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. CONCLUSION: The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.
19 May 2026
Read appraisal →The Journal of clinical endocrinology and metabolism
Mortality risk and causes of death in exogenous Cushing's syndrome: a systematic review and meta-analysis
CONTEXT: Chronic oral glucocorticoids (GCs) are widely prescribed for multiple diseases. Although long-term GC exposure causes systemic toxicity, the magnitude, dose-response relationship, and causes of GC-associated mortality remain incompletely defined. OBJECTIVE: To quantify overall and cause-specific mortality associated with chronic oral GC exposure and evaluate dose-response relationships across underlying disease groups. METHODS: We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO CRD42017067530). PubMed/MEDLINE, EMBASE, Cochrane Library, Web of Science, and CINAHL were searched from 1945 to March 2019. Eligible studies reported standardized mortality ratios (SMRs) or absolute deaths among adults receiving chronic oral GCs. Random-effects meta-analysis and mixed-effects meta-regression were used to synthesize mortality and dose-response associations across GC exposure metrics, exposure duration, and disease subgroups. RESULTS: One-hundred and sixteen studies encompassing 128 cohorts and 51 380 patients were included. Chronic GC exposure was associated with excess mortality (pooled SMR 1.87; 95%CI 1.32-2.61; I2 74.0%). The pooled proportion of death was 12.0% (95%CI 10-14%). Mortality risk was highest in inflammatory diseases (30.0%) and the vasculitides (18.0%). Higher cumulative dose (≥5 g prednisolone-equivalent), average daily dose >5 mg/day, and higher initial dose were each independently associated with increased mortality. Cardiovascular disease was the leading causes of death (25.6%), followed by malignancy (15.7%) and infection (13.4%). CONCLUSION: Chronic oral GC exposure was associated with increased mortality across disease groups, with higher cumulative and early-treatment doses correlating with higher risk. However, causal attribution remains uncertain due to confounding by indication, limited disease-severity data, and exposure misclassification. These findings support GC stewardship and targeted cardiovascular and infection risk mitigation, rather than indiscriminate dose reduction.
19 May 2026
Read appraisal →Circulation
Effect of APOC3 Inhibition With Olezarsen on Coronary Atherosclerosis: Essence-TIMI 73b Imaging Study
BACKGROUND: Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS: We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS: Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS: Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.
19 May 2026
Read appraisal →Drug discoveries & therapeutics
Trends in the prescription of constipation medications in Japan (fiscal years 2019-2023): A nationwide baseline study prior to the 2023 clinical guidelines.
Constipation is a common gastrointestinal disorder that markedly affects health and quality of life. In Japan, magnesium-based and contact laxatives have long been widely prescribed. Since the launch of lubiprostone in November 2012, several new agents with novel mechanisms have been introduced, and their use has increased. However, to our knowledge, no nationwide study has examined their use. This study aimed to analyze nationwide trends and regional differences in the prescription of medications for constipation. We used data from the Japanese National Health Insurance Claims and Specific Health Checkup Database Open Data from fiscal years (FYs) 2019 to 2023, covering the period when all currently available constipation medications were on the market in Japan, and prior to the inclusion of the drug selection flowchart in the Evidence-Based Clinical Guidelines for Chronic Constipation 2023. Prescription trends were evaluated using defined daily doses per 1,000 inhabitants per day (DID), and regional variations were assessed using standardized claim ratios (SCRs). The DID for contact laxatives decreased during the study period, whereas the DID for other constipation medications increased. Magnesium oxide showed the smallest regional variation, whereas polyethylene glycol and linaclotide showed the largest variations in FY 2019 and FY 2023, respectively. Throughout the 5-year period, the highest SCRs for contact laxatives were observed in Akita, Iwate, and Aomori prefectures. Our findings provide a comprehensive nationwide picture of evolving constipation treatment patterns and regional variations in Japan, establishing baseline data for evaluating the impact of guideline dissemination and evidence accumulation on clinical practice.
18 May 2026
Read appraisal →Drug discoveries & therapeutics
Efficacy and safety of filgotinib versus tocilizumab in active rheumatoid arthritis: A randomized, open-label, multicenter study with clinical and musculoskeletal ultrasound evaluation (TRANSFORM study)
Janus kinase (JAK) and interleukin-6 (IL-6) inhibitors are therapeutic options for patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); however, no randomized controlled trial has compared their efficacy and safety. Since both act through the JAK-signal transducer and activator of transcription pathway, a comparative evaluation is warranted. We conducted a prospective, randomized, open-label trial at 55 centers in Japan, randomizing patients with active RA despite csDMARD therapy in a 1:1 ratio to receive 200 mg/day filgotinib or subcutaneous tocilizumab as monotherapy; the primary endpoint was American College of Rheumatology (ACR) 50 at week 12, and secondary endpoints included clinical disease activity indices, musculoskeletal ultrasonography scores, patient-reported outcomes, and serum biomarkers through 52 weeks. Twenty-six patients were enrolled (13 per group) before study termination due to insufficient recruitment, and descriptive analyses were performed. At week 12, ACR50 was achieved in 38.5% (5/13) patients in the filgotinib group and 46.2% (6/13) in the tocilizumab group (risk difference: -7.69%; 95% confidence interval: -42.26 to 28.8). Both groups showed early and sustained improvements in disease activity from week 2. The improvement in patient global assessment scores was greater with filgotinib at week 2 but the difference diminished thereafter, and serum IL-6 level decreased with filgotinib but increased with tocilizumab. Four serious adverse events occurred with filgotinib, including infections and cardiac events. Because this study was underpowered and the analysis was descriptive, larger studies are needed to confirm these findings and define optimal use. (The study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) as jRCTs071200107 and in ClinicalTrials.gov as NCT05090410.).
18 May 2026
Read appraisal →Journal of pharmacokinetics and pharmacodynamics
Development of a novel rabeprazole modified release formulation to reduce the dosing frequency: A trial and triumph with physiologically based biopharmaceutics modeling.
Advanced in silico tools, such as physiologically based biopharmaceutics models (PBBM) and physiologically based pharmacokinetic models (PBPK), play a pivotal role in model-informed formulation development (MIFD). In the present study, these methodologies were utilized in the development of a novel rabeprazole modified-release (MR) formulation for improved patient compliance by reducing the dosing frequency relative to existing delayed-release (DR) formulation. A MR formulation containing combination of delayed release and pulsatile release components was designed based on the hypothetical dissolution targets. A PBBM was first established using literature-derived clinical data and used to simulate the performance of formulations with varied dissolution profiles. Initial MR formulation prototypes (once a day) were evaluated in pilot-1 bioequivalence (BE) study against reference formulation (twice a day) but results indicated infra bioequivalence outcome. After pilot-1 study, the formulation and the dissolution method were optimized and then model was refined to predict the pilot 1 outcomes. The validated model was then employed to select suitable pilot-2 prototypes and to prospectively predict their BE outcomes under fasted and fed conditions. The predicted BE ratios were in good agreement with the observed pilot-2 study results. Therefore, the same model was used to make prospective predictions with increased subjects to understand the in vivo performance of pivotal test formulation and lead to the successful bioequivalence outcome, product commercialization, ultimately aiding in increased patient compliance. This work highlights the value of a model-informed strategy in accelerating formulation optimization, reducing development timelines and costs, and strengthening decision-making within pharmaceutical development programs.
18 May 2026
Read appraisal →The Journal of infectious diseases
Safety, Tolerability, and Pharmacokinetics of 6-Diazo-5-Oxo-L-Norleucine in Malawian Adults With and Without Malaria: A Phase 1 Dose-Escalation Clinical Trial
BACKGROUND: Cerebral malaria (CM) is a common cause of febrile coma among African children. Despite treatment with highly efficacious intravenous artesunate, CM remains associated with high mortality and neurologic sequelae. In a mouse CM model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) demonstrated robust efficacy as a potential adjuvant therapy. Before testing DON in children with CM, we investigated tolerability in African adults, including individuals with malaria. METHODS: We conducted an open-label, prospective, dose-escalation, phase 1 clinical trial of single-dose intravenous DON in Blantyre, Malawi. Participants included healthy adults and adults with uncomplicated malaria, enrolled in dose-cohorts of 10 and administered DON at 0.1, 1.0, 5.0, or 10 mg/kg. We assessed adverse events (AEs) and plasma pharmacokinetics. RESULTS: Forty healthy adults and 38 adults with uncomplicated malaria received DON. Transient, asymptomatic creatinine elevation occurred 12 hours postinfusion in 18% of all participants. Nausea and vomiting were uncommon at 0.1 and 1.0 mg/kg but occurred more frequently at 5.0 and 10 mg/kg DON. All DON-related AEs resolved rapidly, without sequelae, and did not significantly differ between healthy and uncomplicated malaria participants. In healthy adults, maximum plasma concentrations increased proportional to dose, but adults with malaria had greater than dose-proportional increases. Terminal half-life ranged from 1.7 to 4.1 hours. CONCLUSIONS: DON was well tolerated in healthy adults and adults with uncomplicated malaria. Higher doses were associated with transient gastrointestinal AEs. Pharmacokinetics were minimally influenced by malaria disease. These results provide critical data to guide dosing strategies for adjunctive DON in children with CM. Clinical Trials Registration. NCT05478720.
18 May 2026
Read appraisal →European journal of preventive cardiology
Effect of intensive blood pressure control in patients with resistant hypertension: insights from the STEP trial
AIMS: Resistant hypertension is defined as uncontrolled blood pressure (BP) despite the use of ≥3 antihypertensive drugs or controlled BP with ≥4 antihypertensive drugs. Whether intensive BP control is beneficial for the management of resistant hypertension is unknown. METHODS AND RESULTS: Intensive (<130 mmHg) BP control in patients is compared with standard (130-150 mmHg) BP control in patients with resistant hypertension, using the Strategy of Blood Pressure Intervention in Older Hypertensive Patients (STEP) trial data. Patients were divided into those with and without resistant hypertension. The primary outcome was a composite of cardiovascular events. Hazard ratios (HRs) were calculated using the Fine-Gray sub-distribution hazard model for primary and secondary events and the Cox regression model for all-cause death. In patients with resistant hypertension, intensive BP control was associated with a lower risk of primary outcomes (HR, 0.36; 95% CI, 0.14-0.93; P = 0.035). Results were consistent across different BP thresholds used to define resistant hypertension and in patients with true resistant hypertension. The benefit of intensive BP control was consistent across resistant hypertension status. Intensive BP control was not associated with an increased risk of adverse events in patients with resistant hypertension. Patients with resistant hypertension had increased cardiovascular risk compared with those without (HR, 1.78; 95% CI, 1.13-2.81; P = 0.012). CONCLUSION: Intensive BP control is associated with reduced risk of cardiovascular events in patients with resistant hypertension without increased risk of adverse events. REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT03015311. The present study is a secondary analysis of the effect of intensive blood pressure control in patients with resistant hypertension in the STEP trial. Resistant hypertension is characterized as elevated blood pressure (BP) despite three antihypertensive agents or controlled BP with four or more agents. Intensive BP control in patients with resistant hypertension may reduce the risk of cardiovascular events. Further research is needed to investigate multifaceted treatment approaches, including both pharmacological and non-pharmacological interventions.Intensive blood pressure (BP) control is associated with a reduced risk of cardiovascular events and death in patients with resistant hypertension, compared with standard BP control, without increasing the risk of adverse events.Patients with resistant hypertension remain at higher risk of cardiovascular events compared with patients without resistant hypertension. Intensive BP control in this population may lower the risk of cardiovascular events.
18 May 2026
Read appraisal →The American journal of cardiology
CagriSema Versus Semaglutide Monotherapy or Placebo for Obesity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with GRADE Assessment
The obesity epidemic is a major health burden that enhances susceptibility to a broad spectrum of metabolic-associated comorbidities, ranging from fatty liver disease and endocrine dysfunction to traditional risks like type 2 diabetes mellitus and cardiovascular disease. Glucagon-like peptide-1 receptor agonists, including semaglutide, facilitate weight loss alongside glucose metabolism. The dual therapy CagriSema, which combines semaglutide with cagrilintide was developed. We systematically searched MEDLINE (via PubMed), Web of Science, Scopus, and Cochrane Library, from inception to July 2025, for randomized controlled trials (RCTs) comparing CagriSema with semaglutide monotherapy or placebo in patients with obesity. Four RCTs (n = 4,419) were included (CagriSema: 3,055; control: 1,364). Pooled analysis showed that CagriSema significantly reduced percent weight loss (Cohen's d: -1.38; 95% CI: -1.84 to -0.91; I² = 94.8%). CagriSema also resulted in greater absolute weight loss (MD: -11 kg), waist circumference (MD: -9.41 cm), and systolic blood pressure (MD: -7.06 mmHg). Gastrointestinal adverse events were more frequent (RR: 1.32). CagriSema therapy was associated with superior weight reduction compared with semaglutide or placebo. In conclusion, CagriSema achieves greater weight loss than semaglutide or placebo but increases gastrointestinal adverse events, warranting careful tolerability monitoring and longer-term data.
18 May 2026
Read appraisal →Journal of pharmacokinetics and pharmacodynamics
Multi-objective optimization in population pharmacokinetic model selection and optimization: application of NSGA-II in pyDarwin
The selection of a "good" model usually involves a combination of objective and subjective criteria. Although many aspects of model quality can be expressed numerically, certain desirable characteristics remain difficult-or even impossible-to quantify precisely. Multi-objective optimization (MOO) provides a systematic way to handle this challenge by explicitly incorporating and balancing both objective (measurable) and subjective (judgment-based) considerations when choosing among candidate solutions. The generated Pareto front represents a set of non-dominated models where no single solution can be improved in one objective without sacrificing the performance in another objective. Using the non-dominated sorting genetic algorithm II (NSGA-II), an implementation of MOO, we simultaneously considered objective function value and number of estimated parameters as competing criteria. Concentration measurements of 17-DMAG, quetiapine, clozapine and ziprasidone were applied to build population pharmacokinetic models through traditional stepwise search, machine learning based single-objective hybrid genetic algorithm (SOHGA) and MOO. Local downhill search with MOO was also assessed in this study. While both objectives improved, models with lower objective function value generally contained more estimated parameters. The number of non-dominated solutions for DMAG, ziprasidone, clozapine, and quetiapine was 17, 9, 9, and 13, respectively. The optimal model selected by SOHGA appeared on the Pareto front for DMAG, ziprasidone and clozapine datasets. Overall, MOO provides objective transparency to the cost of tradeoffs between competing model objectives, allowing researchers to better contextualize subjective criteria (e.g., biological plausibility, improvements in diagnostic plots) when aligning model selection with clinical context.
18 May 2026
Read appraisal →Journal of affective disorders
Adverse events related to buspirone: a real-world pharmacovigilance study using the FAERS database
Buspirone, a widely used anxiolytic, has incompletely characterized adverse effects. This study aimed to comprehensively characterize buspirone's safety profile by a large-scale analysis of real-world data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering Q1 2006 to Q1 2025. We collected 1744 buspirone-related adverse event reports and analyzed them utilizing various signal detection techniques, including proportional reporting ratio (PRR), reporting odds ratio (ROR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN). The most common adverse events were categorized into nervous system disorders and psychiatric disorders, with "dizziness" (n = 141), "anxiety" (n = 133), "drug interaction" (n = 86), "serotonin syndrome" (n = 83), and "tremor" (n = 71) being the most frequently reported. Notably, several safety issues linked to suicide exhibited considerable signals. In addition to the adverse events already listed on the package insert, our research identified unanticipated adverse events associated with improper buspirone use, including "drug abuse" (n = 43), "intentional overdose" (n = 30), and "drug level increased" (n = 17). These findings indicated a potential risk of abuse with buspirone exposure during therapeutic use. Moreover, the study detected a relatively rare but noteworthy signal associated with abnormal body weight, such as "obesity" (n = 19), which merits further attention. The median time to onset for adverse events was 10 days (IQR:16). In conclusion, this pharmacovigilance research underscored the safety hazards related to prolonged buspirone usage, confirmed known risks and identified novel safety signals. These findings enriched the awareness of buspirone's safety profile and provided evidence-based guidance in clinical settings.
17 May 2026
Read appraisal →Computers in biology and medicine
Generative deep learning-driven de novo design of targeted MAP4K6 inhibitors
The discovery of selective small-molecule inhibitors for pharmacologically underexplored kinases remains a critical barrier to precision drug development, particularly under data-sparse conditions, where ligand annotations are scarce. Here, we present MolEvoRNN, a generative deep learning (GDL) model that enables the de novo design of chemically valid, structurally diverse, and target-adapted compounds in low-data regimes. Through transfer learning and temperature-controlled sampling, MolEvoRNN efficiently navigates the kinase-relevant chemical space while preserving scaffold novelty, drug-likeness, and synthetic tractability. Applied to MAP4K6, a poorly characterized serine/threonine kinase implicated in hepatocellular carcinoma (HCC), MolEvoRNN generated >49,000 chemically valid molecules with >80% novel Bemis-Murcko scaffolds. MolEvoRNN outperformed the baseline GDL models across key generative metrics, including diversity (1.00), uniqueness (1.00), novelty (1.00), and internal diversity (0.869), demonstrating broad chemical exploration with minimal redundancy. A multilayered virtual screening cascade combining QSAR modeling, pharmacophore mapping, molecular docking, MM-GBSA binding energy estimation, and 1000 ns molecular dynamics simulations identified three lead candidates MINK-5730, MINK-13510, and MINK-16516 with high predicted affinity, favorable ADMET properties, and robust dynamic stability. Unlike end-to-end optimization pipelines, MolEvoRNN decouples generation from evaluation, promoting methodological transparency and rigorous post-hoc triaging. This study establishes a scalable, generalizable paradigm for rational small-molecule design in underexplored target spaces, bridging generative deep learning with structural pharmacology to accelerate early-phase therapeutic discovery.
17 May 2026
Read appraisal →European journal of cancer (Oxford, England : 1990)
Aflibercept and 5-FU vs. FOLFOX as 1st line treatment for older adults or frail elderly patients with metastatic colorectal cancer - The randomized phase 2 AIO / IKF ELDERLY trial (AIO-KRK-0117 / IKF 629)
BACKGROUND: Fluoropyrimidines + angiogenesis inhibitor or dose-reduced doublets are used for (frail) elderly patients with metastatic colorectal cancer (mCRC). This non-comparative trial evaluated two 1st line regimens for patients not eligible for full-dose combinations. METHODS: This open-label, multicenter, phase II study randomized untreated mCRC patients ≥ 70 years ± frailty 1:1 to dose reduced mFOLFOX7 in Arm A or aflibercept (4 mg/kg) plus dose reduced mLV5FU2 in Arm B. Primary endpoint was the 6-months PFS rate (PFS@6), secondary endpoints included safety, overall survival (OS), overall response rate (ORR), patient reported outcomes and overall treatment utility (OTU). FINDINGS: The full analysis population comprised 120 patients (62 Arm A, 58 Arm B; 63% male), with a median age of 78.5 years. 82% frail patients were included. PFS@6 was 68% [95%CI 56%;80%] in Arm A and 46% [32%;59%] in Arm B. Median PFS was 7.9 and 5.5 months, median OS was 20.4 and 19.0 months and ORR was 47% and 22% in Arm A and B, respectively. At 3 months, 52% in Arm A and 35% in Arm B had a good OTU. Most frequent grade ≥ 3 AEs in Arm B were hypertension (41%) and proteinuria (10%). More patients in arm B had treatment-related SAEs grade ≥ 3 (17% in arm B and 5% in arm A). INTERPRETATION: Both regimens were feasible in this (frail) elderly population. Dose-reduced mFOLFOX7 and, to a lesser extent, 5-FU/aflibercept showed good PFS and 3-month OTU. Although most patients were regarded frail, survival rates were promising, most likely due to effective further-line treatments.
17 May 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Efficacy and Safety of Belantamab Mafodotin with Bortezomib plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: The DREAMM-6 Arm B Trial
PURPOSE: The phase I/II DREAMM-6 arm B study (NCT03544281) explored belantamab mafodotin combined with bortezomib/dexamethasone (BVd) in relapsed/refractory multiple myeloma (RRMM). PATIENTS AND METHODS: Adults with RRMM were enrolled sequentially in two belantamab mafodotin (intravenous) dose-escalation (DE) cohorts (2.5 then 3.4 mg/kg every 3 weeks). Additional patients enrolled sequentially to eight dose-expansion cohorts: 1.9, 2.5, or 3.4 mg/kg every 3 weeks; 2.5 or 3.4 mg/kg every 3 weeks split dose (days 1 and 8); 1.9 or 2.5 mg/kg every 6 weeks; or 2.5 mg/kg in cycle 1 stepped down to 1.9 mg/kg every 6 weeks thereafter. Patients received bortezomib twice weekly and dexamethasone four times weekly. Endpoints were dose-limiting toxicities (DLT; DE), adverse events (AE), serious AEs (SAE; DE and expansion), overall response rate (ORR; expansion), and pharmacokinetics. RESULTS: One hundred seven patients (median 4 prior lines of therapy) received BVd (n = 12-18/cohort). The median follow-up was 15.2 to 25.4 months. No DLTs occurred during DE. The most common grade 3/4 AE was keratopathy (53%). Protocol-defined ocular events (change in best corrected visual acuity and/or corneal examination findings) were reported in 93% of patients (grade 3/4: 77%). Twenty-eight (26%) patients experienced any study treatment-related SAEs; 3 of 7 fatal SAEs had a treatment-related primary cause. The ORR was 70% (95% confidence interval, 60.5-78.6). Higher initial exposures had higher probabilities of response and ocular events; lower exposures resulted in fewer deep responses, with small differences in ocular events. CONCLUSIONS: BVd demonstrated manageable safety and clinical activity across all dosing cohorts in heavily pretreated RRMM, supporting the 2.5 mg/kg every 3 weeks dose.
17 May 2026
Read appraisal →European journal of preventive cardiology
Effect of incretin-based therapies on blood pressure: a systematic review and meta-analysis
AIMS: Hypertension and obesity frequently coexist and synergistically increase cardiovascular (CV) risk. Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1-RAs), gastric inhibitory polypeptide (GIP)/GLP1-RAs, and glucagon/GIP/GLP-1RAs lead to substantial weight loss. However, their antihypertensive efficacy and safety profile have not been comprehensively quantified. Our study aimed to evaluate the effects of incretin-based therapies on office systolic blood pressure (BP) (SBP), diastolic BP (DBP), all-cause mortality, and key safety outcomes, i.e. hypoglycaemia and pancreatitis episodes, in adults with overweight or obesity. METHODS AND RESULTS: We searched PubMed, EMBASE, and ClinicalTrial.gov from inception to 30 April 2024 for randomized controlled trials (RCTs) comparing incretin-based therapy with placebo and ≥1 month of follow-up. The primary outcome was change in SBP; secondary outcomes were change in DBP, all-cause mortality, hypoglycaemia, and pancreatitis. Random effects meta-analyses generated mean differences (MDs) or risk ratios (RRs) along with 95% confidence intervals (CIs). Heterogeneity was explored with I2 statistics, subgroup analyses, and meta-regression. Eighty-five RCTs encompassing 90 977 participants (median follow-up time 8 months) met the eligibility criteria. GLP1-RAs reduced SBP by 3.4 mmHg (95% CI 2.8-4.0) and DBP by 0.9 mmHg (95% CI 0.5-1.2). A higher weight loss was significantly associated with a greater reduction in BP. The most significant BP reduction was associated with dual (SBP 5.1 mmHg; DBP 1.8 mmHg) and triple (SBP 6.6 mmHg; DBP 2.1 mmHg) receptor agonists. All-cause mortality was reduced by 18% (RR 0.82, 95% CI 0.76-0.90). Incretin-based therapy did not increase the risk of hypoglycaemia (RR 1.05, 95% CI 0.83-1.33) or pancreatitis (RR 0.84, 95% CI 0.61-1.15). CONCLUSION: Incretin-based therapy led to a modest but clinically meaningful BP reduction and lower all-cause mortality in adults with overweight or obesity, without excess in hypoglycaemia or pancreatitis episodes. There was a significant association between weight loss and the reduction in SBP and DBP. Dual and triple agonists exhibited the most pronounced antihypertensive effect. These findings support the use of incretin-based therapies as part of an integrated and multidisciplinary approach to managing obesity and hypertension, with multiple agonists showing particular promise. Our findings also underscore the need for long-term RCTs to clarify weight-independent mechanisms and the durability effect of BP reduction. Incretin-based therapy, now widely used for weight loss, also modestly reduces blood pressure and mortality, providing an additional health benefit to people with obesity or diabetes.Across 85 clinical trials (more than 90 000 adults), incretin-based therapy lowered systolic blood pressure by about 3 mmHg; the most significant falls occurred with the dual and triple agonists, and every kilogram lost made the reduction larger.Incretin-based therapy use was associated with an 18% lower mortality, with no increase in hypoglycaemia or pancreatitis episodes, supporting their safe dual role in weight control and cardiovascular protection.
16 May 2026
Read appraisal →Journal of neurology, neurosurgery, and psychiatry
Intravenous methylprednisolone as add-on induction therapy for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial
BACKGROUND: Most patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) require maintenance treatment. We aimed to determine whether combined treatment with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone (IVMP) increases remission rates compared with IVIg and placebo. METHODS: We performed a randomised, double-blind, placebo-controlled study. Adults with CIDP who were treatment naive, relapsed after a remission or required continued treatment after a single IVIg dose were included. Participants were treated with IVMP (1000 mg) or placebo (sodium chloride) every 3 weeks for 18 weeks. All participants received IVIg treatment consisting of a loading dose (2 g/kg) and serial maintenance treatments (1 g/kg). The primary outcome was remission, defined as sustained improvement on disability scales at 52 weeks without need for further treatment. RESULTS: Enrolment was halted after the inclusion of 77 of the 96 planned participants because of safety concerns: four thromboembolic events occurred in the IVIg/IVMP group compared with none in the IVIg/placebo group. 14 of 37 (38%) participants in the IVIg/IVMP group were in remission at 52 weeks compared with 11 out of 40 (28%) in the IVIg/placebo group, with a difference of 10% (95% CI -11 to 31; p=0.47). Several secondary outcomes showed a greater magnitude of improvement in disability and impairment at 18 and 52 weeks in the IVIg/IVMP group. CONCLUSIONS: The study was prematurely stopped due to safety concerns after four thromboembolic events in the IVIg plus IVMP group. Combined treatment did not lead to significantly more frequent remissions than IVIg alone in the doses used in this study. TRIAL REGISTRATION NUMBER: ISRCTN15893334.
16 May 2026
Read appraisal →BMJ open
Regular human insulins versus rapid-acting insulin analogues in children and adolescents with type 1 diabetes: a systematic review with meta-analysis and trial sequential analysis
OBJECTIVES: To assess the beneficial and harmful effects of regular human insulins versus rapid-acting insulin analogues in children and adolescents with type 1 diabetes. DESIGN: Systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. DATA SOURCES: CENTRAL, MEDLINE, Embase, LILACS and other sources from inception to 30 January 2026. STUDY SELECTION: Randomised clinical trials comparing regular human insulins versus rapid-acting insulin analogues (insulin aspart, lispro, glulisine) in children and adolescents with type 1 diabetes. ANALYSES: Data were analysed using meta-analysis and trial sequential analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool, V.2, and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. PRIMARY OUTCOMES: Severe hypoglycaemia, ketoacidosis and serious adverse events. RESULTS: 10 trials randomising 1107 participants were included. The certainty of evidence was very low mainly due to high risk of bias and small sample sizes. Meta-analysis showed no evidence of a difference between regular human insulins and rapid-acting insulin analogues on severe hypoglycaemia (risk ratio (RR) 1.28, 95% CI 0.81 to 2.03; I2=0.0%; p=0.2851; nine trials), ketoacidosis (RR 0.88, 95% CI 0.26 to 2.93; I2=0.0%; p=0.8593; two trials) and serious adverse events (RR 1.00, 95% CI 0.44 to 2.25; I2=0.0%; p=0.9958; two trials). Trial sequential analysis showed that all meta-analyses of primary outcomes were underpowered. CONCLUSIONS: Current research shows no differential effects between regular human insulins and rapid-acting insulin analogues for children and adolescents with type 1 diabetes, but the evidence is very uncertain. PROSPERO REGISTRATION NUMBER: CRD42024508625.
16 May 2026
Read appraisal →Current allergy and asthma reports
Pharmacotherapeutic Medication Adherence in Patients With Allergic Rhinitis: A Systematic Review and Meta-Analysis
PURPOSE OF REVIEW: Medication adherence is essential for effective management of allergic rhinitis (AR), yet real-world adherence to guideline-recommended pharmacotherapies remains poorly characterized. This systematic review and meta-analysis aims to estimate pooled adherence proportions to prescribed intranasal corticosteroids and oral antihistamines in adults with AR, further stratified by adherence measurement method and geographic region. RECENT FINDINGS: Twelve studies encompassing 191,103 AR patients were included. Overall pooled adherence to both intranasal corticosteroids and oral antihistamines was 43%, with substantial heterogeneity across studies. Adherence estimates differed significantly by measurement method with self-reported adherence consistently exceeding pharmacy refill-based estimates for both medication classes. Significant geographic variation was also observed, with intranasal corticosteroid adherence ranging from 17% in North America to 61% in Asia, and oral antihistamine adherence ranging from 26% in North America to 48% in Northern and Western Europe. Peters' test did not indicate any significant publication bias and a Leave-One-Out (LOO) sensitivity analysis showed that no single study had a disproportionate effect on the overall effect size. Adherence to pharmacotherapy in AR is suboptimal, highly method-dependent, and varies significantly across geographic regions. These findings suggest that reported adherence rates are not only influenced by patients' behaviour, but also by the methods used to measure adherence and the broader healthcare environment. Integrating methodological rigour with geographic stratification provides more informative benchmarks for clinical practice and highlights the need for context-sensitive strategies to improve real-world AR management. Future research should prioritize standardized adherence measurement and prospective studies in underrepresented regions.
15 May 2026
Read appraisal →Journal of affective disorders
Systematic review and meta-analysis of intranasal esketamine for treatment-resistant depression: Evidence from real-world studies
BACKGROUND: Intranasal esketamine has demonstrated efficacy and safety for treatment-resistant depression in randomized controlled trials, however the generalizability of these findings to clinical practice remains unclear. This systematic review and meta-analysis aimed to synthesize real-world evidence of intranasal esketamine in patients with treatment-resistant depression. METHODS: A systematic search was conducted in PubMed, Embase, and PsycINFO up to April 2025 to identify observational studies reporting clinical outcomes of intranasal esketamine in adults with treatment-resistant depression. Standardized mean changes in depressive symptoms and odds ratios for remission were calculated. Random-effects meta-analyses were performed, followed by meta-regression to explore potential moderators. The study protocol was prospectively registered in PROSPERO (CRD420251025075). RESULTS: Nine studies were included in the final synthesis. The analyses demonstrated that intranasal esketamine showed substantial effectiveness, with an effect size of Hedges' g = -1.98 (95% CI -2.94 to -1.03; p < 0.0001). Patients were about five times more likely to achieve remission at three months compared with the induction phase (OR = 5.1, 95% CI 2.29-11.39). Treatment effectiveness was not influenced by factors such as gender or the presence of comorbidities, such as anxiety, personality, or substance use disorders. The pooled prevalence of any adverse event, based on studies that reported safety data, was 82% (95% CI 69-92). The most frequent was dissociation, reported in 49% of patients (95% CI 37-62). CONCLUSIONS: This study provides consistent real-world evidence supporting that Intranasal esketamine was associated with meaningful symptom reduction and rising remission rates over time in real-world settings. Given the observational nature of the evidence and the absence of control groups, effect sizes should be interpreted with caution. Nonetheless, these findings provide valuable insight into esketamine's effectiveness and tolerability in routine practice and highlight the need for controlled comparative studies to guide long-term treatment strategies.
15 May 2026
Read appraisal →Neurology. Clinical practice
Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial
BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers. METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score. RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005). DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.
15 May 2026
Read appraisal →BMJ (Clinical research ed.)
Efficacy of dual antiplatelet therapy for three months versus 12 months after coronary artery bypass grafting: multicentre, double blinded, randomised controlled trial
OBJECTIVES: To evaluate the efficacy of dual antiplatelet therapy (DAPT) for three months versus 12 months in saphenous vein graft occlusion while reducing bleeding risk. DESIGN: Multicentre, non-inferiority, double blind, randomised controlled trial. SETTING: 13 cardiac surgery centres in China, with enrolment between February 2023 and July 2024. PARTICIPANTS: 2300 participants aged 18 to 80 years who underwent elective primary coronary artery bypass grafting with ≥1 saphenous vein graft. INTERVENTIONS: Participants were randomly assigned (1:1) to receive DAPT (ticagrelor 90 mg twice daily plus aspirin 100 mg once daily) for 12 months or the same dual antiplatelet regimen for the first three months, followed by placebo plus aspirin for nine months. MAIN OUTCOME MEASURES: The primary outcomes were saphenous vein graft occlusion at one year (non-inferiority) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (superiority). Secondary outcomes were major adverse cardiovascular events (MACCE), saphenous vein graft failure, venous or arterial graft stenosis, and venous or arterial graft occlusion. RESULTS: 2290 patients (mean age 61.5 (standard deviation (SD) 8.4) years, 20.6% (n=472) women) were included in the modified intention-to-treat set. The mean number of saphenous vein graft segments was 2.5 (SD 0.8). 2070 patients (90.4%) with a total of 5125 saphenous vein graft segments were assessed at one year. Saphenous vein graft occlusion occurred in 280 of 2596 (10.8%) in the three month DAPT group and 283 of 2529 (11.2%) in the 12 month DAPT group (absolute difference -0.31%, 95% confidence interval (CI) -3.13% to 2.52%; P=0.008 for non-inferiority). During a median follow-up of 368 (interquartile range 358-382) days, BARC type 2, 3, or 5 bleeding occurred in 95 patients (8.3%) in the three month DAPT group and 149 patients (13.2%) in the 12 month DAPT group (absolute difference -4.67%, 95% CI -7.18% to -2.16%; P<0.001). The number needed to treat to prevent one bleeding event was 21 (95% CI 13 to 46). MACCE occurred in 26 (2.3%) patients in the three month DAPT group and 27 (2.7%) in the 12 month DAPT group (absolute difference -0.11%, 95% CI -1.48% to 1.26%). The findings for other secondary outcomes were also similar between the two groups. CONCLUSIONS: A three month DAPT strategy was non-inferior to the 12 month DAPT strategy in saphenous vein graft occlusion and was superior in reducing bleeding risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT05380063.
15 May 2026
Read appraisal →Renal failure
Comparative efficacy and safety of apixaban and rivaroxaban versus warfarin in atrial fibrillation patients with end-stage renal disease: a systematic review and meta-analysis
This study aimed to evaluate the comparative efficacy and safety of apixaban and rivaroxaban versus vitamin K antagonists (VKAs) in anticoagulation management in a dialysis population. PubMed, Embase, and the Cochrane Library were searched for studies comparing apixaban or rivaroxaban with VKAs in patients with atrial fibrillation (AF) undergoing dialysis. The primary efficacy endpoints included stroke/systemic embolism (SSE) and all-cause mortality. Safety outcomes encompassed major bleeding, intracranial hemorrhage, and gastrointestinal bleeding. Risk ratios (RR) with 95% confidence intervals (CI) were synthesized using random-effects models. The meta-analysis included three randomized controlled trials (RCTs) and eight observational studies. Pooled analyses showed that apixaban and rivaroxaban were associated with lower risks of major bleeding (RR 0.57, 95% CI: 0.51-0.63), gastrointestinal bleeding (RR 0.66, 95% CI: 0.57-0.76), and intracranial hemorrhage (RR 0.54, 95% CI: 0.36-0.83) compared with VKAs. Additionally, apixaban and rivaroxaban were associated with reduced risk of SSE (RR 0.57, 95% CI: 0.46-0.72) and all-cause mortality (RR 0.73, 95% CI:0.63-0.83), although substantial heterogeneity was present. Exploratory dose-stratified analyses suggested both standard- and low-dose apixaban regimens were associated with favorable efficacy and hemostatic safety relative to warfarin. Consistent numerical trends were observed in the RCT-only analysis, though none reached statistical significance owing to limited sample size. In conclusion, apixaban and rivaroxaban are associated with lower risks of bleeding compared with VKAs in patients with AF and ESRD. However, evidence regarding their efficacy in preventing SSE, all-cause mortality and the optimal apixaban dosing regimen remains inconclusive and requires validation in large, dedicated RCTs.
15 May 2026
Read appraisal →PLoS computational biology
Teaching artificial intelligence through drug-drug interaction clustering analysis: Integrating project-based learning and large language models.
In recent years, artificial intelligence (AI) has increasingly influenced daily life and scientific research. Traditionally, AI-related courses have targeted computer science majors, while systematic instructional opportunities for early-stage undergraduates from non-computing backgrounds remain limited. To bridge this gap, we developed an AI course that integrates project-based learning with large language models (LLMs). Specifically, we designed four progressive assignments based on our research project (i.e., drug-drug interaction network clustering analysis). The course does not require prior knowledge of pharmacology or programming. Instead, LLMs are used as assistive tools to support programming, data analysis, and result interpretation. Students engage in a complete workflow, including data curation, algorithm implementation, and critical evaluation of results. Preliminary feedback shows that this approach supports the development of problem-solving skills and increases student engagement. This study provides a framework for integrating LLMs into project-based learning. We believe that this teaching proposal will be valuable and inspiring for educators seeking to design or enrich similar courses.
15 May 2026
Read appraisal →The New England journal of medicine
A Phase 3 Trial of Brepocitinib in Dermatomyositis
BACKGROUND: Brepocitinib is a first-in-class, oral, selective TYK2-JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence. RESULTS: A total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, -2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial. CONCLUSIONS: In adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.).
15 May 2026
Read appraisal →Journal of computer-aided molecular design
Dynamic stability-driven machine learning improves binding pose identification on human serum albumin.
Accurate identification of ligand binding modes on human serum albumin (HSA) is important for understanding drug-protein interactions that influence pharmacokinetics, including site-specific competition and protein-binding displacement. However, because HSA is a large, multisite binding protein that permits diverse binding configurations, conventional molecular docking often struggles to distinguish crystal-like poses from nonspecific surface-binding poses using static scoring functions alone. Here, we developed a machine-learning framework for HSA binding-pose identification that incorporates dynamic stability information derived from short molecular dynamics (MD) simulations. Time-dependent interaction patterns observed during MD trajectories, including contact persistence, distance fluctuations, and interaction energy-related descriptors, were quantified as interpretable features and integrated with docking scores. Using Leave-One-PDB-Out cross-validation on 31 HSA-ligand crystal structures, models incorporating MD-derived features significantly outperformed the docking score-only model under both pose-level (root-mean-square deviation [RMSD] ≤ 2.5 Å) and site-level (RMSD ≤ 5.0 Å) criteria (Holm-corrected p < 0.001). External validation using a temporally independent nateglinide-HSA complex further supported the utility of the framework for discriminating plausible binding modes within the HSA setting. Notably, informative dynamic features were obtained from 5 ns MD simulations, indicating that early-stage dynamic behavior is sufficient to improve pose discrimination. These findings show that short MD simulations can provide practically useful and interpretable features for machine-learning-based binding-pose identification on HSA. While broader validation will be required to establish applicability beyond HSA, the proposed framework offers a practical strategy for improving binding-mode analysis in pharmacokinetically relevant HSA studies.
15 May 2026
Read appraisal →Journal of the American College of Cardiology
Single-Pill Low-Dose Triple Combination Therapy vs Standard-Dose Monotherapy in Patients With Mild-to-Moderate Hypertension
BACKGROUND: Single-pill low-dose combination (LDC) antihypertensive therapy is an emerging strategy for improving blood pressure (BP) control. Although previous phase II and pragmatic studies suggested promise, these are the first phase III, double-blind, active-controlled trials comparing a single-pill ultra-low-dose triple combination with standard-dose monotherapy. OBJECTIVES: In these studies, we sought to compare a single-pill combination of 1.67 mg amlodipine, 16.67 mg losartan potassium, and 4.17 mg chlorthalidone (LDC-ALC) with standard-dose monotherapy-5 mg amlodipine or 50 mg losartan potassium-in patients with mild-to-moderate hypertension. METHODS: HM-APOLLO-301 (Study 301, May 2022-June 2023) and HM-APOLLO-302 (Study 302, March-December 2024) were multicenter, randomized, double-blind, active-controlled, phase III studies in South Korea. Study 301 compared LDC-ALC and amlodipine; Study 302 compared LDC-ALC and losartan. Adults (≥19 years of age) with systolic blood pressure (SBP) 140 to <180 mm Hg and diastolic blood pressure (DBP) <110 mm Hg after 4-week placebo run-in were randomized to 8 weeks of treatment. The primary endpoint was SBP reduction at week 8, assessed first for noninferiority, then for superiority. RESULTS: In Study 301, LDC-ALC exhibited noninferiority to amlodipine in reducing SBP at week 8 (upper bound of 1-sided 97.5% CI: 2.8 mm Hg [<3 mm Hg noninferiority margin]), and similar efficacy (least-squares mean change: -19.1 vs -19.9 mm Hg; 95% CI: -1.5 to 3.1; P = 0.495), with similar DBP reduction and blood pressure control rate. In Study 302, LDC-ALC was both noninferior (upper bound of one-sided 97.5% CI: -0.6 mm Hg) and superior to losartan (least-squares mean change: -19.9 vs -16.4 mm Hg; 95% CI: -6.6 to -0.2; P = 0.037) in SBP reduction at week 8, with greater DBP reduction and a higher blood pressure control rate than losartan. Adverse events were similar between groups (LDC-ALC vs amlodipine: 11.7% vs 13.9%; LDC-ALC vs losartan: 6.4% vs 3.3%), with ≤1% treatment withdrawals and no serious drug-related events. CONCLUSIONS: Single-pill LDC-ALC achieved BP reductions similar to those with amlodipine and greater than those with losartan monotherapy over 8 weeks, with similar short-term tolerability. These findings support LDC-ALC as an effective and well tolerated alternative initial therapy for mild-to-moderate hypertension, expanding the set of validated strategies alongside established monotherapies. (A Study to Evaluate Efficacy and Safety of HCP1803 in Patients With Essential Hypertension [HM-APOLLO-301; NCT05362110]; A Study to Evaluate Efficacy and Safety of HCP1803 Compared to RLD2001-1 in Patients with Essential Hypertension [HM-APOLLO-302, NCT06438172]).
14 May 2026
Read appraisal →Journal of the American College of Cardiology
Natriuretic Peptide Receptor-1 Agonist for Resistant Hypertension: A Randomized Phase 2 Trial
BACKGROUND: XXB750 is a potent and long-acting human monoclonal antibody agonist of the natriuretic peptide receptor-1 (NPR-1), the receptor for atrial natriuretic peptide and B-type natriuretic peptide. Activation of NPR-1 may lower blood pressure (BP) in patients with resistant hypertension through increases in the second messenger cyclic guanosine monophosphate. OBJECTIVES: The aim of this study was to determine the effect of NPR-1 agonism on 24-hour BP. METHODS: This phase 2, multicenter, randomized, double-blind, placebo-controlled trial evaluated 4 once-monthly subcutaneous doses of XXB750 (30 mg, 60 mg, 120 mg, and 240 mg) administered at baseline, week 4, and week 8 in patients with resistant hypertension. Resistant hypertension was defined as 24-hour systolic BP (SBP) ≥135 mm Hg despite treatment with 3 or 4 guideline-directed antihypertensive agents. The primary endpoint was the dose-response relationship of XXB750 vs placebo in reducing the mean 24-hour SBP from baseline to week 12. RESULTS: The study population (N = 189) had a mean age of 61 years, was 69% male, 61% White, 20% Asian, and 14% Black/African American, and had a baseline mean 24-hour ambulatory BP of 148/81 ± 11/10 mm Hg. Plasma concentrations of XXB750 dose-dependently increased in the XXB750 groups, and XXB750 dose-dependently increased plasma and urine cyclic guanosine monophosphate concentrations by week 12. However, paradoxically, there was no significant dose-dependent change from baseline in mean 24-hour SBP at week 12. In fact, none of the doses of XXB750 had a greater BP-lowering effect than placebo. Changes in ambulatory BP were not affected by the development of anti-drug antibodies. Although there were no changes from baseline in urinary sodium excretion, there were small increases in plasma renin levels in the XXB750 groups. Adverse events with XXB750 were numerically higher than with placebo. Adherence to background antihypertensive medications, assessed by drug assays in 88 patients with available plasma samples, was consistent across all treatment groups at both baseline and week 12. CONCLUSIONS: XXB750, an NPR-1 agonist, had a neutral effect on 24-hour ambulatory SBP in patients with resistant hypertension, despite showing a robust dose-response relationship for engagement of the target of pharmacologic action as indicated by increases in cyclic guanosine monophosphate levels. (An Efficacy, Safety, Tolerability and Dose Finding Study of XXB750 in Resistant Hypertension Patients; NCT05562934).
14 May 2026
Read appraisal →Journal of the American College of Cardiology
Efficacy of Tonlamarsen in Patients With Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial
BACKGROUND: Angiotensinogen production represents the rate-limiting step in activation of the renin-angiotensin-aldosterone system. Tonlamarsen is an investigational antisense oligonucleotide directed against hepatic angiotensinogen synthesis; its efficacy and safety among patients with hypertension are unknown. OBJECTIVES: The aim of this study was to assess the safety and efficacy of 90 mg tonlamarsen administered subcutaneously once monthly for 5 months compared with a single dose of tonlamarsen and subsequent placebo. METHODS: This randomized, placebo-controlled trial enrolled adults with office systolic blood pressure (BP) >135 mm Hg receiving 2 to 5 antihypertensive medications. Participants entered a 3-part treatment period with monthly administration of the study drug, consisting of a 4-week placebo lead-in, followed by 4-week active run-in with a single dose of tonlamarsen and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks. The coprimary endpoints were the between-group differences in the change from baseline to week 20 in plasma angiotensinogen and in office systolic BP. RESULTS: A total of 279 participants received placebo lead-in, 206 received 90 mg tonlamarsen during the active run-in, and 198 were randomized. The mean BP among randomized participants before and after the placebo lead-in was 147/90 and 147/89 mm Hg, respectively. Following active run-in with tonlamarsen, the mean BP was 140/87 mm Hg. Twenty weeks following the first dose of tonlamarsen, least squares (LS) mean percentage changes in plasma angiotensinogen levels were -23.0% (95% CI: -27.8% to -18.2%) with a single dose of tonlamarsen and subsequent placebo and -67.2% (95% CI: -71.9% to -62.4%) with monthly tonlamarsen administration, with a LS mean difference of -44.1% (97.5% CI: -51.9% to -36.4%; P < 0.0001). The LS mean changes in office systolic BP were -6.7 mm Hg (95% CI: -9.8 to -3.5 mm Hg) for participants following a single dose of tonlamarsen and subsequent placebo and -6.7 mm Hg (95% CI: -9.8 to -3.6 mm Hg) for participants treated with monthly tonlamarsen, with a LS mean difference of -0.1 mm Hg (95% CI: -4.5 to -4.4 mm Hg; P = 0.97). Serious adverse events were infrequent and similar between treatment groups. CONCLUSIONS: Among individuals with uncontrolled hypertension, monthly tonlamarsen administration was more effective at lowering plasma angiotensinogen compared with a single tonlamarsen dose, but there was no additional BP reduction. (A Study to Investigate Tonlamarsen for the Treatment of Adults With Uncontrolled Hypertension [KARDINAL]; NCT06864104).
14 May 2026
Read appraisal →JMIR mental health
Machine Learning for Comparative Antidepressant Selection in Major Depressive Disorder: Systematic Review
BACKGROUND: Major depressive disorder (MDD) affects approximately 1 in 6 adults during their lifetime, yet antidepressant selection relies predominantly on trial-and-error, with response rates of only 42% to 53%. While machine learning (ML) models have shown promise in predicting treatment outcomes, most focus on single treatments rather than comparative selection across therapeutic alternatives, limiting their clinical utility for the medication choice decisions that clinicians face in practice. OBJECTIVE: This systematic review evaluates ML approaches that examine 2 or more pharmacological interventions for predicting treatment outcomes in MDD, with a focus on their capacity to facilitate comparative treatment selection between medications or medication classes for individual patients. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched PubMed, Scopus, and Web of Science for studies published from 2015 to 2025. We included studies involving adults with MDD that used ML models to predict treatment outcomes across 2 or more pharmacological treatments and reported medication-specific prediction outcomes. Risk of bias was assessed using PROBAST-AI (Prediction Model Risk of Bias Assessment Tool for Artificial Intelligence). We conducted a narrative synthesis organized by modeling strategies, data integration approaches, validation methodologies, and performance patterns. RESULTS: From 5370 initial records, 19 studies met the inclusion criteria, with dataset sample sizes ranging from 49 to 77,226 participants. Studies employed 3 distinct modeling strategies: drug-specific supervised models trained independently for each medication, subtype- or trajectory-based approaches using clustering methods to identify differential response patterns, and a unified differential prediction framework generating calibrated cross-treatment predictions. Performance varied substantially, with area under the curve values ranging from 0.59 to 0.95 and classification accuracies between 62% and 95.4%, though high performance was concentrated in studies with small samples, high-dimensional neurobiological features, and internal-only validation. Only 7 studies conducted external validation, which generally yielded more conservative performance estimates. Feature informativeness was more consistently associated with performance variation than algorithm complexity. Most studies did not formally distinguish between prognostic features predicting general outcomes and predictive features identifying differential medication responses, and none applied formal explainability techniques. CONCLUSIONS: ML for comparative antidepressant selection remains in an early stage of development. Only 1 study implemented a unified framework directly supporting patient-level treatment ranking. Key barriers to clinical translation include insufficient distinction between prognostic and predictive markers, limited cross-trial validation, near-absent calibration reporting, and absent explainability. Future research should prioritize unified comparative frameworks with calibrated predictions, rigorous external validation on diverse cohorts, explicit modeling of heterogeneous treatment effects, and integration of explainability into model development.
14 May 2026
Read appraisal →Journal of the American College of Cardiology
Behavioral Economics and Medication Adherence for Hypertension: A Randomized Clinical Trial
BACKGROUND: Nonadherence to antihypertensive medications is common. Mobile health (mHealth)-based behavioral economic interventions may improve adherence, but remain largely untested, especially in vulnerable populations. OBJECTIVE: The study sought to test whether an mHealth incentive lottery would lower systolic blood pressure (SBP) and improve adherence. METHODS: BETTER-BP (Behavioral Economics Trial To Enhance Regulation of Blood Pressure) was a randomized trial conducted in 3 safety-net clinics in New York City. Eligible participants were adults with hypertension prescribed at least 1 antihypertensive medication, with SBP >140 mm Hg, and poor self-reported adherence. In the intervention arm, an incentive lottery was administered via SMS messaging. All participants received passive adherence monitoring. The intervention lasted 6 months, with continued monitoring until 12 months. The primary clinical endpoint was change in SBP at 6 months. The primary process endpoint was adequate antihypertensive medication adherence (≥80% days adherent) from baseline to 6 months. RESULTS: Four-hundred participants (265 intervention:135 control) were enrolled with median age 57 years, 60.5% women, 61.5% Hispanic, and 20.3% non-Hispanic Black. Over 70% had Medicaid or no insurance. At 6 months, intervention arm participants were twice as likely to achieve adequate adherence (71% vs 34%; adjusted risk ratio: 2.04; 95% CI: 1.58-2.63), but there was no significant change in mean SBP (-6.7 mm Hg intervention vs -5.8 mm Hg control; P = 0.62). From 6 to 12 months, adherence was similar (31% intervention vs 26% control; adjusted risk ratio: 1.17; 95% CI: 0.83-1.65). CONCLUSIONS: In a diverse safety-net population, the BETTER-BP intervention doubled the rate of adequate antihypertensive medication adherence but did not reduce SBP at 6 months.
14 May 2026
Read appraisal →The Cochrane database of systematic reviews
Pharmacological treatments for Friedreich ataxia
RATIONALE: Friedreich ataxia (FRDA) is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, and slowly progressing to wheelchair dependency, usually in the late teens or early twenties. Scoliosis, pes cavus and cardiomyopathy are often present at diagnosis. As the disease progresses, individuals usually develop slurred speech, auditory impairment (especially in a noisy environment), urinary tract morbidity, diabetes, anxiety, depression, muscle spasticity and visual disturbances. Cardiac abnormalities cause premature death in 60% of people with FRDA. There is no easily defined clinical or biochemical marker to assess progression and no known curative treatment. This is the third update of a review published in 2009 and updated in 2012 and 2016. OBJECTIVES: To assess the effects of pharmacological treatments for people with Friedreich ataxia (FRDA) after 12 months of treatment. SEARCH METHODS: To identify studies for inclusion in this review, we searched CENTRAL, MEDLINE, Embase, CINAHL Plus, TRIP, Orphanet, WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov. We also checked reference lists of relevant studies and contacted study authors. The most recent search was on 4 February 2025. ELIGIBILITY CRITERIA: We were interested in randomised controlled trials (RCTs) and quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed FRDA. To be included in the review, studies had to last at least 12 months. OUTCOMES: We assessed the following outcomes after 12 months of treatment: change in score on a validated ataxia rating scale; change in interventricular septal thickness in diastole (IVSTd) by cardiac magnetic resonance imaging or echocardiogram; change in activities of daily living (ADL) using a validated questionnaire; change in upper limb dexterity; and change in cardiopulmonary exercise testing (CPET). We also assessed treatment-related adverse events with medication continued for the study period, and treatment-emergent adverse events leading to cessation of medication or death during the study period. RISK OF BIAS: Using the Cochrane risk of bias tool RoB 2, we assessed the risk of bias in the seven outcomes reported in our summary of findings tables. SYNTHESIS METHODS: We synthesised the results of the studies for each outcome using meta-analysis, where possible. We calculated the mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, and the risk ratio (RR) for dichotomous outcomes, all with 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for our prespecified outcomes as high, moderate, low or very low. INCLUDED STUDIES: We included eight RCTs in this updated review. We included seven of them in meta-analysis, and these studies enroled a total of 574 participants, with sample sizes ranging from 29 to 232 participants per study. One study was international, with centres in North America, Europe and Australia. There were four other multicentre studies (three in Europe and one in North America). Single-centre studies were conducted in the UK, Italy and France. Participants in the studies ranged from eight to 70 years of age at enrolment, with the mean age in each study being between 18 years and 35 years (with an unweighted pooled mean age across studies of 25.9 years). All of the studies enroled both males and females, with the proportion of female participants ranging from 21% to 58%. Sixty-eight per cent of participants had severe ataxia, while the other 32% had moderate ataxia. The studies tested epoetin alpha, CoQ10 and vitamin E, idebenone, leriglitazone, omaveloxolone, and RT001. One study tested pioglitazone but has not published any results. Four of the studies were pharmaceutical-industry-controlled. SYNTHESIS OF RESULTS: Meta-analysis of seven studies demonstrated that pharmacological treatment probably makes little or no difference to scores on the ataxia rating scale after 12 months of treatment (SMD 0.02, 95% CI -0.23 to 0.26; I² = 42%; 7 studies, 513 participants; moderate-certainty evidence). The evidence was very uncertain about the effects of treatment on IVSTd (MD -0.51, 95% CI -1.10 to 0.09; I² = 80%; 2 studies, 72 participants; very low-certainty evidence) and on ADL (MD -0.59, 95% CI -1.39 to 0.21; I² = 24%; 3 studies, 167 participants; very low-certainty evidence). Meta-analysis of three studies showed that treatment probably improves upper limb dexterity (SMD -0.42, 95% CI -0.73 to -0.11; I² = 0%; 3 studies, 166 participants; moderate-certainty evidence). We are very uncertain about the effect of pharmacological treatment on CPET (SMD -0.16, 95% CI -0.46 to 0.13; I² = 0%; 3 studies, 181 participants; very low-certainty evidence). We are very uncertain whether pharmacological treatment has any effect on treatment-related adverse events (RR 0.88, 95% CI 0.63 to 1.22; I² = 0%; 2 studies, 104 participants; very low-certainty evidence). There were only 104 participants in this analysis out of a total of 545 participants, so the result may have little relevance. Meta-analysis of six studies found that there may be little to no difference between pharmacological treatment and placebo in treatment-emergent adverse events leading to cessation of medication or death (RR 1.24, 95% CI 0.44 to 3.48; I² = 0%; 6 studies, 313 participants; low-certainty evidence). Our certainty in the evidence ranged from very low to moderate. We downgraded all outcomes by one or two levels for imprecision, with further downgrades for inconsistency (for the outcomes of IVSTd, ADL, CPET) and suspected publication bias (for the outcomes of IVSTd, ADL, CPET and adverse events). AUTHORS' CONCLUSIONS: In this updated Cochrane systematic review, meta-analysis of results on the ataxia rating scale showed that pharmacological treatments probably make little or no difference compared with placebo after 12 months of treatment. Given this result, the probable improvement that we found in upper limb dexterity was unexpected. Treatment-emergent adverse events leading to cessation of medication or death may be no more common in treatment groups than placebo groups as there were few adverse events detected in the treated groups. However, the studies may not have detected all rare and serious adverse events. FUNDING: The authors in this review received no funding. REGISTRATION: Protocol (2009) DOI: 10.1002/14651858.CD007791 Original review (2009) DOI: 10.1002/14651858.CD99791.pub2 Update (2012) DOI: 10.1002/14651858.CD007791.pub3 Update (2016) DOI: 10.1002/14651858.CD007791.pub4.
14 May 2026
Read appraisal →Gut
Simvastatin in the prevention of recurrent pancreatitis: a triple-blinded randomised clinical trial (the SIMBA trial)
BACKGROUND: Recurrent acute pancreatitis (RAP) or acute-on-chronic flares in chronic pancreatitis (CP) have limited preventive options beyond addressing the underlying aetiology. Statins, due to their anti-inflammatory properties, have been proposed as a potential prophylactic treatment. OBJECTIVE: We aimed to evaluate whether simvastatin could reduce the recurrence of pancreatitis. DESIGN: At 23 centres, we conducted a triple-blind, randomised, controlled, superiority trial enrolling patients with at least two episodes of RAP or CP flares in the previous 12 months. Participants were randomly assigned to receive simvastatin or placebo for 1 year. The primary endpoint was the recurrence of pancreatitis. The target sample size was 144 patients; however, an interim analysis was planned in the event of slow recruitment. RESULTS: A total of 85 patients (42.1% women) were included in the interim analysis. In the intention-to-treat analysis, no significant differences were observed regarding recurrence: 46.2% simvastatin versus 44.4% placebo; OR 1.07, 95% CI 0.43 to 2.66; p=0.88, or time to recurrence. No statistically significant differences were observed in recurrence in per-protocol analysis (35.5% simvastatin vs 41.9% placebo; OR 0.76, 95% CI 0.27 to 2.12; p=0.60). Development of diabetes mellitus was more frequent in the simvastatin group (4 vs 0 patients; OR not calculable, p=0.04). CONCLUSION: This trial, evaluating simvastatin versus placebo for the prevention of pancreatitis, did not demonstrate a reduction in recurrence rate, although results might be underpowered due to early termination. The relationship between statins in these patients and new-onset diabetes requires further investigation. TRIAL REGISTRATION NUMBER: NCT04021498.
14 May 2026
Read appraisal →Journal of molecular modeling
Exploring human GABA transporter 3 binders for epilepsy through quantum reactivity analysis, molecular dynamics, machine learning prediction, and network pharmacology
CONTEXT: Drug-resistant epilepsy (DRE) remains a major therapeutic challenge, affecting millions of patients globally who do not respond to conventional antiepileptic medications. Recent evidence highlights GABA transporter 3 (GAT3), a glial subtype responsible for regulating extracellular GABA levels, as a promising molecular target for seizure control. Despite its therapeutic potential, selective and potent GAT3 inhibitors remain largely unexplored. This study aims to identify novel GAT3 inhibitors through an integrative computational strategy combining quantum chemical, molecular dynamics, and machine learning approaches to accelerate antiepileptic drug discovery. The cryo-EM-resolved human GAT3-SNAP-5114 complex structure was used for virtual screening, leading to the identification of three highest-ranking compounds, viz. Comp_1, Comp_2, and Comp_3, from the diverse chemically optimized screening library. Analysis of their quantum chemistry profiles indicated HOMO-LUMO energy gap values of 4.14 eV, 4.21 eV, and 3.26 eV, respectively, suggesting them to be maximally reactive with favorable electronic properties for interacting with biological molecules. Molecular dynamics simulations were performed in a fully hydrated POPC lipid bilayer using the AMBER force field, providing a physiologically relevant environment for assessing ligand binding and transporter dynamic, revealed stable binding modes, with the highest structural integrity or least deviations in the structure with Comp_2, having RMSD values ranging from 2.5 to 3.0 Å, with strong hydrogen bonding, while the binding mode was more flexible with strong anchorage for Comp_3, with its mode involving diverse interactions in the complex. Principal component and free energy landscape analyses identified energetically favorable, ligand-induced conformational states. Machine learning-based pIC₅₀ predictions using the AdaBoost regressor yielded values of 7.95 (Comp_1), 7.98 (Comp_2), and 7.63 (Comp_3), all comparable or superior to the reference inhibitor (7.89). A novel approach for network pharmacology integrating detailed drug-gene interaction profiling was additionally used to improve systems-level understanding of the discovered compound. These findings validate the potential of Comp_1-3 as lead GAT3-targeting antiepileptic agents. METHODS: A docking-based virtual screening of a structurally diverse compound library was performed against the cryo-EM structure of human GAT3 in complex with the reference inhibitor SNAP-5114. The top-scoring ligands were subjected to density functional theory (DFT) analysis to assess electronic properties such as HOMO-LUMO energy gaps, reflecting potential binding reactivity. Lead candidates were refined, docked, and evaluated through 500 ns molecular dynamics (MD) simulations, analyzing structural stability via RMSD, RMSF, hydrogen bonding, and interaction network profiles. Principal component analysis and free energy landscape evaluations were used to explore ligand-induced conformational dynamics. Furthermore, machine learning (ML) models-particularly the AdaBoost algorithm-were employed to predict pIC₅₀ values, confirming bioactivity trends. Finally, network pharmacology analysis was conducted to elucidate gene targets and pathway interconnections, revealing the multi-pathway involvement of top candidates in seizure regulation. This integrative computational framework underscores the potential of GAT3-focused modelling and ML-guided screening for rational antiepileptic drug design.
14 May 2026
Read appraisal →Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Efficacy and safety of CGRP monoclonal antibodies for cluster headache: a systematic review and network meta-analysis of randomized controlled trials
INTRODUCTION: Cluster headache (CH) is a severe unilateral trigeminal autonomic cephalalgia with limited well tolerated therapies. Calcitonin gene related peptide monoclonal antibodies, including galcanezumab, fremanezumab, and eptinezumab, have established efficacy in migraine and are under evaluation in CH. This study assesses their efficacy and safety using pairwise and network meta analysis. METHODS: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched through April 2025. Randomized controlled trials enrolling adults with episodic or chronic CH were included. The primary endpoint was change in weekly attack frequency. Secondary outcomes included subtype specific effects and adverse events. Frequentist random effects network meta analysis and pairwise meta analysis were performed in R. RESULTS: Five trials with approximately 1,000 participants were included. No agent demonstrated statistically significant reduction in weekly attack frequency versus placebo, although consistent numerical improvements were observed. Dose specific network estimates showed mean differences of - 0.81 for galcanezumab 300 mg, - 0.17 for eptinezumab 400 mg, 0.71 for fremanezumab 675/225 mg, and - 1.27 for fremanezumab 900/225 mg. Pooled dose estimates were - 0.81 for galcanezumab, - 0.27 for fremanezumab, and - 0.17 for eptinezumab. Pairwise meta analysis yielded a pooled mean difference of - 0.41. Subgroup analysis indicated minimal change in chronic CH and greater numerical reduction in episodic CH. CONCLUSION: CGRP monoclonal antibodies demonstrate modest directional reductions in attack frequency without statistical significance. Signals appear more pronounced in episodic CH, supporting the need for adequately powered, subtype specific trials.
14 May 2026
Read appraisal →Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Oral antipyretics for fatigue alleviation and exercise enhancement in adults with multiple sclerosis: a systematic review and meta-analysis
AIMS: This review aims to explore the potential role of oral antipyretics (aspirin (ASA)/ acetaminophen), commonly known for fever and pain control, in managing fatigue, temperature regulation, and exercise capacity in patients with Multiple Sclerosis (MS), with a focus on nursing implications for symptom management. DESIGN: A systematic review of existing clinical studies assessing the effects of aspirin/ acetaminophen on MS-related fatigue, thermoregulation, and exercise performance. DATA SOURCES: Electronic databases including Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PubMed, Scopus, Web of Science, Wiley, Google Scholar, and ClinicalTrials.gov were searched up to March 2024. REVIEW METHODS: Quality assessment was conducted using the Cochrane risk of bias tool 2. to evaluate the methodological rigor of included studies. Outcomes analyzed included clinically assessed fatigue scores, exercise endurance, and post-exercise thermoregulation, with attention to potential risks associated with aspirin use. RESULTS: After assessment of 57 reports for eligibility, only seven studies met inclusion criteria; results indicated that aspirin pretreatment significantly improved Time to Exhaustion (TTE) in heat-sensitive MS patients (p = 0.013), though one study reported no significant effect. Aspirin reduced post-exercise temperature rise by 56%, but this was not statistically significant in one trial (p = 0.178), while another showed significant reductions (p = 0.002). CONCLUSION: Aspirin and acetaminophen may offer benefits in alleviating fatigue, enhancing thermoregulation, and improving exercise endurance in MS patients. These findings suggest that nurses should consider the potential role of aspirin in symptom management, with further research needed to confirm efficacy and safety. IMPACT: This review highlights a potential adjunct therapy for nurses to incorporate into comprehensive MS care, emphasizing symptom control and quality of life improvements. PATIENT OR PUBLIC CONTRIBUTION: Not applicable. TRIAL REGISTRATION: This review is PROSPERO registered having ID CRD420251000875.
14 May 2026
Read appraisal →BMC psychiatry
N-acetylcysteine for patients with alcohol use disorder, post-traumatic stress disorder, and their co-occurrence: a systematic review of placebo-controlled randomized trials
INTRODUCTION: Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are thought to be significant global contributors to the burden of mental illness. According to recent WHO epidemiological estimates, 3.9% of people worldwide have experienced PTSD at some point in their lives; this number rises to roughly 5.6% among those who have experienced trauma. NAC has shown promise in reducing PTSD symptoms and cravings in veterans, according to recent trials. Our analysis aims to resolve the conflict between results and determine whether NAC is an effective add-on therapy for PTSD, AUD, and co-occurring PTSD/AUD. METHODS: We conducted this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, following our protocol (CRD420251170956). We searched PubMed, Scopus, Cochrane CENTRAL, Embase, EBSCO, and the Web of Science for relevant studies. Only randomized placebo-controlled trials were included. The primary outcomes were severity of PTSD and alcohol craving, while secondary outcomes were anxiety, depression, and alcohol use patterns and biomarkers. RESULTS: Seven randomized, double-blind, placebo-controlled trials were included in this meta-analysis, enrolling a total of 566 participants. There were no significant differences between NAC and placebo in craving (SMD= -0.40, 95% CI [-1.05, 0.25], P = 0.22, I² = 56.1%). Regarding PTSD severity, the PCL scale pooled analysis demonstrated no significant difference between NAC and placebo (SMD = 0.04, 95% CI [-0.40, 0.48], P = 0.8) (I² = 65.9%, P = 0.05), while the CAPS scale pooled analysis demonstrated no significant difference between NAC and placebo (SMD = -0.13, 95% CI [-0.50, 0.24], P = 0.49) (I² = 54.8%, P = 0.109). Leave-one-out sensitivity analysis showed that exclusion of the Back et al. (2025) study resulted in a significant effect favoring NAC (SMD = -0.35, 95% CI [-0.70, -0.01], P = 0.04), with no observed heterogeneity (I² = 0%). CONCLUSION: Our meta-analysis indicates that N-acetylcysteine, when compared to placebo, does not demonstrate consistent efficacy in reducing the primary symptoms of AUD or PTSD in broad patient populations. However, the treatment is relatively safe. A noteworthy signal of potential efficacy for PTSD symptoms emerged in a sensitivity analysis, suggesting that the therapeutic promise of NAC should not be entirely dismissed. CLINICAL TRIAL NUMBER: Not applicable.
14 May 2026
Read appraisal →European journal of clinical pharmacology
Comparison of loop diuretics for chronic heart failure: a systematic review and meta-analysis
BACKGROUND: Loop diuretics relieve congestion in chronic heart failure (CHF). We systematically reviewed randomised clinical trials (RCTs) evaluating their effects. METHODS: A systematic search was conducted across major databases. We included RCTs that compared a loop diuretic to another loop diuretic, placebo, or "no intervention". The primary outcome was all-cause mortality, and secondary outcomes were all-cause hospitalisation, serious adverse events (SAEs), and change in body weight (kg). RESULTS: This review included 23 RCTs that enrolled 4,902 patients. Treatment with alternative loop diuretics (torsemide, azosemide and piretanide) compared with furosemide did not reduce all-cause mortality (risk ratio 1.00, 95% CI 0.89, 1.12); I2 = 0%; p = 0.95), nor did it reduce all-cause hospitalisations (risk ratio 0.99, 95% CI 0.84, 1.17); I2 = 53,46%, p = 0.92). In a pooled analysis of alternative loop diuretics (including torsemide and piretanide) the risk of SAEs was higher compared to furosemide (risk ratio 1.32, 95% CI 1.03, 1.68); I2 = 0%), although this finding was based on a limited number of trials with inconsistent definitions and should therefore be interpreted cautiously. The pooled meta-analysis of change in body weight did not show a difference between loop diuretics (mean difference 0.00 kg, 95% CI -1.19, 1.20; I2 = 92.43), indicating substantial heterogeneity. Azosemide resulted in a significant weight loss reduction compared to furosemide (mean difference - 1.00 kg, 95% CI -1.42, -0.58) based on a single small study. CONCLUSIONS: The choice of loop diuretic did not seem to influence the risk of mortality. In a pooled analysis of torsemide and piretanide, the risk of SAEs was higher when compared to furosemide, but the certainty of this finding is limited. Azosemide was associated with weight loss compared to furosemide in one small trial.
14 May 2026
Read appraisal →European journal of heart failure
Surrogate markers of clinical endpoints in clinical trials of heart failure.
AIMS: We aimed to determine whether treatment related changes in surrogate markers predict longer-term therapeutic effects on all-cause mortality and heart failure (HF) hospitalization in randomized trials of HF. METHODS: Systematic literature search included randomized trials of interventions in patients with HF until October 2024. Random-effects meta-regression models with inverse variance weighting were calculated between fifteen surrogate markers and the clinical endpoints of (i) all-cause mortality and (ii) HF hospitalization. The degree of heterogeneity of each model explained by the surrogate marker was determined with R2. Surrogate threshold effects (STEs) were also calculated. RESULTS: Ninety-six randomized trials with median follow-up 12 months were included, enrolling a total of 120 304 patients with HF. Treatment related changes in natriuretic peptides (NPs) were weakly correlated with all-cause mortality (64 comparisons, P = .002, R2 = 12%, and STE = -34%) and HF hospitalization (41 comparisons, P < .001, R2 = 32%, and STE = -30%). Changes in LVEF were moderately correlated with mortality (69 comparisons, P < .001, R2 = 59%, and STE = +6%) and strongly correlated with HF hospitalization (45 comparisons, P < .001, R2 = 90%, and STE = +2%), although this finding was only observed in trials of HFrEF. LV end-diastolic diameter was correlated with HF hospitalization but not mortality. Other echocardiographic markers were not predictive of clinical endpoints. Treatment related changes in patient reported outcomes and exercise capacity were either weakly correlated with clinical outcomes or derived from small clinical trials. CONCLUSION: In HF trials, most surrogate markers, including NPs and echocardiographic measures were only weakly or moderately correlated with treatment effects on all-cause mortality. There is insufficient evidence to support the use of a single biomarker or echocardiographic measure in regulatory trials of HF.
14 May 2026
Read appraisal →European journal of heart failure
Finerenone, polypharmacy, and clinical outcomes in heart failure: pre-specified analysis from the FINEARTS-HF trial
AIMS: Patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high comorbidity burden, which may necessitate numerous medications. Patients and clinicians may be hesitant about initiating another medication, especially among those already experiencing polypharmacy. This pre-specified analysis sought to examine the efficacy and safety of adding finerenone based on the concomitant medication number. METHODS: In the FINEARTS-HF trial, baseline medication use was collected in all 6001 participants with HFmrEF/HFpEF. Clinical outcomes and treatment effects were assessed by the categories of total medication count ('non-polypharmacy': ≤4 medications; 'polypharmacy': 5-9 medications; and 'hyper-polypharmacy': ≥10 medications) and as continuous variables. The primary outcome was a composite of cardiovascular death and total HF events. RESULTS: Overall (age: 72 ± 10 years; 46% women), the total number of medications at baseline ranged from 0 to 29 (mean: 8.4 ± 3.6), with 3588 (60%) meeting polypharmacy and 1878 (31%) meeting hyper-polypharmacy. Incidence rates for the primary outcome increased across medication categories: non-polypharmacy, 10.2; polypharmacy, 12.3; and hyper-polypharmacy, 26.1 per 100 person-years. The treatment benefits of finerenone in reducing the primary outcome were consistent across the spectrum of total medication count (Pinteraction = 0.94). Any serious adverse events and study drug discontinuation were not more frequent with finerenone vs placebo, regardless of polypharmacy categories. CONCLUSION: In FINEARTS-HF, >90% of patients with HFmrEF/HFpEF met the criteria for polypharmacy or hyper-polypharmacy, and these patients faced excess risks of cardiovascular events. Finerenone safely reduced cardiovascular death and total HF events across a broad range of baseline medication use.
14 May 2026
Read appraisal →Blood advances
Early mortality with bispecific antibody therapy in RRMM: an IMWG immunotherapy database real-world analysis
Recent therapeutic advances, including bispecific antibodies (bsAbs), have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, a total of 441 patients were treated across 7 countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%), with a median time from bsAb initiation to death of 2.87 months (interquartile range, 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of the cause of death, 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.
13 May 2026
Read appraisal →PloS one
Efficacy and safety of the ayurvedic formulation 'Trikatu' as an add-on to standard care in dyslipidemia: Study protocol for a randomized, double-blind, placebo-controlled trial evaluating lipid parameters, and gut microbiota.
BACKGROUND: Dyslipidemia is a leading modifiable risk factor for cardiovascular disease (CVD), with early and sustained LDL-C reduction offering significant preventive benefits. However, in low- and middle-income countries, long-term adherence to statin therapy remains alarmingly low, highlighting the need for culturally acceptable and safer adjunctive options. Trikatu, a classical Ayurvedic formulation traditionally known to enhance metabolism, may offer supportive benefits in lipid regulation. This study protocol was developed to assess the efficacy and safety of Trikatu as an add-on to standard statin therapy on lipid parameters and assess changes in gut microbiota in response to the intervention and identify microbial correlates associated with favorable lipid outcomes. METHODS: This randomized, double-blind, placebo-controlled clinical trial is being conducted at AIIMS Bhubaneswar, a tertiary care center. Total 170 participants (aged 25-60 years) with moderate to high Atherosclerotic cardiovascular disease (ASCVD) risk. Dyslipidemia, as defined by the 2019 ACC/AHA Guidelines and indicated for statin therapy, will be randomized in a 1:1 ratio to receive either Trikatu (1000 mg) or matching placebo, administered orally twice daily after food for 12 weeks along with standard statin therapy (dose/intensity as per guidelines). Primary outcome includes change in fasting serum LDL-C from baseline to 12 weeks. Secondary outcomes include changes in total cholesterol, HDL-C, triglycerides, glycemic markers (fasting glucose, HbA1c, insulin, HOMA-IR), inflammatory and metabolic markers (hs-CRP, TNF-α, IL-6, adiponectin, ghrelin, ApoA1, ApoB), resting blood pressure, and gut microbiota. The proportion of participants achieving normal cholesterol levels (<200 mg/dL) will also be assessed. Drug compliance and any adverse events will also be recorded. DISCUSSION: In individuals with moderate to high ASCVD risk, achieving and sustaining optimal lipid control remains a cornerstone of cardiovascular prevention. However, poor long-term adherence to statin therapy, especially in low-resource settings, limits real-world impact. By assessing Trikatu, effects on lipid profiles, glycemic and inflammatory markers, and gut microbiota, the study aims to explore its potential to augment cardiovascular risk reduction in a holistic and culturally acceptable manner. If proven effective and safe, Trikatu could serve as a valuable complementary strategy in dyslipidemia management. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI/2023/04/051942) Registered on 25/04/2023.
13 May 2026
Read appraisal →Blood advances
Belantamab mafodotin, carfilzomib, lenalidomide, and dexamethasone for relapsed or refractory multiple myeloma
Belantamab mafodotin (belamaf), an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated single-agent activity in relapsed/refractory multiple myeloma (RRMM) but is associated with ocular toxicity. This phase 1/2 study evaluated the safety and preliminary efficacy of belamaf administered every 8 weeks in combination with carfilzomib, lenalidomide, and dexamethasone (KRd-b) in patients with RRMM. Eligible patients had received at least 1 previous line of therapy and had not progressed on full-dose lenalidomide. In the dose-escalation phase (3+3 design), belamaf was administered at 1.4 or 1.9 mg/kg every 8 weeks. The recommended phase 2 dose was 1.9 mg/kg, with no dose-limiting toxicities at this level. Among 19 patients treated, the overall response rate was 89.5%, and 78.9% achieved very good partial response or better, with minimal residual disease negativity in all complete responders. At a median follow-up of 19.3 months, 24-month progression-free survival and overall survival rates were 74.3% and 85.1%, respectively. Keratopathy occurred in 94.7% of patients but was mostly grade 1 to 2, reversible, and manageable without permanent discontinuation. Grade ≥3 keratopathy (31.6%) was comparable with historical rates despite the less frequent dosing. Other adverse events, including hematologic and gastrointestinal toxicities, were manageable and consistent with known profiles of KRd or belamaf. The combination demonstrated deep and durable responses, including in patients at high-risk and with lenalidomide maintenance dose-refractory disease. These results support the feasibility of KRd-b with extended-interval belamaf and warrant further evaluation in phase 2 trials to confirm its clinical benefit in RRMM. This trial is registered at www.clinicaltrials.gov as NCT04822337.
13 May 2026
Read appraisal →Journal of computer-aided molecular design
Ensemble learning-guided discovery of anti-tuberculosis phytochemicals: computational prediction and mechanistic insights
Tuberculosis (TB) remains a major global health challenge driven by persistent Mycobacterium tuberculosis infection and increasing drug resistance. Phytochemicals represent a structurally diverse and underexplored chemical space for anti-TB drug discovery, yet systematic prioritization strategies integrating machine learning and structure-based validation are limited. A curated phenotypic anti-TB dataset of 425,180 compounds was used to train ensemble ExtraTrees models based on ECFP4 fingerprints and physicochemical descriptors. The models achieved strong predictive performance (ROC-AUC up to 0.983; MCC up to 0.871). SHAP analysis enabled mechanistic interpretation by identifying the key molecular descriptors and fingerprint features driving anti-TB activity predictions. The validated ensemble was applied to screen 4707 phytochemicals, yielding 3209 predicted actives, of which 778 satisfied applicability domain criteria. High-confidence candidates were subsequently evaluated by molecular docking against twelve structurally validated essential M. tuberculosis targets spanning cell wall biosynthesis, energy metabolism, nucleotide synthesis, and cofactor pathways. Docking analysis identified 486 phytochemicals with favorable predicted binding affinities, including 193 compounds exhibiting multi-target engagement. Several top-ranked candidates reproduced canonical interaction patterns of co-crystallized inhibitors, supporting mechanistic plausibility. This integrated chemoinformatics and structure-based framework enables robust prioritization of phytochemicals with biologically meaningful and multi-target antitubercular potential. The study provides a computationally grounded strategy for accelerating lead identification against drug-resistant TB.
13 May 2026
Read appraisal →Psychological medicine
Risk factors associated with blood dyscrasia during clozapine treatment: a systematic review and meta-analysis
Clozapine is the only effective treatment for treatment-resistant schizophrenia, but concerns over blood dyscrasia and need for monitoring limit its use. Evidence suggests many hematological abnormalities may result from surveillance bias, with agranulocytosis being the primary adverse effect directly induced by clozapine. This systematic review (PROSPERO: CRD42024487199) investigates non-genetic risk factors associated with blood dyscrasia during clozapine treatment, focusing on neutropenia and agranulocytosis. Random-effect meta-analyses were performed on studies reporting quantitative risk data. Due to inconsistent neutropenia definitions, analyses used absolute neutrophil count (ANC) thresholds of <2000/mm3, <1500/mm3, and <500/mm3. Forty-four studies were included in the systematic review, 15 in meta-analyses. No significant association was found between agranulocytosis and female gender (OR = 1.48, 95% CI: 0.92-2.38; p = 0.106) or age (pooled standardized mean difference [SMD] = 0.32, 95% CI: -0.26 to 0.90, p = 0.285), whilst a modest inverse association with clozapine dose (SMD = -0.32, 95%CI: -0.50 to -0.14, p < 0.001) and baseline white cell count (SMD = -0.21, 95%CI: -0.40 to -0.03, p = 0.026) was found. Neutropenia (ANC < 2000/mm3) was positively associated with concomitant psychotropic use (OR = 2.15, 95% CI: 1.13-4.07, p = 0.019). Clozapine rechallenge studies revealed no significant associations with gender, age, duration of initial clozapine trial, or length of discontinuation period prior to rechallenge. No strong predictors of clozapine-associated blood dyscrasia were identified. Findings may be limited by study variability, surveillance bias, and lack of consistent differentiation between agranulocytosis and milder neutropenia, highlighting limitations in current evidence.
13 May 2026
Read appraisal →Journal of chemical information and modeling
A Transformer for Reaction-Aware Compound Explorations with GFlowNet in QSAR-Guided Molecular Design
In drug discovery tasks, achieving a balance between high biological activity toward therapeutic targets and synthetic chemical feasibility is critically important. While the recently proposed deep learning-based molecular generation models have enabled explorations of vast chemical spaces, most existing approaches do not consider synthetic routes for generated compounds. To address this issue, TRACE-GFN is proposed for molecular optimization; this method incorporates chemical reaction pathways into a quantitative structure-activity relationship (QSAR)-guided molecular design procedure. The method integrates a transformer model to explicitly learn chemical reactions with a generative flow network (GFlowNet) that efficiently samples diverse candidates. In benchmark experiments involving dopamine receptor D2 (DRD2), AKT serine/threonine kinase 1 (AKT1), and C-X-C motif chemokine receptor 4 (CXCR4), TRACE-GFN demonstrated the ability to identify compounds with high QSAR values while maintaining strong diversity, outperforming the existing molecular generation models. These results demonstrate that the proposed model can efficiently explore promising compounds while accounting for real-world chemical reactions. The source code is publicly available under an MIT license at https://github.com/sekijima-lab/TRACE-GFN.
13 May 2026
Read appraisal →Journal of chemical information and modeling
mDADGAN: Predicting miRNA-Drug Response Associations Using lncRNAs and a Diffusion-Based Generative Adversarial Network
MicroRNAs (miRNAs) are key regulators of anticancer drug response, including sensitivity and resistance. Accurate prediction of miRNA-drug response associations is important for understanding response mechanisms and guiding targeted therapy. Existing prediction methods are difficult to fully capture complex high-order biological interactions and are sensitive to data sparsity and class imbalance. In this paper, we present an miRNA-drug response association prediction method called mDADGAN by constructing a diffusion-based generative adversarial network. First, we curated a large-scale and biologically informative data set from four public data resources by aggregating functional associations to facilitate model training. Second, we built a miRNA-lncRNA-drug interaction network by integrating lncRNA into the miRNA-drug network to address data sparsity and employed heterogeneous graph convolution to extract latent features from the interactions among miRNAs, lncRNAs, and drugs. Third, we applied diffusion-based perturbation to denoise and enhance the robustness of feature representations. Finally, we performed cost-sensitive learning to optimize the objective function in an adversarial training process to address class imbalance. The experimental results on four data sets demonstrated that, compared with the existing six methods, mDADGAN achieved higher values for AUC, AUPR, ACC, Recall, and F1-score. The case study demonstrates that integrating lncRNA information effectively enhances miRNA-drug response association prediction. mDADGAN can not only accurately identify known associations in the data sets but also predict previously unreported candidate associations supported by published evidence. Overall, our method mDADGAN has the ability to identify potential miRNA-drug response associations and can provide guidance for future biological experiments to enhance experimental efficiency and reduce experimental costs.
13 May 2026
Read appraisal →Lancet (London, England)
Enpatoran, a Toll-like receptor 7/8 inhibitor, in moderate-to-severe systemic lupus erythematosus: findings from Cohort B of a multicentre, international, double-blind, placebo-controlled dose-finding phase 2 trial
BACKGROUND: Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE). METHODS: Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score. The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis. Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. FINDINGS: Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively. INTERPRETATION: In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. FUNDING: Merck Healthcare (Darmstadt, Germany).
13 May 2026
Read appraisal →Journal of chemical information and modeling
DRHIN: An Integrated and Interactive Web Server for Drug Repositioning
Drug repositioning (DR) identifies new therapeutic uses for approved drugs, reducing development burdens and offering safer treatment options for patients. While high-throughput technologies generate complex, large-scale multiomics data, existing DR tools struggle to comprehensively analyze the resulting biological networks. To address this challenge, we present DRHIN, an integrated, interactive web server for DR over heterogeneous information networks (HINs) using advanced deep learning techniques. DRHIN integrates transcriptomics, proteomics, and microbiome data, incorporating eight biological entities and 19 association types to build diverse HINs and elucidate the underlying molecular mechanisms. It includes 19 state-of-the-art graph representation algorithms, enabling flexible training, comparison, and evaluation of heterogeneous network data. The platform provides a code-free portal supporting three key predictive tasks: discovering drug-disease associations, repurposing existing drugs for new indications, and identifying potential therapies for specific diseases, making analyses accessible and reproducible. Leveraging high-performance computing, DRHIN efficiently processes million-scale networks, ensuring practical applicability in real-world scenarios. The web server is freely accessible at http://drhin.tianshanzw.cn.
13 May 2026
Read appraisal →Journal of chemical information and modeling
In Silico Prediction of Potential Bile Salt Export Pump Inhibitors Using Pharmacophore Models and Consensus Machine Learning
The ATP-dependent bile salt export pump (BSEP) is a transporter responsible for moving bile salts from hepatocytes into bile canaliculi. Inhibition of BSEP is a known risk factor of cholestatic-drug-induced liver injury (DILI) probably caused by the accumulation of toxic bile salts in the liver. Since DILI is a major cause for attrition during drug development and postmarketing withdrawal or black box warnings, an IC50 of BSEP higher than 25 μM is advised. Here, we describe the investigation of several in silico approaches to map potential BSEP inhibitors. A consensus machine learning classification model is presented, which accurately predicts BSEP inhibitors and can assist in the prioritization of in vitro testing. An applicability domain was derived for the model, and it was validated by in vitro measurements of predicted BSEP inhibitors where the model was able to correctly flag eight out of 11 compounds.
13 May 2026
Read appraisal →Journal of chemical information and modeling
Artificial Intelligence for Predicting Small-Molecule Bioactive Conformations
Precise prediction of bioactive conformations represents a central challenge in drug discovery. Traditional computational methods often rely on the assumption that the global minimum energy state corresponds to the bioactive conformation─a hypothesis with inherent limitations. Data-driven artificial intelligence (AI) models have revolutionized research methodologies in this domain. By learning the implicit probability distributions of conformations, AI demonstrates the potential to achieve high-precision predictions of bioactive structures. This review systematically surveys technical advancements ranging from geometric regression to generative and conditional generative models, analyzing their effectiveness in benchmarks and de novo design experiments. We deeply explore critical challenges, including data sparsity, sampling efficiency, generation capability, and interpretability. Finally, we provide an outlook on bridging the gap from "structural prediction" to "functional design" through the construction of dynamic data sets, the development of efficient algorithms, and the implementation of human-in-the-loop collaborative decision-making systems.
13 May 2026
Read appraisal →European journal of clinical pharmacology
The impact of gene polymorphisms on the response of methotrexate-based treatments
PURPOSE: Methotrexate (MTX) is a long-standing drug used to treat leukemia (at high doses to inhibit DNA/RNA synthesis) and rheumatoid arthritis (at low doses for anti-inflammatory effects). Its characteristic narrow therapeutic range, in terms of efficacy and safety associated with MTX, are important factors to consider when deciding whether to prescribe it. A major challenge in its use is interindividual variability which is largely attributed to germline genetic polymorphisms in genes encoding proteins that control the pharmacokinetics or pharmacodynamics of MTX. METHODS: This study updates a previous 2018 review using a systematic literature search in PubMed/MEDLINE, Scopus, and SciELO. The search, conducted according to the PRISMA protocol, employed predefined keywords to identify studies published up to June 2025. RESULTS: This systematic review identified that, to date, only a few genetic polymorphisms influence clinical decision-making. Specifically, the MTHFR 677T allele and the MTHFR 677T-1298 A haplotype (rs1801133- rs1801131) have been associated with toxicity in both adults and children. Furthermore, the 677T-1298 A haplotype has been linked with reduced event-free survival in Caucasian patients with either adult RA or pediatric ALL. Regarding other markers, the TYMS rs34743033 3R allele has been implicated with reduced efficacy in adult patients receiving low-dose MTX, while the FPGS rs1544105 T allele has shown an association with diverse toxicities in ALL pediatric patients. CONCLUSION: Although considerable research has been conducted and numerous results have been obtained, the available evidence remains predominantly of moderate quality. Consequently, current guidelines from CPIC and the DPWG do not recommend routine MTX dose adjustments based solely on single gene variants. It is, therefore, imperative to develop and validate multifactorial risk prediction tools that integrate a range of other clinical factors. Accordingly, the establishment of a comprehensive pharmacogenetics-guided dosing guideline for MTX remains an elusive goal.
13 May 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Phase I Study of Mosperafenib, a Novel Paradox Breaker B-Raf Proto-Oncogene Serine/Threonine Kinase (BRAF) Inhibitor, in Patients With BRAF V600-Mutant Solid Tumors
PURPOSE: BRAF V600 mutations are tumor-agnostic oncogenic drivers whose targeted inhibition is challenged by therapeutic resistance. Mosperafenib is a novel paradox breaker and brain-penetrant BRAF inhibitor (BRAFi), tested in this study for safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary clinical activity. PATIENTS AND METHODS: This phase Ia/b study was conducted in patients with advanced solid tumors harboring a BRAF V600 mutation (ISRCTN13713551). The modified continuous reassessment method guided dose escalation of mosperafenib, which was given orally up to 3,600 mg once daily in 28-day cycles. The primary objective was to estimate the MTD and/or recommended phase II dose(s). RESULTS: Eighty patients (60% BRAFi-exposed)-63 with colorectal cancer (CRC), 13 with melanoma, and 4 with other solid tumors-received ≥1 dose of mosperafenib as a single agent for a median of 3.7 months (range, 0.2-28.6). Two dose-limiting grade 3 toxicities of rash and rash maculopapular were reported. MTD was not reached. Grade 3 to 4 treatment-related adverse events (TRAEs) occurred in 13 patients (16.3%); no grade 5 TRAEs events were reported. Two patients (2.5%) discontinued study treatment due to TRAEs. There were no reports of palmar-plantar erythrodysesthesia or keratoacanthoma. Linear and time-independent PK was demonstrated across the tested dose range, achieving exposure levels with sustained PK-derived pERK inhibition ≥90%. An exposure-response relationship was observed. Overall response rate was 24.2%, including two complete responses and 14 partial responses. Median progression-free survival was 6.4 months in patients with CRC (200 mg once daily-1200 mg three times a day) and 3.5 months in patients with melanoma (200 mg once daily-800 mg twice a day). CONCLUSION: Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-naïve and BRAFi-exposed patients.
13 May 2026
Read appraisal →mAbs
Machine learning predictions of IgG1 and IgG4 self-association and high-concentration solution properties
To meet the widespread demand for subcutaneous delivery of antibody therapeutics, candidates with low viscosity, high solubility, and/or low aggregation propensity in concentrated formulations must be identified. Moreover, early identification of candidates with low self-association increases the likelihood of success at later stages of the development process. Here, we experimentally profile the self-association behavior of a panel of clinical-stage antibodies as a function of pH, excipient content, and antibody isotype. We find that acidic formulations (pH 5) with proline (200 mM) are most effective at suppressing self-association for both IgG1 and IgG4 variants. Moreover, our self-association measurements are correlated with antibody viscosity measurements and inversely correlated with antibody recovery after their concentration using membrane filters. Notably, we developed interpretable machine learning-based classifier and regressor models for predicting IgG1 and IgG4 self-association and demonstrated that they identify antibodies with favorable high-concentration properties. These findings are expected to improve the antibody development process by facilitating the identification of drug-like molecules during their discovery and optimization.
13 May 2026
Read appraisal →Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Efficacy and safety of GLP-1 receptor agonists in Parkinson's disease: a systematic review and meta-analysis of randomized clinical trials
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder with no proven disease-modifying therapies to date. Because changes in cerebral glucose metabolism and insulin resistance have been linked to PD pathophysiology, glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for diabetes, have been investigated as potential neuroprotective treatments. METHODS: This study systematically assessed the efficacy and safety of GLP-1RAs in PD through a systematic review and meta-analysis of randomized controlled trials identified in PubMed, Embase, and the Cochrane Library. The primary outcomes were motor function improvements measured by the MDS-UPDRS Part III in both on- and off-medication states at study endpoints and at intermediate timepoints of interest. Secondary outcomes included MDS-UPDRS Parts I, II, and IV, quality of life assessed by the PDQ-39, levodopa equivalent daily dose (LEDD), and the occurrence of adverse events. RESULTS: The meta-analysis found no statistically significant difference in favor of GLP-1RAs over placebo for motors and non-motors outcomes, except for PDQ-39 (MD: - 0.75; 95% CI: [- 1.34, - 0.17], P = 0.01). Regarding safety, GLP-1RAs were associated with a higher incidence of adverse events, especially gastrointestinal effects such as nausea, vomiting, and constipation. CONCLUSIONS: Overall, current evidence does not demonstrate consistent clinical benefit of using GLP-1RAs for treating motor or non-motor symptoms in PD nor support GLP-1RAs as disease-modifying therapy, underscoring the need for further research.
13 May 2026
Read appraisal →Med (New York, N.Y.)
Mazdutide 9 mg in Chinese adults with a body mass index ≥30 kg/m2 but without diabetes: A phase 2 randomized controlled trial
BACKGROUND: Once-weekly dual glucagon and glucagon-like peptide-1 receptor agonist mazdutide, administered at 4 and 6 mg, provides substantial weight loss in Chinese adults with overweight or obesity. This trial aimed to evaluate the efficacy and safety of mazdutide 9 mg in Chinese adults with obesity. METHODS: In this randomized, double-blind, placebo-controlled phase 2 trial (NCT01904913), participants with a body mass index (BMI) ≥30 kg/m2 and without diabetes were randomized 3:1 to receive mazdutide 9 mg or placebo for 24 weeks. The primary endpoint was the percentage change in body weight from baseline to week 24. FINDINGS: Eighty participants were randomized and received mazdutide 9 mg (n = 60) or placebo (n = 20). At week 24, the mean percentage change in weight from baseline was -12.78% with mazdutide 9 mg and 1.80% with placebo (treatment difference: -14.58% [95% confidence interval (CI) -18.00, -11.16], p < 0.0001). Weight reduction ≥5% was achieved by 81.7% of participants with mazdutide after 24-week treatment, while no participants with placebo achieved this threshold. Mazdutide treatment was associated with greater improvements in cardiometabolic risk factors vs. placebo. The most common adverse events included nausea (50.0% with mazdutide vs. 0% with placebo), diarrhea (38.3% vs. 10.0%), and vomiting (36.7% vs. 10.0%), predominantly mild to moderate in severity. CONCLUSIONS: Mazdutide 9 mg was safe and led to substantial weight reductions in Chinese adults with a BMI ≥ 30kg/m2 but without diabetes after 24-week treatment. These results support further clinical development of mazdutide 9 mg for the treatment of obesity. FUNDING: This study was sponsored by Innovent Biologics.
12 May 2026
Read appraisal →The oncologist
Characterization and clinical management of adverse events following treatment with repotrectinib: a TRIDENT-1 analysis
BACKGROUND: Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. PATIENTS AND METHODS: The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. RESULTS: In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. CONCLUSION: Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.
12 May 2026
Read appraisal →Med (New York, N.Y.)
Evaluation of recombinant human prourokinase for acute pulmonary embolism: A phase 2, randomized clinical trial
BACKGROUND: Recombinant human prourokinase (rhPro-UK) is a novel plasminogen activator under investigation for acute pulmonary embolism (aPE). We aimed to explore the efficacy and safety of rhPro-UK vs. alteplase (recombinant tissue plasminogen activator [rt-PA]) in patients with aPE. METHODS: In this phase 2, randomized, single-blind, multicenter, active-controlled, randomized trial involved eighteen centers from university-affiliated tertiary hospitals across China. Patients aged 18-75 years with high or intermediate-to-high risk aPE were randomized to receive intravenous rhPro-UK (40 mg, n = 37; 50 mg, n = 35) or rt-PA (n = 35) and were followed for 7-30 days. The primary efficacy outcome was the change from baseline in systolic pulmonary artery pressure (sPAP) at 24 h post-treatment. Secondary outcomes include changes in right ventricular function parameters. Safety outcomes include all-cause mortality, recurrent PE, hemodynamic deterioration within 7 days, and bleeding events within 30 days. FINDINGS: All treatment groups showed a reduction in sPAP at 24 h (mean change: 40 mg rhPro-UK, -13.40 mmHg [95% confidence interval (CI): -24.10 to -2.71]; 50 mg rhPro-UK, -15.42 mmHg [95% CI: -25.93 to -4.91], and rt-PA: -16.02 mmHg [95% CI: -25.53 to -6.51]), with improvements sustained through 30 days. The incidence of non-major bleeding events was numerically lower in the rhPro-UK groups (40 mg: 63.9%; 50 mg: 55.6%) compared to the rt-PA group (82.9%; p = 0.04). Two deaths occurred, each in the 40 mg rhPro-UK group and rt-PA group. CONCLUSION: rhPro-UK tended to result in early hemodynamic improvement comparable to rt-PA and seemed to have a numerically lower risk of non-major bleeding events. The ClinicalTrials.gov identifier is NCT03108833. FUNDING: This work was funded by Tasly Biopharmaceuticals Co., Ltd.
12 May 2026
Read appraisal →Journal of ethnopharmacology
Anti-inflammatory properties of Dendrobium: A systematic review of pharmacological mechanisms
ETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Chinese Medicine (TCM), Dendrobium species have long been used to alleviate various inflammatory conditions, particularly those characterized by Yin deficiency with internal heat and stomach deficiency-heat, including impaired fluid production, stomach Qi dysfunction, and poor appetite. The inflammatory response is regulated by multiple signaling pathways that drive disease pathogenesis, making these pathways promising targets for anti-inflammatory therapy. Medicinal Dendrobium, enriched with anti-inflammatory bioactive constituents, exhibits substantial systemic anti-inflammatory activity. Its growing research interest stems from favorable properties such as low toxicity, broad therapeutic efficacy, and minimal risk of drug resistance. AIM OF THE STUDY: Medicinal Dendrobium and its bioactive constituents have demonstrated significant anti-inflammatory properties, underscoring their pharmacological potential. Nevertheless, substantial efforts remain an urgent priority to advance the translation of basic research findings into clinical applications. Therefore, pharmacological studies published within the past six years were systematically reviewed to elucidate the mechanisms by which Medicinal Dendrobium and its bioactive constituents modulate inflammatory processes, thereby evaluating their potential as multi-targeted natural anti-inflammatories. This will facilitate the translation of anti-inflammatory research on medicinal Dendrobium from basic research to clinical investigation, thereby laying a solid foundation for its eventual clinical application in managing inflammatory diseases. MATERIALS AND METHODS: A literature search and screening strictly followed the PRISMA 2020 guidelines and employed a predefined Boolean strategy. A comprehensive search was conducted across Web of Science, PubMed, Elsevier, ScienceDirect, Scopus, CNKI, Wanfang Data, Baidu Scholar, and Google Scholar. No language restrictions were applied; this review includes key findings from Chinese-language literature. The predefined keywords included "Dendrobium," "Shihu," "bioactive constituents," "anti-inflammatory," "cytokines," "signaling pathways," as well as their corresponding Chinese terms. Taxonomic validation was conducted using the World Flora Online (http://www.worldfloraonline.org) and the Medicinal Plant Names Services (http://mpns.kew.org) databases. RESULTS: Eight Medicinal Dendrobium species and their bioactive constituents-such as polysaccharides, alkaloids, flavonoids, bibenzyls, polyphenols and stilbenoids-exert anti-inflammatory effects by modulating multiple signaling cascades, including NF-κB, MAPK/NF-κB, TLR4/NF-κB, PI3K/AKT, Nrf2/HO-1, JAK/STAT, and AMPK/SIRT1 pathways, indicating their multi-target therapeutic potential for inflammatory diseases. This review further underscores the innovative role of Dendrobium in regulating these pathways and its potential for integration with conventional pharmacological treatments, supporting its synergistic use in precision medicine. CONCLUSIONS: Medicinal Dendrobium represents a promising ethnopharmacological resource, exhibiting broad-spectrum anti-inflammatory effects through multi-target, multi-pathway, and multi-organ mechanisms. To advance its modernization, therapeutic development, and clinical translation, future research should prioritize several key directions: establishing standardized quality control system and prioritizing the structures of core bioactive constituents; applying a multi-omics approach combined with artificial intelligence-assisted modeling, network pharmacology and advanced molecular imaging techniques to systematically map its systemic anti-inflammatory regulatory network; strengthening systematic pharmacokinetic and bioavailability studies; exploring precision and synergy delivery formulations; and conducting rigorous assessments of safety profiles and side-effect management. By focusing on these priorities, research can further elucidate the systemic anti-inflammatory mechanisms of medicinal Dendrobium, thereby bridging its traditional use with contemporary precision medicine, and supporting integrated interventions for complex inflammatory diseases.
12 May 2026
Read appraisal →Journal of ethnopharmacology
Senecio scandens Buch. - Ham.: A comprehensive review of botany, phytochemistry, biological activity, toxicity, quality control, application, and practical domain.
ETHNOPHARMACOLOGICAL RELEVANCE: Senecio scandens Buch.-Ham., a medicinal herb from the Asteraceae family, contains flavonoids, terpenoids, and alkaloids as its primary bioactive compounds. It is commonly used in the treatment of ocular diseases and dermatological conditions. However, with its expanding applications across various fields, growing attention has been directed toward the potential safety concerns associated with its use. AIM OF THE REVIEW: This article systematically reviews existing literature on S. scandens, examining its botany, phytochemistry, biological activity, toxicity, applications, and development utilization, to provide a theoretical basis for in-depth exploration of its pharmacological mechanisms and resource development. MATERIALS AND METHODS: This study conducted a systematic review of literature on S. scandens published from 1972 to 2025, based on databases including PubMed and Web of Science. Plants names are provided in accordance with "The Plant List" (https://wfoplantlist.org/). RESULT: Over 200 chemical constituents, primarily flavonoids, terpenoids, and alkaloids, have been isolated and identified from S. scandens, endowing it with diverse biological activities such as anti-inflammatory, antibacterial, antioxidant, and anti-tumor effects. To address potential hepatorenal toxicity from its pyrrolizidine alkaloids, relevant safety guidelines have been gradually established alongside various clinical dosage forms. It is also widely used in fields including medicine, animal husbandry, agriculture, and cosmetics. CONCLUSION: By systematically reviewing the botany, phytochemistry, biological activity, toxicity, application, and development and utilization of S. scandens, this paper identifies key utilization obstacles, proposes future research directions, and provides a theoretical framework for its further development.
12 May 2026
Read appraisal →Journal of ethnopharmacology
Long Gu (Os Draconis): Textual research, modern scientific evaluation, and quality control challenges.
ETHNOPHARMACOLOGICAL RELEVANCE: Long Gu (Os Draconis), a mineral medicine with over 2000 years of use in traditional Chinese medicine, is facing a critical juncture. Its identity has been clarified scientifically-from a mythologized "dragon bone" to a fossilized mammalian bioapatite-yet its sustainable clinical application is threatened by resource depletion, widespread domestic and international adulteration, and the lack of modern quality standards. AIM OF THE STUDY: This review aims to systematically analyze the evolution of Long Gu through historical materia medica, define its authentic characteristics using modern science, diagnose the root causes of its current market and regulatory crisis, and propose a robust, multi-dimensional framework for quality evaluation and sustainable sourcing. MATERIALS AND METHODS: A systematic review of Chinese materia medica literature from the Pre-Qin to Qing Dynasties was conducted. Historical textual research was integrated with evidence from modern mineralogy, paleontology, geochemistry, and pharmacology to validate traditional knowledge and establish scientific identification criteria. RESULTS: The understanding of Long Gu evolved from mythological origins to a scientific conclusion in the Ming Dynasty, with Li Shizhen correctly identifying it as fossilized ancient mammalian bones. Modern research confirms authentic "Wuhua Long Gu" from the Shanxi-Shaanxi region is primarily carbonated hydroxyapatite, characterized by high porosity (>35%), significant hygroscopicity, and a unique trace element profile (Zn, Sr). These properties underpin its advertised therapeutic effects. However, the market is now saturated with dangerous adulterants, including fluoride-rich dinosaur fossils and processed modern bones, due to resource exhaustion and inadequate pharmacopoeial standards focused solely on calcium content. CONCLUSION: The future of Long Gu depends on transcending outdated quality controls. Ensuring its efficacy and safety necessitates a paradigm shift to a comprehensive standard system that combines paleontological and geochronological origin verification, quantitative microstructural analysis, chemical fingerprinting of key components, and strict safety monitoring. Complementary research into biomimetic synthesis and accelerated mineralization is urgently needed to develop sustainable alternatives for this invaluable yet endangered medicinal resource.
12 May 2026
Read appraisal →Neurology
IV Fosphenytoin for Acute Trigeminal Neuralgia: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
BACKGROUND AND OBJECTIVES: Trigeminal neuralgia (TN) is a debilitating condition characterized by sudden, severe facial pain. IV medications for acute TN exacerbations have not been investigated in randomized controlled trials (RCTs). Oral medications are often insufficient for acute attacks, and surgery is not immediately available. We conducted an RCT to evaluate IV fosphenytoin therapy (IFT) as a rapid-acting rescue treatment for acute TN exacerbations. We hypothesized that, compared with placebo, IFT would reduce acute TN pain. METHODS: This multicenter, double-blind, placebo-controlled phase 3 trial was conducted at 6 institutions (April 2023-April 2024). Patients with classical or idiopathic TN who were experiencing TN exacerbation (numerical rating scale [NRS] score ≥5) were recruited from emergency and outpatient settings, and all study drugs were administered during hospital admission. Participants were randomized 1:1 to IFT (initial dose: 18 mg/kg, maintenance: 7.5 mg/kg for 4 days) or placebo. The primary end point was the change in NRS pain scores from baseline to 120 minutes after the initial dose. Secondary end points included attack frequency, the proportion achieving ≥50% NRS score improvement, and adverse events. Data were collected by blinded personnel and analyzed using repeated-measures mixed-effects models. RESULTS: Of 31 participants screened, 22 were randomized; 1 placebo-assigned participant did not meet the NRS ≥5 criterion and was excluded, leaving 21 for analysis (IFT: 11; placebo: 10). Participants had a mean age of 65.2 years (range 42-83; 8 men, 13 women). Compared with placebo, IFT significantly reduced pain (NRS change: -6.1 vs -2.4; between-group difference -3.8; 95% CI -6.4 to -1.1; p = 0.008), decreased attack frequency within 24 hours (2.5 ± 5.3 vs 16.1 ± 19.6, difference -13.6; 95% CI -26.4 to -0.7), and increased the proportion achieving ≥50% NRS improvement (90.9% vs 40.0%, difference 50.9%; 95% CI 5.6%-81.6%). Adverse events (somnolence, hypotension, and nausea) were mild and transient. DISCUSSION: IFT provided rapid and well-tolerated pain relief in acute TN exacerbations. Although findings are preliminary because of the small sample size, IFT may be a viable short-term treatment option, meriting further investigation. TRIAL REGISTRATION INFORMATION: Japan Registry of Clinical Trials, jRCT2011220043. Registered March 3, 2023. First enrollment April 25, 2023. jrct.mhlw.go.jp/en-latest-detail/jRCT2011220043. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with acute TN exacerbations, IV fosphenytoin is superior to placebo in reducing pain intensity at 120 minutes.
12 May 2026
Read appraisal →The oncologist
Characterization and clinical management of adverse events following treatment with repotrectinib: a TRIDENT-1 analysis
BACKGROUND: Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. PATIENTS AND METHODS: The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. RESULTS: In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. CONCLUSION: Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.
12 May 2026
Read appraisal →Journal of Crohn's & colitis
Safety of advanced therapies during pregnancy in women with immune-mediated inflammatory diseases: a systematic review and meta-analysis
BACKGROUND AND AIMS: We aimed to assess the safety of advanced therapies, excluding tumor necrosis factor inhibitors (anti-TNFs), for the treatment of immune-mediated inflammatory diseases (IMIDs), on pregnancy and neonatal outcomes. METHODS AND ANALYSIS: We performed a systematic review and meta-analysis. Study selection and data extraction were conducted independently by two reviewers. Primary outcomes included live births, major congenital malformations (MCMs), miscarriages, and stillbirths. Risk of bias was assessed using ROBINS-I, and the certainty of evidence was evaluated using GRADE. Meta-analyses of prevalence and odds ratios (ORs) comparing advanced therapies with anti-TNFs were conducted using fixed and random effect models. RESULTS: Of 14 661 manuscripts screened, 49 studies met the inclusion criteria: eight cohorts, nine case series, and 32 case reports. Most cohort studies were at a critical risk of bias. The majority of the available data related to ustekinumab (1324 exposed offspring) and vedolizumab (585 exposed offspring) whereas data on other biologics and JAK inhibitors were very limited. Pregnancies exposed to biologics had a pooled prevalence of 82.43% for live births, 0.55% for MCMs, 8.16% for miscarriage, and 0.00% for stillbirths. No significant differences in adverse pregnancy or neonatal outcomes were observed compared with women exposed to anti-TNFs. Overall, the level of evidence was very low, due largely to reliance on small observational studies and case reports. CONCLUSION: Current evidence does not suggest an increased risk of adverse pregnancy or neonatal outcomes with advanced therapies for IMIDs. However, larger, high-quality studies are needed, and these findings should be interpreted as hypothesis-generating.
12 May 2026
Read appraisal →European journal of pediatrics
Piperacillin-tazobactam versus cefepime monotherapy in pediatric patients with febrile neutropenia: a systematic review and meta-analysis
UNLABELLED: The purpose of this study is to evaluate whether piperacillin-tazobactam therapy, compared with cefepime monotherapy, results in significant difference in treatment success, mortality, and duration outcomes in pediatric patients with febrile neutropenia (FN). A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted following PRISMA guidelines. PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL were searched up to February 3. No starting limits for dates were used. We only included studies of pediatric patients with FN comparing piperacillin-tazobactam to cefepime monotherapy. Risk of bias was assessed using Cochrane RoB 2 tool. Meta-analysis was performed using random-effects model to calculate risk ratios (RR) and mean differences (MD). Five RCTs involving 470 episodes were included. The pooled analysis for treatment success showed no statistically significant difference between groups (RR = 1.02; 95% CI [0.89; 1.18]; P = 0.76) with low heterogeneity (I2 = 0.0%). No significant differences for mortality (RR = 2.09; 95% CI [0.62; 7.03]; P = 0.23; I2 = 0.0%). Duration of treatment was 0.9 day shorter for cefepime group (MD = 0.9 day; 95% CI [0.2; 1.6]; P < 0.1; I2 = 0%). CONCLUSION: No statistically significant difference was found in treatment success or mortality between the groups. Patients receiving cefepime had a treatment duration 0.9 days shorter than those receiving piperacillin-tazobactam, although this finding should be interpreted with caution. The available evidence remains limited. Further RCTs are needed to elucidate potential differences in treatment success, mortality, and duration between the drugs. REGISTRATION: PROSPERO (CRD420261296621). WHAT IS KNOWN: • Cefepime and piperacillin-tazobactam are widely utilized as empirical monotherapy for febrile neutropenia, but evidence regarding their comparative clinical efficacy and safety in children remains inconclusive. WHAT IS NEW: • This meta-analysis quantifies differences in treatment success, mortality and duration of treatment outcomes in pediatric patients with febrile neutropenia.
12 May 2026
Read appraisal →European journal of clinical pharmacology
Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on lipid profiles in patients with chronic kidney disease: a systematic review and meta-analysis
BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel oral agents for treating anemia in chronic kidney disease (CKD), with potential effects on lipid modulation. We aimed to systematically evaluate the effects of HIF-PHIs on lipid profiles and cardiovascular outcomes in CKD patients. MATERIALS AND METHODS: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase (Ovid) were searched for randomized controlled trials comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in dialysis-dependent (DD) or nondialysis-dependent (NDD) CKD patients. Primary outcomes included changes in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C). Secondary outcomes included cardiovascular outcomes, including cardiovascular death, myocardial infarction, stroke, and all-cause mortality. RESULTS: A total of 20 trials involving 12,155 patients were analyzed in this review. Roxadustat significantly reduced LDL-C (mean difference [MD], -16.07 mg/dL; 95% CI, -17.92 to -14.21; 14 randomized controlled trials [RCTs], 10,510 patients), total cholesterol (MD, -25.25 mg/dL; 95% CI, -29.70 to -20.81; 10 RCTs, 5,538 patients), triglycerides (MD, -19.70 mg/dL; 95% CI, -30.78 to -8.61; 9 RCTs, 4,616 patients), but also decreased HDL-C (MD, -4.91 mg/dL; 95% CI, -6.80 to -3.02; 9 RCTs, 5,132 patients). Desidustat significantly reduced LDL-C and total cholesterol, but showed no significant effects on triglycerides or HDL-C, whereas molidustat showed no significant lipid-lowering effects. Overall, treatment with HIF-PHIs was not associated with significant differences in cardiovascular death (RR, 1.00; 95% CI, 0.84 to 1.18; 10 RCTs, 9,371 patients), myocardial infarction (RR, 1.12; 95% CI, 0.90 to 1.38; 15 RCTs, 11,265 patients), stroke (RR, 1.18; 95% CI, 0.86 to 1.61; 14 RCTs, 11,136 patients), or all-cause mortality (RR, 1.06; 95% CI, 0.96 to 1.17; 19 RCTs, 11,903 patients), compared with ESAs or placebo. CONCLUSION: Roxadustat showed the most substantial lipid-lowering effects, while desidustat showed significant reductions in LDL-C and total cholesterol but no significant effects on triglycerides or HDL-C, and molidustat showed no significant effects. Despite these changes in lipid profiles, no significant differences in cardiovascular outcomes were observed for these three HIF-PHIs, compared with ESAs or placebo.
11 May 2026
Read appraisal →PloS one
DeepDRP: Dose-response predictions of drug pairs using deep learning based on data-driven feature representation and dose-response curve characteristics
Combination therapies have become a cornerstone of modern medicine, offering improved treatment outcomes and reduced side effects compared to monotherapies. However, the efficacy and safety of drug combinations depend heavily on the specific doses of each component, making the optimization of dosing regimens a crucial yet challenging task. Despite the importance of dose optimization, few computational methods address this challenge. Here, we propose DeepDRP, a novel approach that integrates two complementary models: the global model, which is trained using all available combinations, and the local model, which utilizes only samples with similar information to queries. The DeepDRP architecture comprises three main modules: the first module has three embedding networks to extract features from drugs, doses, and cell lines, and then predicts synergy using the fused knowledge. The second module constructs a graph using the input query and the set of similar retrieved training samples fed into a semi-supervised graph convolutional network to predict the synergy value. Finally, these two models are aggregated to have the final predicted value. To evaluate the proposed approach, it is applied to the NCI-ALMANAC dataset and O'Neil dataset. The obtained results denote that the proposed method achieves superior performance with respect to the other approaches.
11 May 2026
Read appraisal →Signal transduction and targeted therapy
Acute hemodynamic effects of TPN171H in pulmonary arterial hypertension: a randomized, controlled, phase 2a trial
Pulmonary arterial hypertension (PAH) has a poor prognosis despite available treatments. TPN171H, structurally modified from traditional Chinese medicine (Epimedium), was reported to have a high affinity for phosphodiesterase type 5 and exhibited anti-inflammatory and vasodilatory effects in preclinical studies. This phase 2a randomized trial (NCT04483115) evaluated the hemodynamic effects and safety of TPN171H in PAH. Sixty patients with PAH were randomly assigned to receive placebo, TPN171H (2.5, 5, or 10 mg) or tadalafil (20 or 40 mg) and evaluated for hemodynamic changes for 24 h. The primary endpoint was the maximum change (%) in pulmonary vascular resistance (PVR) from baseline. The key secondary endpoint was the change (%) in PVR to systemic vascular resistance (SVR) ratio at each observation point from baseline. Compared to the placebo group, the least square mean differences in the maximum change in PVR were -16.8% (95% CI, -29.1 to -4.5, p = 0.008) in TPN171H 5 mg, -15.4% (95% CI, -28.2 to -2.7, p = 0.019) in tadalafil 20 mg, and -13.3% (95% CI, -25.6 to -0.9, p = 0.036) in the tadalafil 40 mg group. Moreover, TPN171H 5 mg, but none of the tadalafil doses, showed a significant reduction in PVR/SVR ratio at 2 h (p = 0.026), 3 h (p = 0.030), and 5 h (p = 0.046) compared to the placebo group. No serious adverse events occurred. TPN171H 5 mg demonstrated favorable acute hemodynamic effects and an acceptable short-term safety profile in this exploratory trial, supporting further evaluation in adequately powered trials.
11 May 2026
Read appraisal →Behavioral and brain functions : BBF
Neuropeptide S modulation of learning and memory: a systematic review
BACKGROUND: In the last two decades, Neuropeptide S (NPS) has been identified as a key bioactive peptide in the mammalian brain, influencing fear, anxiety, wakefulness, reward, and learning. While some reviews have addressed its role in reward-seeking and anxiety, few have addressed its particular role in learning and memory. The neuropeptide S receptor 1 is highly expressed in key areas for learning processing, such as the hippocampus, cortex, thalamus, and amygdala. This review aims to examine evidence from human and animal studies that focused on the NPS system's role in modulating learning and memory. A special focus is given to experiments addressing the impact of NPS on associative learning leading to addiction and in fear conditioning, pointing to its potential therapeutic value in associated pathologies. MAIN BODY: An advanced search was conducted using the databases PubMed, Google Scholar, Web of Science, and Scopus, focusing on memory and Neuropeptide S. The reviewed data suggest that NPS modulation occurs at all memory phases, including acquisition, consolidation, and retrieval, and in extinction learning, whether motivated by appetitive or aversive stimuli. The summarized evidence shows that the NPS system interferes with working and short-term memory, mitigates learning impairments, enhances spatial and object memory consolidation, supports fear extinction learning and inhibitory avoidance consolidation, and reinstates drug-seeking behaviors. The NPS system closely interacts with key neuromodulators, including orexinergic, dopaminergic, and noradrenergic systems, in influencing memory. CONCLUSION: The Neuropeptide S system emerges as a critical modulator of memory processes. The NPS signaling may preferentially influence learning that involves emotionally or motivationally relevant stimuli. This highlights the NPS system's potential as a target for therapeutic interventions for particular memory impairments.
11 May 2026
Read appraisal →The Journal of dermatological treatment
Comparative efficacy and safety of oral azithromycin versus doxycycline in moderate-to-severe Acne vulgaris: a systematic review and meta-analysis
BACKGROUND: Acne vulgaris is a chronic inflammatory disease and is one of the leading causes of dermatological morbidities among young adults. Doxycycline is widely recommended as first-line therapy for moderate to severe acne; however, its use is limited. OBJECTIVE: To systematically compare the efficacy and safety of oral azithromycin pulse therapy versus doxycycline in patients with moderate to severe acne vulgaris. METHODS: This systematic review and meta-analysis followed PRISMA guidelines. A comprehensive literature search on different databases was performed. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models based on heterogeneity. RESULTS: A total of 23 comparative studies comprising 2,769 patients were included. Pooled analysis demonstrated a statistically significant improvement in global acne severity favoring azithromycin (GAGS reduction: MD 1.81; 95% CI 1.28-2.34; I2 = 0%). Azithromycin achieved a significantly greater reduction in non-inflammatory lesion counts (MD -7.56; 95% CI -14.33 to -0.79). No significant differences were observed in inflammatory lesion reduction (MD 1.08; 95% CI -0.03 to 2.18). CONCLUSION: Oral azithromycin pulse therapy appears to have similar efficacy, better tolerability, and fewer side effects as compared to doxycycline.
11 May 2026
Read appraisal →European journal of medicinal chemistry
AI-driven identification of a selective dual function inhibitor blocking HK2 activity and HK2-VDAC1 interaction displaying enhanced anticancer efficacy under hypoxia
Selective inhibition of hexokinase 2 (HK2) represents a promising therapeutic strategy due to the pivotal role of HK2 in the Warburg effect, enhancement of glycolysis and anti-apoptosis via HK2-Voltage-Dependent Anion Channel 1 (VDAC1) protein-protein interaction. Moreover, HK2 initiates glycolysis to generate lactate, hence this central enzyme can be pharmacologically targeted to enhance therapy outcomes. Currently, no HK2 inhibitors (HK2is) exist in the clinic. Herein, we employed GCVec, an artificial intelligence (AI)-based compound-protein interaction (CPI) prediction tool, along with molecular docking, to identify the HK2i, 106. This compound exhibited an IC50 of 0.79 ± 0.07 μM and a consistent Kd of 0.41 ± 0.03 μM against HK2 enzyme. It also apparently blocked HK2-VDAC1 interaction as indicated by the disrupted colocalization of HK2-GFP and VDAC1-mCherry. Furthermore, 106 demonstrated enhanced anticancer efficacy under hypoxia in tumor cells with elevated HIF-1α/HK2 and VDAC1 levels. Compound 106 selectively targeted SW480 colorectal cancer cells with high HK2 expression, achieving a growth inhibition IC50 value of 5.00 ± 0.94 μM. Consistently, knockout of HK2 in these tumor cells significantly rescued the IC50 values and eliminated the glycolytic inhibition induced by 106. We further showed that 106 reduced lactate and ATP levels and induced markers of apoptosis, including increased p-AMPK/AMPK ratio and increased Bax levels, as well as decreased Bcl2 levels. Collectively, our findings highlight the potential of GCVec in identifying 106, a first in class dual-function HK2i which emerges as a promising lead compound for further development into a possible anticancer therapeutic agent.
11 May 2026
Read appraisal →Molecular pharmaceutics
mRNASyner: An Integrative Framework for Full-Length mRNA Sequence Optimization via Multimodule Synergistic Design
Messenger RNA (mRNA) technology holds great promise in biomedicine; however, its therapeutic efficacy relies heavily on translation efficiency and the in vivo stability of mRNA sequences, both of which are governed by dynamic interactions between the coding and noncoding regions. Existing optimization approaches typically focus on individual sequence components and lack the capacity for global, synergistic optimization. Moreover, their performance is often limited when processing long sequences or supporting iterative sequence refinement. To overcome these challenges, we propose a unified and interpretable in silico framework for full-length mRNA sequence design, integrating CDS optimization, UTR generation, and degradation modeling. In silico case studies based on respiratory syncytial virus (RSV) vaccine design demonstrated that mRNASyner achieved a favorable balance between translational accessibility and structural stability. mRNASyner thus enables the design of full-length mRNA sequences, supports long-sequence optimization, and offers a novel solution for the development of personalized mRNA therapeutics.
11 May 2026
Read appraisal →Briefings in bioinformatics
Comprehensive evaluation of artificial intelligence-empowered approaches for protein-aptamer complex prediction
Drug discovery is a time-consuming, expensive, and high-risk process. Recent advances in artificial intelligence (AI) have enabled major breakthroughs in small-molecule and protein therapeutics. However, AI-driven design of aptamer drugs remains largely unexplored. Aptamers are short (15-100 nt) single-stranded DNAs or RNAs that exhibit high binding affinity, high specificity, and low immunogenicity, making them promising candidates for disease (such as cancer) therapeutics. Compared with protein-ligand or protein-protein systems, protein-aptamer complexes are under-represented in public structural databases, and aptamers themselves are highly flexible and relatively large molecules. These characteristics present distinct challenges for AI-based structural modeling. Here, we systematically evaluate recent AI frameworks, including AlphaFold3, Chai-1, Boltz-2, and RoseTTAFold2NA, along with a template-based approach, in predicting protein-aptamer complex structures and estimating binding free energies. We establish an independent benchmark to assess their performance in structural accuracy, stability, and energetic consistency. This study provides a foundation for the application of AI in aptamer drug design and offers a reference framework for future research in nucleic-acid therapeutics and biomolecular modeling.
10 May 2026
Read appraisal →The Journal of dermatological treatment
A safety checklist before initiating second-generation immunomodulating drugs for inflammatory dermatoses: a systematic review
BACKGROUND/AIM: Second-generation immunomodulating drugs for inflammatory dermatoses have expanded over the past decades. Contraindications and special warnings must be considered before starting any treatment, but identifying all relevant safety information can be time-consuming. The objective is to provide an overview of contraindications, special warnings, and boxed warnings with the aim to establish a safety checklist, covering second-generation immunomodulatory therapies. METHODS: We identified contraindications, special warnings and boxed warnings provided by the European Medicines Agency and the US Food and Drug Administration, for second-generation immunomodulating drugs approved for inflammatory dermatoses. Both topical and systemic therapies were included. RESULTS: Most drug classes had warnings related to infections. Herpes zoster was listed for anti-CD20, IL-12/23i, INFi, JAKi and TYK2i, where hepatitis reactivation was reported for anti-CD20, TNFi, IL-17i, anti-BAFF, JAKi and TYK2i. Malignancy risk including skin cancer was mentioned for most classes, except IL-23i, IL-17i, IL-13i, IL-4/13i, IL-31i, IL-36i and PDE4i. Other serious warnings included neurological, cardiovascular, thrombotic, hepatic, renal, gastrointestinal, and psychiatric adverse events. CONCLUSION: This work provides a simple stepwise approach to managing contraindications and special warnings. Our safety checklist gives clinicians a rapid overview of contraindications, special warnings, and boxed warnings for the available drug classes approved for inflammatory dermatoses.
10 May 2026
Read appraisal →European journal of heart failure
Efficacy of finerenone in patients with heart failure and mildly reduced or preserved ejection fraction: a prespecified analysis of heart rate and heart rhythm in the FINEARTS-HF trial
AIMS: The association between heart rate (HR) and clinical outcomes is well understood in patients with heart failure with reduced ejection fraction (HFrEF) but less clear in those with HFmrEF/HFpEF, especially among individuals with atrial fibrillation (AF). In a prespecified analysis of the FINEARTS-HF trial, we examined the association between baseline HR and clinical outcomes by heart rhythm and evaluated finerenone's effect across the spectrum of HR. METHODS: The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events. Heart rhythm (sinus rhythm or AF) was determined from the baseline ECG. Patients with pacemaker rhythm or missing HR/rhythm data were excluded. RESULTS: Among patients with sinus rhythm (SR n = 3497; 62%), higher baseline HR was associated with a higher incidence rate for the primary outcome. In patients with AF (n = 2190; 38%), no association between HR and outcomes was observed. The effect of finerenone on the primary outcome was consistent across the HR spectrum, regardless of rhythm (P for interaction = 0.96 in SR; 0.49 in AF). In patients with SR, there was no significant HR change with finerenone versus placebo. In AF patients, finerenone led to a small but statistically significant HR reduction: a placebo-corrected decrease of 1.35 bpm (95% CI: 0.41-2.29) from baseline to 12 months. CONCLUSIONS: Among patients with HFpEF/HFmrEF in FINEARTS-HF, higher baseline HR was associated with a higher risk of the primary outcome in patients with SR but not in those with AF. Finerenone's effect on the primary outcome was consistent across the HR spectrum, irrespective of rhythm. TRIAL REGISTRATION: ClinicalTrials.gov NCT04435626.
10 May 2026
Read appraisal →Lancet (London, England)
Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial
BACKGROUND: Alcohol use disorder accounts for 5% of deaths worldwide annually, and there is an urgent need for new therapeutic interventions. Preclinical and initial human studies indicate that the GLP-1 receptor agonist semaglutide might reduce alcohol drinking. This study evaluated the efficacy of semaglutide once-weekly in treatment-seeking patients with alcohol use disorder and comorbid obesity. METHODS: In a 26-week, single-centre, randomised, double-blinded, placebo-controlled trial, treatment-seeking participants with moderate to severe alcohol use disorder and comorbid obesity were assigned (1:1) to receive once-weekly semaglutide (2·4 mg subcutaneously) or placebo (saline subcutaneously), in addition to standard cognitive behavioural therapy. The primary endpoint was a reduction in the number of heavy drinking days assessed after 26 weeks of intervention, analysed with an ANCOVA model. Analysis adhered to the intention-to-treat principle, and missing outcome data were addressed using multiple imputations. Safety was assessed in all treated patients. The trial is registered at ClinicalTrials.govNCT05895643, and is complete. FINDINGS: From June 10, 2023, to Feb 4, 2025, 108 participants (53 women and 55 men) were enrolled, with 54 participants in each of the semaglutide and placebo treatment groups, and all were included in the data analysis. Overall, 88 participants (81%) completed the full intervention. Semaglutide was associated with a reduction in heavy drinking days (-41·1 percentage points from baseline, 95% CI -48·7 to -33·5) compared with placebo (-26·4, -34·1 to -18·6; estimated treatment difference -13·7 percentage points, -22·0 to -5·4; p=0·0015), and had substantial effects on multiple secondary alcohol-related and somatic outcomes. Adverse events were transient, generally mild to moderate gastrointestinal effects, and occurred more frequently in the semaglutide group. INTERPRETATION: Semaglutide showed robust therapeutic effects in treatment-seeking participants with obesity and alcohol use disorder and this trial supports previous preclinical and clinical findings suggesting GLP-1 receptor agonists as a potential novel treatment target for alcohol use disorder. FUNDING: The Research Foundation, Mental Health Services (Capital Region of Denmark), the Novo Nordisk Foundation, the Novavi Foundation, the Hartmann Foundation, and the Augustinus Foundation.
10 May 2026
Read appraisal →Lancet (London, England)
Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): a double-blind, randomised, placebo-controlled, phase 3 trial
BACKGROUND: Autoantibody-mediated complement activation drives pathology in acetylcholine receptor (AChR) antibody-positive generalised myasthenia gravis. Newer targeted therapies lower overall antibody concentrations or inhibit complement activity. We aimed to evaluate an siRNA (cemdisiran) targeting complement component 5 (C5) as monotherapy and in combination with a C5 antibody (pozelimab) in generalised myasthenia gravis. METHODS: NIMBLE is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 86 centres in 13 countries. We enrolled patients aged 18 years or older with a diagnosis of generalised myasthenia gravis, positive serology for anti-AChR or anti-LRP4 antibodies, and a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or greater. Patients were randomly allocated to receive cemdisiran monotherapy (600 mg every 12 weeks; cemdisiran group), pozelimab monotherapy (200 mg every 4 weeks; pozelimab group), combined cemdisiran (200 mg every 4 weeks) and pozelimab (200 mg every 4 weeks; combination group), or placebo, all administered subcutaneously, during a 24-week double-blind treatment period. The primary endpoint was change from baseline in MG-ADL scores at week 24, assessed in the modified intention-to-treat (mITT) primary analysis set (the first 245 randomly allocated patients who received any dose of study treatment and had at least one post-baseline assessment). A prespecified hierarchal statistical testing strategy was used; multiplicity was controlled for comparisons of cemdisiran versus placebo and combination versus placebo (pozelimab was not statistically tested against placebo and was used only to assess the contribution of components to the combination treatment). Safety was mainly assessed by recording of treatment-emergent adverse events in all patients who received any dose of study treatment. This study is registered with ClinicalTrials.gov (NCT05070858); the current status is active, not recruiting. FINDINGS: Between Jan 20, 2022 and July 18, 2025, 390 participants were screened and, as of the data cut-off presented in this report (July 8, 2025), 284 were randomly allocated to the cemdisiran group (79 [28%] patients), pozelimab group (50 [18%]), combination group (80 [28%]), and placebo group (75 [26%]). Of 277 patients who received any study treatment, 263 (95%) completed the double-blind treatment period. In the mITT primary analysis set, at week 24, the least-squares mean change from baseline in MG-ADL total score was -4·5 (SE 0·4) in the cemdisiran group (n=64), -4·0 (0·4) in the combination group (n=67), and -2·2 (0·5) in the placebo group (n=59). Placebo-adjusted least-squares mean differences in MG-ADL score at week 24 were -2·3 (SE 0·7; 95% CI -3·6 to -1·0; p=0·0005) in the cemdisiran group and -1·7 (0·7; -3·0 to -0·4; p=0·0086) in the combination group. The proportion of participants with at least one adverse event during the double-blind treatment period was 54 (69%) of 78 in the cemdisiran group, 65 (81%) of 80 in the combination group, 40 (82%) of 49 in the pozelimab group, and 54 (77%) of 70 in the placebo group. The most common adverse event in the cemdisiran group was upper respiratory tract infection (nine [12%] of 78 patients), which occurred at a similar incidence in the placebo group (eight [11%] of 70). No serious or meningococcal infections occurred in the cemdisiran group. Adverse events leading to treatment discontinuation occurred in two participants (3%) in the placebo group and one participant (2%) in the pozelimab group. No deaths occurred during the double-blind treatment period. Two deaths occurred after the double-blind treatment period, one of which was assessed as treatment-related by the investigator but not treatment-related by the sponsor. INTERPRETATION: Cemdisiran monotherapy and combination therapy were effective in the treatment of generalised myasthenia gravis, and were generally well tolerated. Subcutaneous dosing of cemdisiran, administered every 3 months, could provide a convenient treatment approach for generalised myasthenia gravis. FUNDING: Regeneron Pharmaceuticals.
10 May 2026
Read appraisal →Annals of hematology
Hematologic and molecular response to ropeginterferon alfa-2b in patients with polycythemia vera: a systematic review and meta-analysis
Ropeginterferon alfa-2b is an interferon used in the treatment of myeloproliferative neoplasms, particularly polycythemia vera. Its efficacy in achieving hematologic and molecular responses has been demonstrated in clinical trials, but pooled data on long-term outcomes and sustained response remain limited. This systematic review and meta-analysis aimed to evaluate the hematologic and molecular response over 36 months. PubMed, Scopus, Science Direct, and Google Scholar databases were searched to identify studies reporting hematologic and molecular responses to ropeginterferon alfa-2b. Studies were included if they provided data on complete hematologic response (CHR) and JAK2V617F variant allele frequency (VAF) reduction. Pooled proportions and mean reductions were calculated using random-effects models. The pooled proportion of CHR increased progressively from 0.19 (95% CI: 0.04-0.57) at 3 months to 0.73 (95% CI: 0.17-0.97) at 36 months. Molecular response, measured by VAF reduction, deepened over time from - 7.33 (95% CI: -9.85 to -4.81) at 3 months to -54.90 (95% CI: -65.61 to -43.99) at 36 months. Subgroup analyses revealed significant variability in response rates, particularly in early follow-up periods. Ropeginterferon alfa-2b achieves significant and sustained hematologic and molecular responses over 36 months. This makes it a promising treatment for polycythemia vera. While variability in early responses needs further investigation, the sustained long-term efficacy compared to hydroxyurea supports its use in clinical practice. Future studies should focus on identifying predictors of response and optimizing treatment protocols to maximize patient outcomes.
10 May 2026
Read appraisal →European journal of heart failure
Erythropoiesis-stimulating agents to reduce heart failure hospitalization: a systematic review and meta-analysis
AIMS: Anaemia is common in patients with chronic heart failure (CHF), worsening functional status and prognosis. The role of erythropoiesis-stimulating agents (ESAs) to reduce hospitalization remains unclear. METHODS AND RESULTS: A pre-registered systematic search was performed of randomized controlled trials in adults with CHF and anaemia, comparing any ESA at any dose versus placebo or no treatment.Fourteen trials were included with 3128 participants, with moderate quality of evidence for most outcomes and variable risk of bias. Meta-analysis during 5604 person-years of follow-up demonstrated no significant difference in first CHF hospitalization comparing ESAs with control: Peto odds ratio (OR) 0.93, 95% CI 0.78-1.10, P = .37; trial heterogeneity I2 = 36%. ESAs significantly reduced total CHF hospitalization with 622 events/2698 person-years, compared with 761/2914 person-years for control: incidence rate ratio 0.81, 95% CI 0.73 to 0.90, P < .001; no heterogeneity between trials, I2 = 0%. There were no significant differences between treatment groups for all-cause mortality (OR 1.01, 95% CI 0.86-1.18, P = .88; I2 = 35%) or incident adverse events. Patients randomized to ESAs increased their haemoglobin level [mean difference (MD) 1.6 g/dL compared with control, 95% CI 1.6-1.7, P < .001] and exercise tolerance (MD 69 metres, 95% CI 17-122, P = .009), with lower NYHA class on follow-up (MD -0.73 class, 95% CI -1.11 to -0.36, P < .001). CONCLUSION: ESA treatment in patients with CHF and mild anaemia can reduce recurrent CHF hospitalization and improve functional capacity, without any impact on adverse events. Including ESAs in CHF management could be considered in patients with anaemia at high risk of recurrent hospital admissions.
10 May 2026
Read appraisal →European journal of heart failure
The efficacy and safety of qiliqiangxin according to baseline ejection fraction in patients with heart failure and reduced ejection fraction in QUEST.
AIMS: Qiliqiangxin (QLQX), a Chinese traditional medicine, improved outcomes in patients with heart failure and reduced ejection fraction (HFrEF) when added to guideline-directed therapy. As treatment effects in heart failure (HF) may vary with left ventricular ejection fraction (LVEF), this post hoc analysis of the QUEST (Qiliqiangxin in Heart Failure: Assessment of Reduction in Mortality) trial examined whether baseline LVEF modified the efficacy and safety of QLQX. METHODS: QUEST randomized 3110 patients with symptomatic HF and LVEF ≤40%. The primary outcome was cardiovascular death or first HF hospitalization. Baseline LVEF was categorized as ≤25% (n = 482), >25-30% (n = 692), >30-35% (n = 829), and >35% (n = 1107). RESULTS: Mean LVEF was 32% (median 33%, interquartile range 28%-37%). Patients with LVEF ≤25% had the highest rate of the primary outcome (25.4 per 100 patient-years), while rates were similar across higher LVEF groups (18.7-19.8). After multivariable adjustment, lower LVEF was independently associated with higher risks of the primary outcome and mortality. The effect of QLQX on the primary outcome was consistent across LVEF categories (hazard ratio [95% CI] from the lowest to highest: 0.91 [0.64-1.30], 0.65 [0.47-0.89], 0.94 [0.71-1.26], and 0.71 [0.55-0.91], respectively; Pinteraction = .28), and as a continuous variable (Pinteraction = .45). Similar results were observed for individual components and total HF hospitalizations (all Pinteraction > .10). The safety of QLQX was also consistent across LVEF categories. CONCLUSION: In patients with HFrEF, lower LVEF was associated with worse cardiovascular outcomes. QLQX reduced cardiovascular events consistently across the range of LVEF examined in QUEST, despite the limited use of sodium-glucose co-transporter 2 inhibitors. CHICTR REGISTRATION: ChiCTR1900021929.
10 May 2026
Read appraisal →European journal of cancer (Oxford, England : 1990)
Sex differences in efficacy and toxicity of first-line treatment of metastatic colorectal cancer: An analysis of 18,041 patients in the ARCAD CRC database.
BACKGROUND: Greater toxicity of adjuvant chemotherapy in females has been reported previously, but the impact of patients' sex on chemotherapy (CT)+/-targeted therapies for non-resectable, metastatic colorectal cancer (mCRC) has remained unclear. We compared efficacy and toxicity of first-line chemotherapy, with or without targeted therapies, between male and female mCRC patients. METHODS: Twenty-seven randomized trials from the ARCAD CRC database were included. Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate, toxicity (according to NCI-CTCAE). Analyses were performed within three treatment groups: A) CT alone, B) CT+bevacizumab, and C) CT+epidermal growth factor receptor inhibitor. OS and PFS were estimated using Kaplan-Meier method. Associations with sex were assessed using study-stratified Cox models adjusted for age, performance status, body mass index, and CT backbone. RESULTS: Baseline data from 18,041 patients were analysed; among 15,271 included in outcome analyses, no sex differences in OS or PFS were observed. Adjusted OS hazard ratios (95% confidence interval) for females versus (vs.) males were: A: 1.01 (0.95-1.08, P = .69), B: 0.96 (0.89-1.04, P = .36), C: 0.97 (0.87-1.10, P = .67). Females experienced higher toxicity, including grade 1-4 and 3-4 nausea (71.8% vs. 60.5% and 7.5% vs. 4.8%), vomiting (47.7% vs. 35.5% and 6.6% vs. 4.4%), and neutropenia (52.4% vs. 44.4% and 29.2% vs. 18.8%) (P < .001). Conversely, rash (grade 1-4 and 3-4) was more frequent in males (29.6% vs. 24.3% and 5.1% vs. 3.7%, P < .001). CONCLUSIONS: Despite higher chemotherapy-related toxicity in females, treatment efficacy was similar between sexes. Rash was more common in males, highlighting that patients' sex modulates toxicity profiles in both directions. Strategies to reduce adverse events in female patients are warranted.
10 May 2026
Read appraisal →Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
Prevalence of antibody drug conjugated-induced nausea and vomiting (ADCINV) in patients with cancer
INTRODUCTION: Antibody-drug conjugates (ADC) have emerged as an important part of systemic treatment across disease sites. To date, there is no robust pooled prevalence estimate of nausea and vomiting induced by ADCs. Establishing such estimates is essential to determine if ADC-induced nausea and vomiting (ADCINV) represents a clinically significant problem warranting further research into antiemetic prophylaxis. Our aim is to report the prevalence of reported ADCINV across literature. METHODS: A systematic search of Medline, Embase, Cochrane CENTRAL and Web of Science was conducted from database inception until September 24, 2025. Articles were included if they reported nausea and/or vomiting due to ADCs used in cancer treatment, in the abstract. Pooled prevalence was reported. Subgroup analysis was conducted by ADC. Meta-regression was conducted by age and sex. Quality assessment was conducted. Type I error was set at 0.05. RESULTS: A total of 209 studies with 15,493 patients were included. Thirty-nine percent (95%CI, 36-42%) of patients experience any nausea, and 26% (95%CI, 23-29%) experience any vomiting. Younger patients are more likely to experience nausea; each 10-year increase in age is associated with a 12% decrease in nausea rates. Higher emetogenic ADCs include trastuzumab deruxtecan, sacituzumab govitecan, brentuximabvedotin and patritumab deruxtecan. Lower emetogenic agents include disitimab vedotin, telisotuzumab vedotin and rovalpituzumab tesirine. DISCUSSION: This is the first study to report prevalence of ADCINV across ADCs. It is a prevalent adverse effect akin to chemotherapy-induced nausea and vomiting that should be viewed as clinically relevant and further investigated to help develop optimal strategies related to antiemetics.
10 May 2026
Read appraisal →Therapeutic innovation & regulatory science
Applications and Challenges of Artificial Intelligence and Big Data in Drug Regulation
Artificial intelligence (AI) and big data are increasingly applied in drug regulation and have demonstrated significant potential worldwide. The U.S. Food and Drug Administration (FDA) has developed a relatively comprehensive approach through strategic frameworks, regulatory guidelines, and pilot programs. The European Medicines Agency (EMA) has promoted AI adoption via the Big Data Task Force, DARWIN EU®, and a multi-annual work plan, while Japan, Canada, and other countries have also advanced relevant initiatives and strengthened international cooperation. In China, smart regulation has been incorporated into the "14th Five-Year Plan" and subsequent strategies, with progress in establishing national regulatory data platforms, pharmaceutical traceability systems, and pilot AI applications. Nevertheless, AI in drug regulation remains at an exploratory stage, facing challenges such as limited model reliability and interpretability, insufficient data standards and interoperability, regulatory gaps, and ethical as well as public trust concerns. Future progress will depend on strengthening regulatory standards, enhancing data governance, improving regulatory capacity, and deepening international collaboration to achieve more scientific, intelligent, and efficient drug regulation.
9 May 2026
Read appraisal →Drug development research
Artificial Intelligence in Drug Discovery and Development: Transforming Pharmaceutical Innovation
Drug discovery remains a lengthy, costly, and high-risk endeavor, often requiring over a decade from target identification to clinical translation. Artificial intelligence (AI) is reshaping this paradigm by enabling more efficient and accurate decision-making across the discovery and development pipeline. Advances in machine learning, deep learning, and natural language processing now support target identification, hit finding, lead optimization, and drug repurposing with unprecedented speed and precision. AI-driven insilico platforms further enhance early-stage predictability by forecasting toxicity, pharmacokinetics, and developability, thereby reducing late-stage attrition. This review critically examines the evolving role of AI in modern drug discovery and its expanding impact on pharmaceutical formulation development and personalized medicine. Collaborative models between AI developers and the pharmaceutical industries, essential for accelerating translational outcomes, are also highlighted. Finally, key challenges, including algorithmic transparency, data quality, interoperability, and regulatory acceptance, are discussed, along with future directions for harnessing AI's full potential in pharmaceutics.
6 May 2026
Read appraisal →Cell
Deep-learning-based de novo discovery and design of therapeutics that reverse disease-associated transcriptional phenotypes
Identifying drugs that reverse disease-associated transcriptomic features has been widely explored for drug repurposing, but its potential for de novo drug discovery remains underexplored. Here, we present gene expression profile predictor on chemical structures (GPS), a deep-learning-based drug discovery platform, guided by transcriptomic features, that screens large compound libraries and optimizes lead molecules. We first develop a model that captures transcriptomic perturbation signatures solely from chemical structures and deploy it to library compounds. We refine scoring methods and employ a tree-search method for optimization. By incorporating structure-gene-activity relationships, we uncover drug mechanisms from transcriptomic data. We evaluate GPS across multiple diseases and conduct extensive validation in two cases. In hepatocellular carcinoma, we discover two unique compound series with favorable cellular selectivity and in vivo efficacy. In idiopathic pulmonary fibrosis, we identify one repurposing candidate and one novel anti-fibrotic compound by reversing gene expression of multiple distinct cell types derived from single-cell transcriptomics.
5 May 2026
Read appraisal →Annals of biomedical engineering
Stacking Ensemble Machine Learning for Cardiac Safety Assessment Using hiPSC-CM MEA Data
PURPOSE: Prediction of Torsades de Pointes (TdP) risk using hiPSC-CM assays remains challenging, as many models fail to capture nonlinear patterns and exhibit unstable performance across different drugs. We examined whether a stacking ensemble can improve robustness when only two simple Δ F P D c -derived predictors are available. METHODS: Two electrophysiological predictors were derived from MEA-based FPDc measurements: the maximum change ( Δ F P D c ) and the interpolated Δ F P D c at Cmax. These features were used to train a stacking model comprising random forest (RF), XGB, and a shallow artificial neural network (ANN). Performance was assessed on 16 unseen CiPA reference compounds using AUC, likelihood ratios, pairwise accuracy, and classification error. Class weighting addressed class imbalance, and likelihood-based metrics assessed diagnostic consistency. RESULTS: The stacking ensemble consistently outperformed all single classifiers. The XGB-based meta-classifier achieved perfect discrimination for both AUC1 and AUC2 (1.000), with pairwise accuracy reaching 1.000 and classification error remaining below 0.125 across repeated evaluations. CONCLUSIONS: Combining a simple MEA-derived feature set with a stacking architecture provides a more reliable framework for early TdP risk assessment than single-model approaches. External validation using additional MEA datasets and the integration of interpretable modeling strategies will be important for future translational use.
4 May 2026
Read appraisal →Clinical pharmacology and therapeutics
Off-the-Shelf Large Language Models for Guiding Pharmacoepidemiological Study Design
This study aimed to assess the ability of two off-the-shelf large language models, ChatGPT and Gemini, to support the design of pharmacoepidemiological studies. We assessed 48 study protocols of pharmacoepidemiological studies published between 2018 and 2024, covering various study types, including disease epidemiology, drug utilization, safety, and effectiveness. The coherence (i.e., "Is the response coherent and well-formed, or is it difficult to understand?") and relevance (i.e., "Is the response relevant and informative, or is it lacking in substance?") of the large language models' responses were evaluated by human experts across seven key study design components. Coding accuracy was assessed. Both large language models demonstrated high coherence, with over 90% of study components rated as "Strongly agree" by experts for most categories. ChatGPT achieved the highest coherence for "Index date" (97.9%) and "Study design" (95.8%). Gemini excelled in "Study outcome" (93.9%) and "Study exposure" (95.9%). Relevance, however, was more variable, with ChatGPT aligning with expert recommendations in over 90% of cases for "Index date" and "Study design" but showing lower agreement for covariates (65%) and follow-up (70%). Coding agreement percentages reveal varying levels of concordance, with the Anatomical Therapeutic Chemical classification system coding system demonstrating the highest agreement at 50% with experts. In contrast, the Current Procedural Terminology and International Classification of Diseases systems showed agreements of 22.2% and 20%, respectively. While ChatGPT and Gemini show promise in certain tasks supporting pharmacoepidemiological study design, their limitations in relevance and coding accuracy highlight the need for critical oversight by domain experts.
4 May 2026
Read appraisal →Pakistan journal of pharmaceutical sciences
Network pharmacology and machine learning reveal multi-target mechanisms of poly herbal formulation against atherosclerosis
BACKGROUND: Herbs, like Allium sativum, Ginkgo biloba and Nerium oleander are traditional medicinal plants that have been used to treat atherosclerosis and cardiovascular disease. This study provides valuable insights into how network pharmacology (NP) and emerging machine learning are utilized to identify potential drug candidates from these plants for treatment of atherosclerosis. METHODS: NP analysis was employed to screen compounds and their potential gene targets from databases and tools e.g. IMPPAT, PubChem, KNAPSACK, Swiss ADME, Swiss Target Prediction, Disgenet and GeneCard. Cytoscape 3.10.2 was employed to visually understand these networks. DAVID database was used for functional and enrichment analysis of the genes validated through molecular docking using PyRx and Discovery Studio. RESULTS: Computational tools and bioinformatics approaches showed a few core compounds, such as Quercetin, Naringenin, Luteolin, Kaempferol, Apigenin, Daidzein, Luteolin-7-olate, Pinocembrin, Pregnenolone and Fisetin found to be effective against atherosclerosis. Pathway analysis revealed that mechanism of atherosclerosis development is directly associated with cholesterol metabolism, cellular senescence, Ras, NF-κB and PI3K-Akt signaling pathways. CONCLUSION: NP and molecular docking analysis suggested that screened compounds may inhibit progression of atherosclerosis by modulating key associated pathways. Hence, this machine learning aided NP study provides basis for understanding and recognizing the activity of these plants in treating atherosclerosis.
4 May 2026
Read appraisal →Journal of molecular graphics & modelling
DeepHybridCPI: A hybrid deep learning framework for compound-protein interaction prediction
In bioinformatics, deep learning-based methods for Compound-Protein Interaction (CPI) prediction play a vital role in virtual screening, drug discovery, and drug repositioning. Recent improvements in computational methods have shown great possibility to save costs of experiment and speed up target identification. Nevertheless, the current CPI forecasting methods remain severely limited. Many rely on shallow Graph Neural Networks (GNNs) that struggle to capture the global structural context of compounds, while conventional Convolutional Neural Networks (CNNs) focus primarily on local sequence motifs and fail to model long-range dependencies in proteins. Even though a number of recent architectures strive to solve these problems by adding complexity to models, or by adding complex modules, these additions often cause significant computational overhead. To overcome these challenges, we propose DeepHybridCPI, a hybrid deep learning framework designed for accurate and efficient CPI prediction. Our hybrid model integrates a multiscale, densely connected GNN to extract compound features capturing both local substructures and global molecular topology, and employs CNNs with Long Short-Term Memory (LSTM) networks to model both local motifs and extended dependencies in protein sequences. The learned compound and protein representations are fused into a unified latent space to enable effective interaction modeling. Experimental evaluations on benchmark Human and C. elegans datasets demonstrate that DeepHybridCPI consistently outperforms existing state-of-the-art baseline methods in terms of AUC, Precision, and Recall. These findings highlight the importance of combining multiscale compound representations with hybrid sequence encoders within a single unified framework, providing a promising avenue for accelerating computational drug discovery. We release our source code and dataset at: https://github.com/jamshaidwarraich/DeepHybridCPI.
4 May 2026
Read appraisal →Molecular informatics
ADME-DTI: Augmented Deep Meta Ensemble for Drug-Target Interaction Prediction
Drug-target interaction represents a critical focus area in computational drug discovery and pharmaceutical research. However, the process of identifying and analyzing these interactions is often resource-intensive, requiring extensive experimentation to evaluate the binding relationships between numerous drugs and their respective targets. This complexity is further compounded by the fact that a drug can inhibit multiple targets, and a target may also bind to various drugs. To address these issues, advanced deep learning models have been introduced as promising tools, offering the ability to accurately predict binding affinity and other bioactivity values to distinguish between potential drug-target interactions. The proposed model, named the Augmented Deep Meta Ensemble for Drug-Target Interaction (ADME-DTI), leverages multiple descriptors and fingerprint representations to extract meaningful insights from drug and protein data. These submodels from each representation are then combined with a deep learning architecture along with the metadata of the drug and target entries. The proposed approach has proved competitive performance against state-of-the-art models across diverse datasets and evaluation metrics, as evidenced by key metrics, namely r m 2 $r_m^2$ , concordance index, and mean squared error. Specifically, the model achieved mean squared error values of 0.186 (Davis), 0.118 (Kiba), 0.134 (DTC), 0.262 (Metz), 0.300 (ToxCast), and 0.791 (STITCH), all of which are publicly available benchmark datasets commonly used in drug-target interaction prediction tasks. The results highlight the model's effectiveness in reducing prediction errors and improving accuracy. Previous drug-target interaction research often relied on limited, non-diverse datasets, reducing generalizability. Few studies addressed drug-target interaction prediction as a regression task. Our novel deep learning metamodel integrates multiple models and representations, surpassing benchmarks and delivering greater prediction accuracy across varied datasets and evaluation metrics.
4 May 2026
Read appraisal →Journal of computer-aided molecular design
Resolving the ambiguous binding site of quercetin at the calcineurin subunit junction using funnel metadynamics with deep learning collective variables
Calcineurin represents a prominent target for immunosuppressive drugs, where conventional macrocyclic inhibitors utilize an immunophilin-dependent mechanism for their inhibition but are consequently hindered by adverse effects and variable pharmacokinetics. The flavonoid quercetin has been shown to inhibit calcineurin in a non-competitive, immunophilin-independent manner, but its exact binding site remains ambiguous at the junction between calcineurin subunits A and B, with the open solvent-exposed nature of this region proving challenging to model. In this study, we employ funnel metadynamics with collective variables derived from a deep learning model to identify the binding site of quercetin. A selective strategy using multiple simulations with stricter funnel definitions and a smaller number of carefully chosen descriptors for model training proved more effective than a broad-based approach. These simulations were able to effectively distinguish the binding site of quercetin from three experimentally suggested sites, with a calculated free energy of binding of -8.36 ± 0.60 kcal/mol showing excellent agreement with experiment. Ligand-tryptophan distances similarly corroborated measurements from FRET assays with a r2 of 0.85. The corresponding binding pose showed that quercetin inserts itself into a channel between Arg122, Gly123, Tyr124 on one side and Phe160, Thr161, and Asn345 on the other, stabilizing its binding through a network of hydrogen bonds. The findings of this study provide insights into the modelling of challenging binding sites and ligands using deep learning driven metadynamics simulations and provide the foundations for rational development of immunophilin-independent inhibitors of calcineurin.
3 May 2026
Read appraisal →BMJ supportive & palliative care
Memantine efficacy in chemotherapy-induced peripheral neuropathy: double-blind placebo-controlled randomised clinical trial
BACKGROUND AND AIMS: Chemotherapy-induced peripheral neuropathy (CIPN) is a detrimental side effect of chemotherapeutic agents. If left untreated, CIPN can persist for several years following the chemotherapy. CIPN management may enhance the quality of life of the affected patients. This study evaluated the efficacy of memantine, an antagonist of N-methyl-D-aspartate, in CIPN management. METHODS: This double-blinded randomised clinical trial was performed on 176 individuals with CIPN. Patients were randomised to either the memantine or placebo groups (88 in each). The memantine group received a single daily dose of 5 mg for the initial 3 days. Subsequently, the dosage was increased to 20 mg per day, with 5 mg increments every 3 days. The placebo group received tablets of equal shape and size. All individuals received medications for 8 weeks. The McGill pain questionnaire and tuning fork test were used to evaluate the severity of neuropathic pain in patients, both at baseline and after the intervention ended. RESULTS: Based on tuning fork test results, significant improvement in neuropathy was observed among patients who received memantine compared with those who received placebo (p<0.001 vs 0.665). McGill pain questionnaire score revealed a significant difference between memantine and placebo groups (p<0.001 for both groups). This difference was also significant after performing intention-to-treat analysis. Moreover, a higher proportion of patients in the memantine group achieved minimal clinically important difference. CONCLUSION: The use of memantine mitigated the CIPN intensity. Thus, it appears that memantine is a promising option for the management of patients experiencing CIPN.
3 May 2026
Read appraisal →Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Bacterial quantitation in clinical infection: a systematic review
Pivotal clinical studies of new anti-infective drugs enrol patients with strictly defined clinical syndromes, with clinical and laboratory endpoints used to define treatment success. Assessing bacterial killing in the host by serial quantitation has potential as a more efficient pharmacometric approach to assess antibiotic efficacy. We conducted a systematic review of the use of bacterial quantitation in clinical infection. The main syndromes studied in the 222 included articles were bacteraemia, chronic respiratory disease, diarrhoea, pneumonia and sexually transmitted infections. Most reports (135 articles, 61%) quantified bacterial load in different specimen types using quantitative polymerase chain reaction (qPCR). For bacteraemias, bacterial DNA load measured in whole blood by qPCR at clinical presentation was typically 2-3 log10 copies ml-1, usually substantially higher than the estimates from quantitative culture. Higher bacterial loads were associated with increased mortality in 28 of 35 studies. Faster bacterial clearance was correlated with appropriate antibiotic therapy and improved outcome in the majority of studies. Most studies sampled too infrequently for accurate characterization of bacterial clearance rates. The rate of bacterial clearance from blood or other compartments is an informative pharmacodynamic endpoint in the assessment of antibacterial therapeutic effects, but standardized approaches to assessment are needed based on optimal study design. This article is part of the Theo Murphy meeting issue 'Evaluating anti-infective drugs'.
3 May 2026
Read appraisal →ChemMedChem
A Novel Triose Phosphate Isomerase Inhibitor With Dual Trypanosomicidal Activity was Identified Using Artificial Intelligence-Based Virtual Screening
Chagas disease and leishmaniasis are neglected protozoan diseases recognized by the World Health Organization as major public health problems. These diseases affect millions of people worldwide, yet effective treatments remain unavailable. Triosephosphate isomerase (TIM), a glycolytic enzyme that exhibits high catalytic efficiency for the isomerization of glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate exclusively in its dimeric form, was subjected to virtual screening. Using a deep neural network for structure-based drug design that predicts binding affinity between small molecules and proteins of known structure, 12.5 million commercially available compounds were screened. From this, 82 compounds were selected for in vitro evaluation. Six compounds inhibited TIM from Trypanosoma cruzi, three of which exhibited anti-T. cruzi activity. Eight compounds demonstrated activity against the parasites T. cruzi and Leishmania infantum. Two compounds showed similar potency against both parasites: 3-(1-acetyl-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (IC50 = 16 ± 3 μM) and 3-[(4-bromophenyl)sulfanyl]-1-(3-nitrophenyl)propan-1-one (IC50 = 12 ± 1 μM). These compounds exhibit favorable selectivity and toxicological profiles, as well as in vivo activity, indicating their potential for future drug development.
2 May 2026
Read appraisal →Journal of chemical information and modeling
Generative AI Uncovers Novel Chrebp/Txnip Axis Inhibitors with Potential Anti-inflammatory Activity
Type 2 diabetes is driven in part by metabolic inflammation, where activation of the Chrebp/Txnip axis promotes NLRP3 inflammasome assembly, leading to pancreatic β-cell dysfunction and pro-inflammatory cytokine release. Despite the therapeutic relevance of this pathway, the Chrebp-14-3-3 (regulatory-protein client) protein-protein interaction (PPI) remains largely underexplored, with only a limited number of small-molecule modulators reported to date. To address this gap, we developed an artificial intelligence-driven generative design framework for de novo discovery of selective PPI-targeting compounds. A conditional recurrent neural network (cRNN), implemented as a quantitative structure-property relationship-guided generative network (QSPR-GEN), was pretrained on a large, chemically diverse corpus to learn general SMILES syntax and structural priors, and subsequently fine-tuned on a curated, target-focused data set of approximately 5900 compounds, achieving high scaffold uniqueness (94.6%). Selectivity-oriented physicochemical descriptors were incorporated as conditional inputs to bias generation away from promiscuous chemotypes, while maintaining anchoring to a known active seed. Structure-based refinement was further applied by focusing on the noncanonical α-helical epitope unique to the Chrebp regulatory-protein interface, establishing a dual-layered strategy for selective PPI modulation. The integrated pipeline, combining virtual screening, molecular dynamics simulations, and MM/PBSA free-energy calculations, prioritized lead candidates with favorable binding energetics and pharmacokinetic profiles. In THP-1 macrophages under metabolic stress, the top candidate T7 markedly suppressed Txnip and NLRP3 expression, reduced IL-1β secretion, and attenuated pyroptotic cell death, outperforming a reference inhibitor. Collectively, this study presents a robust computational framework for the inverse design of challenging PPIs and demonstrates its utility through the identification and experimental validation of mechanistically precise lead compounds, exemplified by T2 and T7.
2 May 2026
Read appraisal →Journal of chemical information and modeling
Development, Evaluation and Application of a Multi-Representation Fusion Model for Accurate Prediction of Per- and Polyfluoroalkyl Substance (PFAS) Binding to Plasma Proteins
Per- and polyfluoroalkyl substances (PFAS) constitute a large and structurally diverse class of man-made chemicals. Their strong carbon-fluorine (C-F) bonds confer high environmental persistence, bioaccumulation, and various associated toxicities. As amphiphilic compounds, most PFAS bind to proteins and accumulate in protein-rich tissues, with such bioaccumulation exerting significant adverse impacts on human health. Accurate evaluation of the binding status between PFAS and proteins constitutes an essential step in health risk assessment. Traditional experiments and certain modeling approaches for analyzing PFAS bioaccumulation suffer from drawbacks such as time-consuming processes, high costs, or inadequate capture of molecular structural information, while existing machine learning-based prediction methods rely on single molecular representation, making it difficult to comprehensively encode the structural information on PFAS. Here, we propose MURNet, a multirepresentation fusion network model integrating chemical descriptors, 2D molecular graphs, and molecular fingerprints to predict PFAS-plasma protein binding. Compared with the state-of-the-art baseline models, MURNet achieves the optimal comprehensive performance. The multirepresentation fusion strategy generates higher-quality molecular features. Tanimoto similarity applicability domain analysis demonstrates MURNet's capability to reliably predict PFAS homologues. Case studies reveal the effectiveness of MURNet in screening PFAS with potential binding affinity to human serum albumin (HSA).
2 May 2026
Read appraisal →The Journal of dermatological treatment
Modulation of mu-opioid pathway for the treatment of pruritus: a systematic review of 1,146 patients
BACKGROUND: Pruritus is a debilitating symptom and conventional therapies often provide incomplete relief. The μ-opioid receptor (MOR) pathway is a key regulator of itch, and μ-pathway-modulating agents are increasingly used off-label for refractory pruritus. AIM: This systematic review evaluates the efficacy, safety, and real-world use of μ-opioid pathway modulators for pruritus of dermatologic and systemic origin. METHODS: Following PRISMA guidelines (PROSPERO CRD420251207101), a comprehensive search of four databases identified 3,274 records, of which 69 studies met inclusion criteria, comprising 14 randomized controlled trials (RCTs; n = 795) and 55 non-randomized studies (n = 351). Owing to substantial clinical and methodological heterogeneity, findings were narratively synthesized. RESULTS: Five RCTs evaluated dermatologic conditions, including atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris, while nine RCTs assessed systemic pruritus, predominantly cholestatic and uremic pruritus. RCTs investigated oral or topical naltrexone, intravenous naloxone, nalmefene, and extended-release nalbuphine, with most demonstrating clinically meaningful reductions in pruritus intensity using validated itch scales. Non-randomized studies reported improvement across a wide range of dermatologic and systemic conditions, with adverse events generally mild and well tolerated. CONCLUSIONS: Overall, μ-opioid pathway modulators show promising efficacy with acceptable short-term safety across diverse pruritic conditions, although larger high-quality RCTs are required to define optimal dosing and support clinical translation.
2 May 2026
Read appraisal →Journal of chemical information and modeling
DWPL-GCNMF: Structure-Aware Dynamic Weighted Pseudo-Label Learning for Adverse Drug Reaction Prediction
Adverse drug reaction (ADR) prediction is typically formulated as drug-ADR association learning on extremely sparse, positive-unlabeled matrices, which limits generalization and makes naive pseudolabel expansion prone to confirmation bias. Here, we propose DWPL-GCNMF, a structure-aware semisupervised framework that combines graph convolutional network (GCN)-based structural embeddings learned from a drug-protein knowledge graph with matrix factorization scoring and introduces a prediction-consistency-driven dynamic weighted pseudolabel learning strategy to expand training pairs while down-weighting unreliable pseudolabels; multiple base models are further fused to improve prediction stability. We evaluate DWPL-GCNMF on a DrugBank-derived benchmark (1,177 drugs × 4,247 ADRs; ∼2.6% observed associations) and an external SIDER benchmark (1,080 drugs × 5,579 ADRs; ∼2.3% observed associations) to assess robustness under different data sets and increased sparsity. DWPL-GCNMF consistently outperforms representative baselines, achieving AUPR/F1 of 0.6656/0.6194 on DrugBank and 0.6106/0.5816 on SIDER, while also improving top-K prioritization (e.g., Recall@15 up to 0.8078 and 0.8146, respectively), indicating that structure-aware representation learning with dynamically weighted pseudolabeling provides a robust approach for prioritizing potential ADRs under severe data sparsity.
2 May 2026
Read appraisal →Journal of chemical information and modeling
Explainability Methods from Machine Learning Detect Important Drugs' Atoms in Drug-Target Interactions
Predicting drug-target interactions (DTI) with graph neural networks (GNNs) is hindered by their lack of interpretability. To address this, we benchmark four explainable artificial intelligence (XAI) attribution methods on GNN models trained for kinase and G-protein-coupled receptors (GPCR) targets. We assess the methods' consistency through atom-level intersection over union (IoU) and validate their biological relevance by mapping attributed atoms to three-dimensional (3D) protein-ligand structures. While consistency across methods was modest, consensus attributions were highly enriched for atoms directly contacting the binding pocket─up to 76% within 2 Å in the kinase-inhibitor complexes. Notably, these attributed atoms were frequently found contacting experimentally important regulatory residues such as those in the DFG motif. This indicates that XAI methods, despite their disagreements, can identify chemically meaningful ligand features, providing a foundation for developing more interpretable GNNs in drug discovery.
2 May 2026
Read appraisal →Journal of chemical information and modeling
A Reinforcement Learning-Guided Genetic Algorithm Integrating Medicinal Chemistry-Inspired Molecular Transformations
Achieving optimal target activity while maintaining synthetic accessibility and drug-likeness represents a major challenge in computational drug discovery. Existing de novo generative models often yield chemically invalid or synthetically intractable structures and struggle to optimize multiple objectives simultaneously. Here, we introduce ALCHIMIA, an interpretable hybrid framework combining reinforcement learning (RL) and a genetic algorithm (GA), built based on a vocabulary of 33 medicinal chemistry-inspired molecular transformations. The RL component trains a policy network to prioritize transformation sequences that improve synthetic accessibility (SA) and the quantitative estimate of drug-likeness (QED) scores, embedding these constraints directly into molecular generation. The GA component applies the learned policy as a mutational operator within population-based optimization guided by molecular docking, enabling the exploration of diverse chemical lineages while converging toward high-affinity ligands. ALCHIMIA was applied to two different pharmacologically relevant targets: human Cannabinoid Receptor 2 (CB2R) and human Sigma nonopioid intracellular Receptor 1 (S1R). We considered three different scenarios: (i) unconstrained hit identification; (ii) scaffold-constrained lead optimization; and (iii) design of dual modulators. The framework generated chemically valid molecules with QED and SA scores comparable to or better than those obtained with random baselines and selected de novo design methods. By codifying typical medicinal chemistry actions as learnable transformations and coupling multiobjective optimization with GA-based diversity maintenance, ALCHIMIA, freely available as a GitHub repository (https://github.com/alberdom88/ALCHIMIA), provides a practical, interpretable, and scalable framework for molecular de novo design.
2 May 2026
Read appraisal →Lancet (London, England)
Clinical and bacteriological effectiveness of three different short-course antibiotic regimens and single-dose fosfomycin for uncomplicated lower urinary tract infections in women (SCOUT): a pragmatic, multicentre, open-label, randomised clinical trial
BACKGROUND: Most guidelines recommend nitrofurantoin, fosfomycin, and sometimes pivmecillinam for uncomplicated urinary tract infections (UTIs), but direct comparisons between these antibiotics are needed. This study evaluated the effectiveness and safety of a single dose of fosfomycin compared with two doses of fosfomycin and short-course regimens of nitrofurantoin and pivmecillinam in women with UTI symptoms. METHODS: This phase 4, pragmatic, multicentre, parallel-group, open-label, randomised clinical trial was conducted in Spanish primary care centres from 2022 to 2024. Women aged 18 years or older with at least one UTI-specific symptom (dysuria, urinary urgency, urinary frequency, or suprapubic tenderness) and a positive urine dipstick test for either nitrites or leukocyte esterase were randomly assigned (1:1:1:1) to one of four treatments: a single 3 g dose of fosfomycin, two 3 g doses of fosfomycin, nitrofurantoin (100 mg three times per day for 5 days), or pivmecillinam (400 mg three times per day for 3 days). Doctors and patients were not masked to group assignment. The primary outcome was the proportion of patients with clinical resolution (defined as the disappearance of all infection symptoms) at day 7. This trial is registered with ClinicalTrials.gov (NCT04959331) and EudraCT (2021-001332-26) and is completed. FINDINGS: Of the 804 patients assessed for eligibility between April 4, 2022 and Nov 14, 2024, 768 patients were randomly allocated (191 to the single-dose fosfomycin group, 194 to the two-dose fosfomycin group, 190 to the nitrofurantoin group, and 193 to the pivmecillinam group). Patients had a median age of 48 years (IQR 34-63). Race and ethnicity data were not collected. Among the 720 women with available data included in the primary analysis, single-dose fosfomycin had the lowest proportion of clinical resolution (109 [59%] of 185 patients), while nitrofurantoin had the highest (128 [74%] of 172 patients; difference 15·5 percentage points [95% CI 5·9 to 25·1] vs single-dose fosfomycin; p=0·0168), followed by pivmecillinam (127 [70%] of 182; difference 10·9 percentage points [1·1 to 20·6]; p=0·2352) and the two-dose fosfomycin group (122 [67%] of 181; difference 8·5 percentage points [-1·4 to 18·3]; p=0·6935). Adverse events occurred in 38 (19·9% [95% CI 14·9 to 26·1) of 191 patients who received single-dose fosfomycin, 51 (26·3% [20·6 to 32·9]) of 194 who received two-dose fosfomycin, 51 (26·8% [21·0 to 33·6]) of 190 who received nitrofurantoin, and 41 (21·2% [16·1 to 27·5]) of 193 who received pivmecillinam. Most adverse events were mild and self-limiting, primarily gastrointestinal. Four serious adverse events occurred, of which one was related to the study treatment (one case of pyelonephritis in the pivmecillinam group). INTERPRETATION: Nitrofurantoin was the most effective treatment and single-dose fosfomycin the least effective treatment for UTIs. Adverse events were mild. The role of fosfomycin as a first-line antibiotic for uncomplicated UTI should be re-evaluated. FUNDING: Carlos III Institute of Health, Spanish Ministry of Science and Innovation, and European Regional Development Fund.
2 May 2026
Read appraisal →Signal transduction and targeted therapy
Abexinostat, a histone deacetylases inhibitor, for patients with relapsed or refractory follicular lymphoma: a multi-center, single-arm phase 2 study
This phase 2, single-arm, multi-center study (NCT03934567) evaluates the efficacy and safety of abexinostat, a histone deacetylase inhibitor, in patients with relapsed or refractory (r/r) follicular lymphoma (FL). Eligible participants had previously received a minimum of two systemic treatment lines, such as cytotoxic agents and/or anti-CD20 monoclonal antibodies. Participants received abexinostat 80 mg oral twice daily on a schedule of seven days on and seven days off, within 28-day cycles, continuing until unacceptable toxicity or disease progression occurred. The primary endpoint was objective response rate (ORR), evaluated by an independent review committee (IRC). Secondary endpoints comprised duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Between May 2, 2019, and November 19, 2023, 90 patients were enrolled. As of October 08, 2024, with a median follow-up of 30.55 months (95% confidence interval [CI] 23.72-33.64), 17.8% (16/90) of patients were still on study treatment. The ORR was 69.5% (57/82, 95% CI 58.4-79.2), with a complete response rate of 14.6% (12/82). The DCR was 91.5% (75/82, 95% CI 83.2-96.5). Tumor size reduced in 89% (73/82) of patients. The median DoR was 13.96 months (95% CI 9.20-not reached [NR]) and the median PFS was 13.80 months (95% CI 9.69-30.26). The median OS was 47.18 months (95% CI 45.70-NR). The most common treatment-emergent adverse events were thrombocytopenia (77/90, 85.6%), neutropenia (53/90, 58.9%), and leukopenia (47/90, 52.2%). The results of this study demonstrated that abexinostat had promising efficacy and manageable safety profile, supporting abexinostat as a new treatment option for the third-line or later-line treatment of r/r FL.
2 May 2026
Read appraisal →The pharmacogenomics journal
The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine
Oral esketamine displays therapeutic potential for treatment-resistant depression. However, treatment is complicated by a low and variable bioavailability. Genetic polymorphisms in the cytochrome P450 (CYP) enzymes responsible for esketamine's metabolism may influence bioavailability. In a subsample of patients included in a placebo-controlled trial investigating repeated, low dose oral esketamine (N = 18), blood samples were collected four hours after dosing. CYP2B6 516 G > T, CYP3A4*22, and CYP3A5*3 genotyping was performed, and the plasma levels of esketamine and its metabolites were measured. CYP2B6 516 G > T carriers (Mdn = 5.1 µg/L) demonstrated higher esketamine plasma levels compared to non-carriers (Mdn = 2.1 µg/L) (U = 45.00, p = 0.032). No significant associations were observed for CYP3A4*22 carriership (n = 2) or CYP3A5*3 heterozygosity (n = 2), nor for esketamine's metabolites. In summary, CYP2B6 516 G > T is associated with higher esketamine plasma concentrations. Further research with more participants is warranted to draw conclusions about CYP3A4*22 and CYP3A5*3. Clinical trial registration: NTR6161 (Dutch Trial Register).
28 Apr 2026
Read appraisal →JMIR dermatology
Public Interest in Janus Kinase (JAK) Inhibitors for Alopecia Areata: A Google Trend Analysis
Public interest in Janus kinase (JAK) inhibitors for alopecia areata increased following media coverage and the 2022 US Food and Drug Administration (FDA) approval of baricitinib, highlighting the need for patient education and physician guidance on appropriate indications and treatment selection for hair loss disorders.
28 Apr 2026
Read appraisal →Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
Cardiac adverse events associated with axitinib: A real-world pharmacovigilance study based on the Japanese adverse drug event report database
OBJECTIVE: To evaluate the disproportionality, times to onset, and outcomes of cardiac adverse events (AEs) associated with axitinib, using data from the Japanese Adverse Drug Event Report (JADER) database. METHODS: We analyzed data for the period from April 2004 to December 2024. Those on cardiac AEs were extracted and the disproportionality of axitinib-associated AEs was assessed by calculating reporting odds ratios (RORs). RESULTS: Of the 2,988,681 reports with sex and age information, we identified 4788 reports of AEs associated with axitinib, including 508 cardiac AEs. Signals were detected for 16 cardiac AEs after adjustment for sex and age. Fatal outcomes were reported for five of these events with particularly high rates observed for cardiac failure, myocarditis, and immune-mediated myocarditis. Median times to onset indicated that cardiac AEs associated with axitinib occurred 14 to 420 days after administration. Weibull distributions showed that seven AEs (blood pressure increased, myocardial infarction, acute myocardial infarction, blood pressure systolic increased, oedema peripheral, oedema, and generalised oedema) occurred constantly throughout the exposure period (random failure type), and stress cardiomyopathy and immune-mediated myocarditis developed in a dose-dependent manner (wear-out failure-type). CONCLUSIONS: We focused on cardiac AEs associated with axitinib as post-marketing AEs. Some with fatal outcomes may occur not only early in treatment but also later in the course. Continuous monitoring is essential to ensure timely detection and management of these potentially serious AEs in clinical practice.
28 Apr 2026
Read appraisal →BMJ open
Breastfeeding initiation and continuation among women on medicines: a systematic review and meta-analysis
OBJECTIVES: Breastfeeding provides essential health benefits for infants and mothers, yet initiation and continuation can be influenced by maternal medication use. Uncertainty regarding medication safety may lead to early discontinuation or avoidance of necessary treatment. We conducted a systematic review and meta-analysis to estimate the prevalence of breastfeeding initiation and continuation at 6 months post partum among women using medications. DESIGN: Systematic review and meta-analysis using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. DATA SOURCES: PubMed, Web of Science, Academic Search Premier (EBSCO) and Google Scholar were searched up to 30 November 2024. ELIGIBILITY CRITERIA: For selecting studies: We included cohort, cross-sectional and observational studies reporting breastfeeding initiation at birth and continuation at 6 months post partum among women aged ≥18 years using medications during pregnancy or post partum. Studies reporting medication type and duration of breastfeeding were prioritised. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened, extracted and coded data using standardised methods. Risk of bias was assessed using validated tools. Pooled prevalence estimates were calculated using a random effects meta-analysis and meta-regression was performed to explore factors associated with breastfeeding outcomes. Findings were summarised in GRADE evidence profiles and synthesised qualitatively. RESULTS: Of 286 retrieved articles, 29 met the inclusion criteria and 28 were included in the meta-analysis. 14 (48%) were cohort studies reporting breastfeeding prevalence while using medications. The pooled prevalence of breastfeeding initiation among women on medication during pregnancy or post partum was 75.2% (95% CI 69.8% to 80.7%; range 14-98%), with high heterogeneity (I²=99.2%, p<0.001). Overall prevalence of breastfeeding at 6 months post partum was 53.2% (95% CI 43% to 63%). Meta-regression showed that women in high-income countries were less likely to initiate (β=-0.27, 95% CI -0.54 to -0.00, p=0.04) or continue breastfeeding at 6 months (β=-0.27, 95% CI -0.54 to -0.01, p=0.04). Women using antidepressants (β=-0.45, 95% CI -0.87 to -0.02, p=0.04) and opioids (β=-0.50, 95% CI -0.93 to -0.08, p=0.02) were less likely to continue breastfeeding at 6 months. Women living with HIV on ART in low- and middle-income countries had higher continuation rates, likely due to supportive public health programmes. CONCLUSION: Breastfeeding initiation among women using medications is generally high, but continuation declines substantially, particularly among women on psychotropic, opioid or antiepileptic drugs. HIV status, medication type, healthcare support and national guidelines influence breastfeeding outcomes. Targeted interventions, including provider education, medication-specific lactation guidance and supportive workplace policies, are essential to promote sustained breastfeeding among women using medications.
27 Apr 2026
Read appraisal →Journal of ethnopharmacology
Salvia plebeia R.Br.: A comprehensive review of its ethnopharmacology, phytochemistry, pharmacological activities, quality control, and current applications.
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia plebeia R.Br. (Lamiaceae), the dried aerial parts, has been traditionally used across China and East/South Asia to treat sore throat, bronchitis, nephritis edema, abscesses, mastitis, hemorrhoids, and bleeding disorders, consistent with traditional indications of heat-clearing, detoxifying, cooling blood, and promoting diuresis. AIM OF THE REVIEW: This study provides a systematic overview of the ethnopharmacology, phytochemistry, pharmacological activities, quality control, and current applications of S. plebeia, while highlighting current research gaps and future perspectives. MATERIALS AND METHODS: A comprehensive literature search was conducted using multiple scientific databases, including Web of Science, PubMed, Elsevier, ACS, CNKI, and Google Scholar, covering publications from database inception to October 2025. Relevant information on the ethnopharmacology, phytochemistry, pharmacological activities, quality control, and applications of S. plebeia was systematically collected, screened, and synthesized according to predefined inclusion/exclusion criteria. RESULTS: To date, 325 constituents have been identified, dominated by flavonoids, phenolic acids, terpenoids, volatile oils, sterols, lignans, and others. Extracts and purified compounds show tradition-relevant anti-inflammatory, antiviral, immunoregulatory, and antioxidant activities, while other reported effects (hepatoprotective, hypolipidemic, cardiovascular-protective, sedative/anticonvulsant, anticancer, and anti-photoaging) are presented as exploratory findings. Quality evaluation evolved from UV and HPLC to UPLC-MS fingerprinting using flavonoids and sesquiterpenes as markers. In practical applications, S. plebeia has been used in medicinal preparations for the management of pharyngitis, bronchitis, nephritis, dermatitis, and anorectal inflammation. In food sector, it has been developed into functional products, including health teas, chewable or effervescent tablets, composite beverages, and co-fermented vinegars. CONCLUSION: Although S. plebeia shows broad pharmacological potential, current investigations remain constrained by incomplete chemical space coverage, limited pharmacokinetic and toxicological characterization, and insufficient well-designed clinical evidence. Future research should focus on comprehensive constituent profiling, mechanism-oriented validation aligned with traditional indications, standardized quality markers/fingerprints, and rigorous PK-toxicology-clinical translation, to promote safe, effective, and evidence-based utilization of S. plebeia in medicine and functional food development.
27 Apr 2026
Read appraisal →PloS one
Effects of peppermint (Mentha x piperita L.) oil on cardiometabolic outcomes in patients with pre- and stage 1 hypertension: A placebo randomized controlled trial.
Hypertension represents the predominant risk factor for cardiovascular disease morbidity and mortality; with significant healthcare utilization and expenditure. Pharmaceutical management is habitually adopted; although its long-term effectiveness remains ambiguous, and accompanying adverse effects are disquieting. Peppermint, which is rich in menthol and flavonoids, may exert potential benefits relevant to hypertension. This trial aimed to explore the effects of twice-daily peppermint oil supplementation in individuals with pre- and stage 1 hypertension. A 20 day, parallel randomized, placebo-controlled trial was adopted (NCT05561543). 40 individuals with pre- and stage 1 hypertension were randomly assigned to receive 100 μL per day of either peppermint oil or peppermint-flavoured placebo. The primary trial outcome was the between-group difference in systolic blood pressure from baseline to 20 days. Secondary outcome measurements were the between-group differences in anthropometric, haematological, diastolic blood pressure/resting heart rate, psychological wellbeing, and sleep efficacy indices. Statistical analysis was conducted on an intention-to-treat basis using baseline-adjusted linear regression models comparing post intervention values between trial arms with the corresponding baseline value entered as a covariate; adjusted mean differences (b), 95% confidence intervals, and effect sizes (d) were calculated. In relation to the primary outcome, adjusted systolic blood pressure at 20 days was significantly lower (b = -8.48 mmHg, 95% CI = -14.24 to -2.73, d = -0.94) in the peppermint trial arm (baseline = 130.05 mmHg, 20 days = 121.97 mmHg) than in placebo (baseline = 130.93 mmHg, 20 days = 131.05 mmHg). Loss to follow-up (N = 1) and adverse events (N = 1) were low, both occurring in the peppermint arm, and compliance was very high in the peppermint (93.3%) trial arm. Given the substantial health and economic burden associated with hypertension worldwide, these findings suggest that twice-daily peppermint supplementation may represent a simple, low-cost, and well-tolerated strategy to support blood pressure reduction in this population. Trial registration ClinicalTrials.gov NCT05561543.
27 Apr 2026
Read appraisal →Science advances
Repertoire-scale antibody structural prediction informs therapeutic design
We present AF3-TurboAb, a scalable framework that makes a repertoire-scale antibody-antigen complex structural decoding routine for antibody engineering. By eliminating preprocessing bottlenecks, AF3-TurboAb enables end-to-end complex modeling in 0.5 minutes per seed on a single GPU while preserving near-experimental interface fidelity, as validated on ~1000 posttraining Protein Data Bank (PDB) benchmarks and 12 experimentally determined cryo-electron microscopy nanobody-antigen structures. Applying this capability to 275,371 immunization-derived antigen-specific nanobodies produced 28,013 high-confidence complex predictions, substantially expanding the structural landscape of antibody recognition. The resulting atlas reveals hundreds of previously unmapped epitopes, extensive coverage of solvent-exposed surfaces, and recurrent affinity hotspots enriched in aromatic and charged residues. Despite wide sequence diversity, we observe structural convergence at shared epitopes and consistent physicochemical and geometric features that complement and extend existing PDB entries. We demonstrate translational utility by (i) designing durable (escape-proof), multiepitope neutralizers against highly evolved viruses, (ii) identifying cross-species and glycoform-specific binders to a cancer checkpoint, and (iii) enabling near-real-time in silico binder triage. The models and metadata will be shared for community use, establishing repertoire-scale structural decoding as a practical design modality that transforms the scale and speed of structure-guided antibody engineering.
27 Apr 2026
Read appraisal →The pharmacogenomics journal
A randomized trial to evaluate attitudes regarding pharmacogenomics among pregnant and pediatric populations: design and baseline characteristics.
Pharmacogenomics (PGx) is a key component of precision medicine, yet most PGx studies exclude pregnant people and children. The VICE (Vanderbilt Integrated Center of Excellence)-MPRINT (Maternal and Pediatric Precision in Therapeutics): Maternal and Pediatric Pharmacogenetics Trial is a single-center, randomized control trial to assess how PGx testing and return of results influence patients' understanding and perceived utility of PGx testing in a pregnancy and pediatric cohort. Pregnant individuals and families or guardians of children with a chronic health condition aged 0-16 were recruited. We assessed participants' knowledge and attitudes regarding PGx testing at baseline and after receiving results with patient-friendly interpretations. Cases received an educational video about PGx testing with return of results. Controls received PGx test results alone. We aimed to determine perspectives regarding PGx in these understudied populations with the goal of promoting research and clinical implementation of PGx for pregnant women and children.
26 Apr 2026
Read appraisal →European journal of hospital pharmacy : science and practice
How to manage the overwhelming amount of database-detected interactions? A focus group meeting study on the management of database-detected risks of drug interactions.
OBJECTIVES: Database-assisted screening may help detect the risks of drug interactions, but less than 10% of flagged interactions have clinical manifestations, potentially leading to alert fatigue among healthcare providers. To address this issue, this study aimed to develop a concise framework to support the management of database-indicated interaction risks. METHODS: A grounded theory approach was used to design, evaluate and develop the framework. Participants included healthcare professionals and laypersons with experience using narrow therapeutic index medications, as well as individuals recommended by them. Two focus group discussions were conducted (N1=6 and N2=5), each lasting approximately 2 hours and following the same agenda. In one case, a follow-up one-on-one interview was held because the participant indicated further insights at the end of the session. RESULTS: Participants identified key decision-making questions for the framework, including the evidence base for interacting drugs, severity and documentation level of the interaction, availability of safer alternatives, and the presence of confounding factors. The framework was considered useful and, following refinement, potentially suitable for clinical implementation. A key insight was that integration into healthcare curricula is essential for achieving long-term impact. Overall, the proposed tool may assist in managing interaction risks in diverse clinical scenarios and reduce alert fatigue among healthcare professionals. CONCLUSION: Although further clinical validation is needed, the framework provides a foundation for improving the management of database-detected drug interactions.
26 Apr 2026
Read appraisal →Journal of ethnopharmacology
Neuroprotective effects of Tongxinluo capsule in acute ischemic stroke: A systematic review and meta-analysis
ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo capsule is widely used in patients with acute ischemic stroke (AIS), although the literature does not consistently agree on its efficacy and safety. AIM OF THE STUDY: We aimed to assess the efficacy and safety of Tongxinluo capsule for patients with AIS. MATERIALS AND METHODS: A systematic search of the databases PubMed, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang data, VIP Chinese Journal Service Platform, and SinoMed was conducted from their inception dates to January 2025. Randomized controlled trials (RCTs) that enrolled patients with AIS who receive Tongxinluo capsule and compared effects with placebo or as an add-on therapy to usual care were included. Literature screening, risk of bias assessment, and data extraction were independently conducted in duplicate. Fixed-effects or random-effects models were used to perform meta-analysis for pooling data from eligible studies. The primary outcome was long-term functional independence (defined as modified Rankin Scale [mRS] grade less than 2). Secondary outcomes included all-cause mortality, improvements in activities of daily living (measured with the Barthel Index [BI]), and neurological impairment (measured with the National Institutes of Health Stroke Scale [NIHSS]). Incidence of adverse events were identified as safety outcomes. RESULTS: We included 4842 patients with AIS from 12 RCTs (2422 [50.02 %] treated with Tongxinluo capsule) in the final analysis. Tongxinluo capsule treatment in AIS significantly improved the proportion of patients with mRS less than 2 (RR, 1.21; 95 % CI, 1.02 to 1.44), improved the change in BI score (MD, 11.47; 95 % CI, 10.34 to 12.60) and NIHSS score (MD, 3.48; 95 % CI, 2.87 to 4.09). No significant differences were detected in all-cause mortality (RR, 0.57; 95 % CI, 0.17 to 1.95), or the incidence of overall adverse events (RR, 1.01; 95 % CI, 0.91 to 1.12). CONCLUSION: Administration of Tongxinluo capsule for AIS demonstrated potential benefits in improving the long-term functional outcomes and activities of daily living, and relieving neurological impairment, without observing major safety concerns.
25 Apr 2026
Read appraisal →The New England journal of medicine
Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients
BACKGROUND: Nirmatrelvir-ritonavir has been shown to reduce progression to severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unvaccinated high-risk outpatients. The effectiveness of nirmatrelvir-ritonavir in persons who have been vaccinated, infected naturally, or both is unclear. METHODS: In two open-label platform trials (PANORAMIC in the United Kingdom and CanTreatCOVID in Canada), we enrolled higher-risk adults (≥50 years of age or ≥18 years of age with coexisting conditions) in the community who tested positive for SARS-CoV-2 and had been unwell for 5 days or less. The participants were randomly assigned to receive usual care plus nirmatrelvir (300 mg)-ritonavir (100 mg) twice a day for 5 days or to receive usual care alone. The primary outcome was hospitalization or death from any cause within 28 days after randomization. RESULTS: From December 8, 2021, to September 30, 2024, a total of 3516 participants in the PANORAMIC trial and 716 participants in the CanTreatCOVID trial underwent randomization. In the PANORAMIC trial, 14 of 1698 participants (0.8%) in the nirmatrelvir-ritonavir group and 11 of 1673 participants (0.7%) in the usual-care group were hospitalized or died (adjusted odds ratio, 1.18; 95% Bayesian credible interval, 0.55 to 2.62; probability of superiority, 0.334). In the CanTreatCOVID trial, 2 of 343 participants (0.6%) in the nirmatrelvir-ritonavir group and 4 of 324 participants (1.2%) in the usual-care group were hospitalized or died (adjusted odds ratio, 0.48; 95% Bayesian credible interval, 0.08 to 2.23; probability of superiority, 0.830). In a substudy involving 634 participants, viral load was reduced by the end of treatment with nirmatrelvir-ritonavir. Serious adverse events with nirmatrelvir-ritonavir were reported in 9 participants in the PANORAMIC trial and in 4 participants in the CanTreatCOVID trial. CONCLUSIONS: In two open-label trials, nirmatrelvir-ritonavir did not reduce the incidence of hospitalization or death among vaccinated higher-risk participants with SARS-CoV-2 infection. (Funded by the National Institute for Health and Care Research, and others; PANORAMIC ISRCTN number, 2021-005748-31; CanTreatCOVID ClinicalTrials.gov number, NCT05614349.).
25 Apr 2026
Read appraisal →Renal failure
Dapagliflozin improves hemoglobin and anemia in chronic kidney disease: a systematic review and meta-analysis
Anemia becomes increasingly prevalent as kidney function declines. Current treatments carry multiple safety risks. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), dapagliflozin, have emerged as background anemia modulator, a promising alternative, showing protective effects against anemia. This study synthesizes evidence on dapagliflozin's potential to improve anemia in chronic kidney disease (CKD) patients. A systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, including eight studies identified from six databases. Risk of bias was assessed using tools appropriate for each study design (RoB 2, NOS, JBI). Data were pooled using a random-effects model with RevMan 5.4. The primary analysis for hemoglobin demonstrated significant increase (MD = 4.37; 95% CI = 0.71-8.03; p = 0.02) and remained significant in the sensitivity analysis (MD = 4.11; 95% CI = 0.19-8.04; p = 0.04). A sensitivity analysis for hematocrit revealed a highly significant increase (MD = 2.15; 95% CI = 1.86-2.44; p < 0.00001). In the sensitivity analysis for adverse events dapagliflozin significantly reduced the overall risk (RR = 0.77; 95% CI = 0.59-0.99; p = 0.04). This finding was associated with significantly lower mortality (RR = 0.67; p = 0.02), while no significant differences were observed for cardiovascular (p = 0.22) or genitourinary events (p = 0.70). Dapagliflozin is associated with clinically meaningful improvements in hemoglobin and anemia outcomes in CKD. These findings suggest a potential erythropoietic benefit beyond glycemic control, although dedicated anemia-focused trials are needed to confirm clinical applicability.
25 Apr 2026
Read appraisal →Journal of medicinal chemistry
Automated Molecular Design in BRADSHAW, Applied to the Optimization of ERAP1 Inhibitors
Generative design and machine learning are increasingly prevalent in medicinal chemistry. To pilot the comprehensive use of automated molecular design on a project, the BRADSHAW platform was used to optimize a series of inhibitors of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), an emerging target in cancer immunotherapy and autoimmune diseases. Through four consecutive iterations applying in silico molecular generation, property prediction and filtering, we conducted a multiparameter optimization of potency, physicochemical properties and pharmacokinetics. Continuous refinement of Machine Learning (ML) models led to improved scoring accuracy and compound quality, culminating in identification of in vitro and in vivo tool molecules. We also discuss our reflections on the pilot and integration of automated design into medicinal chemistry projects, including observations of the human factors resulting from increased use of computational design, and recommendations for future projects.
25 Apr 2026
Read appraisal →Journal of medicinal chemistry
The Discovery of RGH-706, a Highly Efficacious MCH1 Receptor Antagonist, for the Treatment of Obesity and Insatiable Hunger
The discovery and characterization of a novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole derivative MCH1 receptor antagonist (37) is disclosed. Starting from our previously investigated pyrazino[1,2-a]indole series and utilizing a scaffold hopping strategy, pyrimidine- and 1,4-diazepine-fused indole derivatives were designed and synthesized. Among these, only the prototype molecule containing the 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole scaffold emerged as a chemically stable and potent MCHR1 antagonist. Previous SAR knowledge coupled with an ex vivo occupancy assay helped us to optimize this advanced lead to our candidate (37). The high MCHR1 potency and excellent receptor occupancy profile of 37 translated into statistically significant body weight loss after 14 days in a DIO mice study, supporting the potential use of this compound as a weight loss agent. Compound 37 (RGH-706) has successfully completed a phase I (SAD & MAD) clinical study in the indication of obesity, followed by an exploratory Phase II study in patients with Prader-Willi Syndrome (PWS).
25 Apr 2026
Read appraisal →BMJ open diabetes research & care
Sex differences in glycemic outcomes: a systematic review and meta-analysis of diabetes treatments
UNLABELLED: Sex differences in glycemic outcomes following insulin therapy remain underexplored despite biological and psychosocial factors that may influence individual responses. This systematic review examines sex-specific differences in glycemic control to guide personalized diabetes care and promote health equity. We searched PubMed, Scopus, Cochrane Library, and Google Scholar (August 2014-December 2025) for randomized and observational studies involving adults of both sexes on insulin. Twenty-four studies were included, with certainty of evidence assessed using GRADE. In type 1 diabetes, women showed no significant difference in achieving HbA1c <7% (RR 1.05, 95% CI 0.91 to 1.22; very low certainty) and toward higher time-in-range (SMD 0.78, -0.01 to 1.57; moderate certainty). In type 2 diabetes, men were more likely to achieve HbA1c targets (RR 0.86, 95% CI 0.72 to 1.03; low certainty), while women required higher weight-adjusted insulin doses (SMD 0.55, 0.23 to 0.86; very low certainty). Hypoglycemia risk showed opposing trends in inpatient (RR 0.78, 95% CI 0.33 to 1.83; very low certainty) versus outpatient settings (RR 1.08, 95% CI 0.61 to 1.89; low certainty) with substantial heterogeneity (I2>70%). These findings suggest that sex-related differences in glycemic outcomes vary by diabetes type and treatment context. Given the low certainty and heterogeneity of current evidence, results should be interpreted as hypothesis-generating. This review supports the consideration of biological sex within a broader, individualized diabetes management framework and highlights the need for future sex-stratified analyses with rigorous control of lifestyle and physiological factors. INTRODUCTION: Sex differences in glycemic outcomes following the same insulin therapy in diabetes remain underexplored. Numerous factors, encompassing both biological and psychosocial aspects, could potentially influence individual responses to insulin therapy. This systematic review examines sex-specific differences in glycemic control to guide personalized diabetes care and promote health equity. METHODS: PubMed, Scopus, Cochrane Library, and Google Scholar were searched (August 1, 2014-December 31, 2025) for randomized and observational studies. Eligible studies included adults of both sexes on insulin reporting sex-specific data for predefined outcomes. Data on glycated hemoglobin (HbA1c), blood glucose metrics, hypoglycemia, and insulin dose were extracted. Certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: Twenty-four studies were included. In type 1 diabetes, women showed no significant difference in achieving HbA1c <7% (risk ratio (RR) 1.05, 95% CI 0.91 to 1.22; very low certainty) and toward higher time-in-range (standardized mean difference (SMD) 0.78, -0.01 to 1.57; moderate certainty). In type 2 diabetes, men were more likely to achieve HbA1c targets (RR 0.86, 95% CI 0.72 to 1.03; low certainty), whereas women required higher weight-adjusted insulin doses (SMD 0.55, 0.23 to 0.86; very low certainty). Hypoglycemia risk showed opposing trends in inpatient (RR 0.78, 95% CI 0.33 to 1.83; very low certainty) versus outpatient settings (RR 1.08, 95% CI 0.61 to 1.89; low certainty), with substantial heterogeneity (I2 >70%). CONCLUSION: Sex-related differences in glycemic outcomes under insulin therapy were observed, with patterns varying by diabetes type, treatment context, and outcome. Given the low certainty and heterogeneity of the evidence, these findings should be interpreted as hypothesis-generating rather than directive for clinical practice. The results support consideration of biological sex as one component within a broader, individualized diabetes management framework. Future studies should prioritize sex-stratified analyses with rigorous control of polypharmacy, body composition, and lifestyle factors to determine whether sex-specific insulin strategies provide meaningful clinical benefit. PROSPERO REGISTRATION NUMBER: CRD420251144696.
25 Apr 2026
Read appraisal →Journal of medicinal chemistry
An Interpretable, Thermodynamics-Based Deep Learning Framework for Predicting and Optimizing Drug Membrane Permeability
Cellular membranes serve as selective barriers, and membrane permeability is crucial for drug pharmacokinetics. While in vitro and in vivo methods exist, predicting and designing membrane permeability remains challenging. We developed a thermodynamics-based deep learning framework to analyze the structure-permeability relationship, based on the concept that interactions between membrane lipids and small molecules influence permeability. We determined the membrane penetration thermodynamics of 8,239 compounds using coarse-grained molecular dynamics simulations and created interpretable graph neural network models to predict and design drug membrane permeability. As a proof-of-concept, we designed a novel nasal-administered melatonin analog, MT-A2, optimized for permeability. Compared with melatonin, MT-A2 showed superior nasal absorption, prolonged brain retention, and enhanced sleep efficacy. Our results provide a promising approach for predicting and designing membrane permeability, aiding in the development of drugs with better pharmacokinetics.
25 Apr 2026
Read appraisal →Journal of neurology
Efficacy and safety of monoclonal antibodies in the treatment of relapsing remitting multiple sclerosis: a systematic review
INTRODUCTION: In relapsing-remitting multiple sclerosis (RRMS), conventional immunomodulatory and immunosuppressive therapies are widely used. However, in many cases, optimal control of inflammatory activity and disease progression is not achieved, which has led to the use of biological drugs such as monoclonal antibodies that act specifically on key components of the immune system. The aim was to evaluate the efficacy and safety of monoclonal antibodies compared to other drugs or placebo in adult patients with RRMS. METHODS: A systematic review was performed based on randomized, double-blind, phase III controlled clinical trials published between 2012 and 2025 in the PubMed, Cochrane Library, and Web of Science databases, assessing efficacy and safety in adult patients with RRMS. The review was carried out following the PICO methodology and PRISMA guidelines. RESULTS: A total of 11 studies were included, evaluating 5 monoclonal antibodies: alemtuzumab, daclizumab, ocrelizumab, ofatumumab, and ublituximab. These therapies showed superior efficacy compared to conventional treatments in reducing the annual relapse rate, MRI inflammatory activity and MRI activity, particularly in patients with highly active disease. However, effects on disability progression were heterogeneous across trials and not consistently significant. In addition, decreases in biomarkers of axonal damage were observed. Nevertheless, relevant adverse effects were identified, including infections, autoimmune reactions, hepatic and cutaneous toxicity, whose incidence varies depending on the drug, requiring close clinical monitoring. CONCLUSIONS: Monoclonal antibodies are an effective option in RRMS, with clinical and radiological benefits superior to those of conventional treatments. Their use requires individualized assessment and close follow-up due to the risk of adverse effects, especially in high-risk patients.
25 Apr 2026
Read appraisal →Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
Predictive biomarkers of placebo response in patients with cancer: an exploratory analysis of the ABCD randomized clinical trial
PURPOSE: Placebo effect is commonly observed in symptom management randomized clinical trials. However, there are currently no established predictive biomarkers of placebo response. We examined the patterns of association between placebo response and baseline plasma cytokine levels for 10 symptoms in patients with cancer. METHODS: This is an exploratory analysis of the double-blind, randomized ABCD trial, which compared high-dose dexamethasone to placebo for dyspnea treatment in patients with cancer (clinicaltrials.gov; NCT03367156). The primary outcome was change in dyspnea intensity. Four plasma cytokines (TNF, IL-6, IL-8, and IL-10) and 10 Edmonton Symptom Assessment System symptoms were measured at baseline, day 7, and day 14. Generalized additive models and exploratory analyses were used to examine the patterns of association between baseline cytokine levels and symptom responses on day 7 and day 14 in placebo and dexamethasone groups. RESULTS: This analysis included data from 45 patients. In the placebo group, we observed a significant negative association (p < 0.05) between ≥ 1 of the measured cytokines' baseline levels across multiple symptoms on day 7 (5/10 symptoms) and day 14 (3/10 symptoms), including appetite, drowsiness, nausea, and pain. Exploratory analysis revealed a negative association in the placebo group in 33/40 cytokine-symptom response combinations for day 7 (p < 0.001) and 29/40 combinations for day 14 (p = 0.006). CONCLUSION: Our preliminary findings suggest patients with high baseline cytokine levels may be less likely to report placebo response for multiple symptoms. Upon further confirmation, these findings may have implications for future clinical trial design. In this exploratory analysis, we observed that patients with cancer were less likely to report placebo response for multiple symptoms if they had higher levels of baseline cytokines. These preliminary findings have important potential implications for placebo-controlled clinical trials, including patient selection, design of interventional controls, and trial interpretation. Additionally, they invite further research on possible mechanistic links between inflammation and placebo effect.
25 Apr 2026
Read appraisal →BMJ open
Effect of early antiplatelet therapy on 30-day mortality after coronary artery bypass grafting: a retrospective target trial emulation using the MIMIC-IV database
OBJECTIVES: The effect of early antiplatelet therapy on 30-day mortality after coronary artery bypass grafting (CABG) remains uncertain. This study aimed to evaluate the association between early antiplatelet therapy initiation and clinical outcomes in post-CABG patients. DESIGN: A retrospective target trial emulation. SETTING: Single academic medical centre in Boston, Massachusetts, USA. PARTICIPANTS: We included adult patients who underwent CABG and were admitted to the intensive care unit at Beth Israel Deaconess Medical Center between 2008 and 2022. METHODS: Patients were classified into the treatment group if they initiated antiplatelet therapy within 24 hours postoperatively; otherwise, they were assigned to the control group. To address immortal-time bias for the primary outcome of 30-day mortality, we used clone-censor-weighting. For the exploratory outcome of 30-day acute kidney injury (AKI) incidence, we employed inverse probability of treatment weighting to balance baseline covariates. RESULTS: The analysis for 30-day mortality included 6887 patients. The mortality was 2.35% in the control group versus 1.44% in the treatment group, yielding an absolute risk difference of 0.90% (control group minus treatment group, 95% CI 0.09% to 1.72%). The difference in restricted mean time lost was 0.19 days (control group minus treatment group, 95% CI 0.03 to 0.36). For AKI incidence, 5543 patients were analysed. The incidence was 78.61% in the control group and 69.13% in the treatment group, with an absolute difference of 9.48% (control group minus treatment group, 95% CI 6.40% to 12.50%; p<0.001). CONCLUSIONS: In this target trial emulation, early antiplatelet therapy initiated within 24 hours after CABG was associated with lower 30-day mortality and a reduced incidence of postoperative AKI. These findings warrant confirmation in prospective randomised controlled trials.
24 Apr 2026
Read appraisal →Cancer immunology, immunotherapy : CII
Envafolimab combined with lenvatinib and albumin-bound paclitaxel in previously treated advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: a prospective, phase II, multi-cohort trial
BACKGROUND: This single-center, open-label, exploratory trial aimed to investigate the efficacy and safety of envafolimab combined with lenvatinib and chemotherapy in previous treated advanced G/GEJ adenocarcinoma. METHODS: Eligible patients with HER2-negative, microsatellite stable (MSS) advanced G/GEJ adenocarcinoma who had progressed after first-line treatment were enrolled in this phase II trial. Patients without previously receiving PD-1/PD-L1 inhibitors were enrolled in Group A, and those who progressed on the first-line PD-1 inhibitors were included in Group B. Patients in both groups received envafolimab (200 mg, subcutaneous injection (sc), days 1 and 15, Q4W) combined with lenvatinib and albumin-bound paclitaxel (100 mg/m2, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or refusal of continuation. The primary endpoint was objective response rate (ORR). RESULTS: A total of 30 patients were included for safety and efficacy analysis. As of data cutoff (Sep 14, 2024), the median follow-up was 17.0 months (IQR: 8.0-18.8) in Group A. The ORR was 60.0%, and the DCR was 100.0%. The mPFS was 8.2 months (95% CI 6.1-10.4) with mOS of 14.8 months (95% CI 7.4-22.2). With a median follow-up of 9.0 months (IQR: 6.1-16.2) in Group B, the ORR was 46.7%, and the DCR was 100.0%. The mPFS was 5.9 months (95% CI 3.8-8.1), and the mOS was 11.5 months (95% CI 3.1-19.9). The overall incidence of adverse events (AEs) of any grade was 100%. While Group A showed numerically better outcomes than Group B, there was no statistically significant difference in PFS (P = 0.629) or OS (P = 0.873) between the two groups. CONCLUSIONS: Second-line envafolimab-based combination therapy demonstrated promising effects in previously treated advanced GC, particularly in those who have not previously received ICIs.
23 Apr 2026
Read appraisal →Circulation
Memantine for Premature Atrial Contractions: A Phase 2 Randomized Clinical Trial
BACKGROUND: Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. METHODS: We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. RESULTS: Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. CONCLUSIONS: In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non-ion channel-based therapeutic strategy targeting the cardiac glutamatergic system. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06501638.
23 Apr 2026
Read appraisal →Nature communications
Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids
Leigh syndrome (Leigh) is an untreatable mitochondrial disorder characterized by lactic acidosis and basal ganglia and midbrain pathology, leading to psychomotor regression and early death. We previously uncovered impaired neuronal morphogenesis in Leigh cerebral organoids carrying SURF1 gene variants. Leveraging this phenotype, we here develop a deep learning algorithm tailored for cell type-specific drug repurposing screening. In parallel, we perform a survival drug screen in a yeast model of Leigh. The two approaches independently converge on azole compounds, two of which - talarozole and sertaconazole - rescue neuronal morphogenesis in Leigh neurons and lower lactate release and improve growth rate in Leigh midbrain organoids. Mechanistically, these compounds modulate the retinoic acid pathway and membrane-associate lipid metabolism. The findings highlight azoles as promising candidates for Leigh and demonstrate the potential of combining in silico screens with human brain organoids as new approach methodologies (NAMs) to advance the discovery of therapeutics addressing rare neurodevelopmental disorders.
22 Apr 2026
Read appraisal →EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology
Impact of renal function on edoxaban antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease: a prespecified analysis of the EPIC-CAD trial
BACKGROUND: Renal function is a critical factor of ischaemic and bleeding risks in patients with atrial fibrillation (AF) receiving antithrombotic therapy. AIMS: This study aimed to evaluate the impact of renal dysfunction in patients with AF and stable coronary artery disease (CAD) undergoing antithrombotic therapy. METHODS: The Edoxaban Versus Edoxaban With antiPlatelet Agent In Patients With Atrial Fibrillation and Chronic Stable Coronary Artery Disease (EPIC-CAD) trial randomised patients to edoxaban monotherapy or dual antithrombotic therapy (edoxaban plus a single antiplatelet agent). In this prespecified analysis, patients were stratified by creatinine clearance into low (<50 mL/min) or high (≥50 mL/min) groups according to edoxaban dose-reduction criteria. The primary endpoint was net adverse clinical events (NACE: death from any cause, myocardial infarction, stroke, systemic embolism, urgent revascularisation, or major/clinically relevant non-major bleeding) at 12 months. RESULTS: Of 1,040 randomised patients, 252 (24.2%) had low creatinine clearance; these patients were older and had more comorbidities compared with the 788 patients (75.8%) with high creatinine clearance. Patients with low creatinine clearance experienced higher risks of NACE (hazard ratio [HR] 1.72, 95% confidence interval [CI]: 1.19-2.49; p=0.004), ischaemic events (HR 2.70, 95% CI: 1.09-6.70; p=0.032), and bleeding (HR 1.54, 95% CI: 1.01-2.34; p=0.046). At 12 months, edoxaban monotherapy reduced NACE compared with dual therapy in both the low (12.1% vs 21.7%, HR 0.52, 95% CI: 0.28-0.98; p=0.042) and high creatinine clearance groups (5.2% vs 14.5%, HR 0.40, 95% CI: 0.25-0.65; p<0.001), with no interaction (p for interaction=0.53). CONCLUSIONS: In patients with AF and stable CAD, edoxaban monotherapy led to a lower risk of primary NACE than dual antithrombotic therapy, regardless of renal function. (ClinicalTrials.gov: NCT03718559).
21 Apr 2026
Read appraisal →Lancet (London, England)
Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial
BACKGROUND: Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. The efficacy and safety of relacorilant plus nab-paclitaxel were assessed in the phase 3 ROSELLA (GOG-3073, ENGOT-ov72, APGOT-Ov10, and LACOG-0223) trial; the combination showed significant improvement in progression-free survival among patients with platinum-resistant ovarian cancer compared with nab-paclitaxel monotherapy. Results of the final overall survival analysis are reported here. METHODS: In this open-label phase 3 trial, patients were randomly assigned 1:1 to receive relacorilant (150 mg orally the day before, day of, and day after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). Patients, aged 18 years or older, with one to three lines of previous anticancer therapy and platinum-resistant disease (progression <6 months from their last dose of platinum) were eligible. The trial was conducted at 117 hospitals and community oncology centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Progression-free survival, assessed by blinded independent central review, and overall survival (time from randomisation to death from any cause) were dual primary endpoints. Additional prespecified endpoints included safety, second progression-free survival (time from randomisation to disease progression on subsequent anticancer therapy or death due to any cause, whichever occurred first), and patient-reported outcomes. This trial is registered at ClinicalTrials.gov, NCT05257408, and is ongoing. FINDINGS: Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the relacorilant combination group (n=188) or the nab-paclitaxel monotherapy group (n=193). All patients had received bevacizumab; 167 (44%) had received three previous lines of therapy, and 234 (61%) had received a poly(ADP-ribose) polymerase inhibitor. At a median follow-up of 24·8 months (95% CI 23·6-25·7), the addition of relacorilant to nab-paclitaxel resulted in a statistically and clinically significant improvement in overall survival compared with nab-paclitaxel monotherapy (hazard ratio for death 0·65 [95% CI 0·51-0·83]; p=0·0004); 18-month overall survival was 46% and 27%, respectively. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16·0 [95% CI 13·0-18·3] vs 11·9 months [10·0-13·8]). Subsequent anticancer treatments were similar across study groups. Adverse events were similar in both groups when adjusted for duration of study treatment. Neutropenia (121 [64%]), anaemia (115 [61%]), fatigue (101 [54%]), and nausea (82 [44%]) were the most common adverse events in the relacorilant combination group. No new safety signals were observed with additional follow-up since the primary analysis. INTERPRETATION: The addition of relacorilant to nab-paclitaxel led to significantly longer overall survival in patients with platinum-resistant ovarian cancer, without the need for biomarker selection. The findings support relacorilant plus nab-paclitaxel as a potential new standard treatment option for patients with platinum-resistant ovarian cancer. FUNDING: Corcept Therapeutics.
21 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Pembrolizumab With or Without Lenvatinib as First-Line Therapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Phase III LEAP-010 Study
PURPOSE: The PD-1 inhibitor pembrolizumab is approved as first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In LEAP-010 (ClinicalTrials.gov identifier: NCT04199104), the multikinase inhibitor lenvatinib plus pembrolizumab was evaluated as first-line therapy in participants with PD-L1 combined positive score (CPS) ≥1 R/M HNSCC. METHODS: In this phase III, randomized, placebo-controlled, double-blind study, participants 18 years and older with PD-L1 CPS ≥1 R/M HNSCC deemed incurable by local therapy were randomly assigned 1:1 to lenvatinib 20 mg plus pembrolizumab 200 mg IV once every 3 weeks for ≤35 cycles or placebo orally once daily plus pembrolizumab 200 mg IV once every 3 weeks for ≤35 cycles. Primary end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Per the prespecified analysis plan, ORR and PFS were reported from the first interim analysis (IA1; data cutoff: July 6, 2022), and OS from IA2 (data cutoff: May 30, 2023). RESULTS: Five hundred eleven participants were randomly assigned to lenvatinib plus pembrolizumab (n = 256) or placebo plus pembrolizumab (n = 255). The median time from random assignment to data cutoff was 11.5 months for IA1 and 21.3 months for IA2. At IA1, the median PFS was 6.2 months for lenvatinib plus pembrolizumab versus 2.8 months for placebo plus pembrolizumab (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.81]; P = .0001040); the ORR was 46.1% versus 25.4%, respectively (difference = 20.2% [95% CI, 10.5 to 29.6]; P = .0000251). At IA2, the median OS was 15.0 months for lenvatinib plus pembrolizumab versus 17.9 months for placebo plus pembrolizumab (HR,1.15 [95% CI, 0.91 to 1.45]; P = .882). At IA2, 170 (66.9%) participants receiving lenvatinib plus pembrolizumab had grade 3-4 all-cause adverse events compared with 97 (38.3%) participants on placebo plus pembrolizumab. CONCLUSION: In participants with PD-L1 CPS ≥1 R/M HNSCC, first-line lenvatinib plus pembrolizumab significantly improved ORR and PFS, but not OS, compared with placebo plus pembrolizumab. The safety profile was consistent with published data.
21 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Efficacy and Safety of Ultra-Low-Dose Immunotherapy in Relapsed Refractory Solid Tumors: Phase III Superiority Randomized Trial (DELII)
PURPOSE: Immune checkpoint inhibitors (ICIs) achieve sufficient receptor occupancy at much lower than standard approved doses. We hypothesized that ultra-low-dose nivolumab would retain clinical efficacy. PATIENTS AND METHODS: In this phase III randomized superiority trial, patients with advanced solid tumors (Eastern Cooperative Oncology Group 0-1) and progression on ≥1 prior line of systemic therapy were randomly assigned 1:1 to ultra-low-dose nivolumab (20 mg intravenously once every 2 weeks) or standard chemotherapy (docetaxel or paclitaxel, as per tumor type). Treatment continued until progression or intolerable toxicity. The primary end point was overall survival (OS). RESULTS: From June 2020 to February 2024, we enrolled 500 patients: 250 per arm; 52% had head and neck and 36% lung cancers. The median number of prior lines of therapy was 1 (range, 1-8); 29% had received ≥2 prior lines. Median OS was significantly longer with ultra-low-dose nivolumab: 5.88 months (95% CI, 4.99 to 7.13) versus 4.70 months (95% CI, 3.91 to 5.65; hazard ratio [HR], 0.80 [95% CI, 0.66 to 0.97]; P = .022). One-year OS was 27.3% versus 16.9%. Median progression-free survival was similar: 2.04 months (95% CI, 2.00 to 2.10) with ultra-low-dose nivolumab and 2.09 months (95% CI, 2.04 to 2.17) with chemotherapy (HR, 1.03 [95% CI, 0.86 to 1.23]; P = .77). Grade ≥3 treatment-related adverse events were less frequent with ultra-low-dose nivolumab (42.5% v 60.8%; P < .001). Quality of life (QoL) was significantly better with ultra-low-dose nivolumab. CONCLUSION: Ultra-low-dose nivolumab significantly improves OS versus chemotherapy in pretreated solid tumors, with fewer severe toxicities and better QoL. These findings support re-evaluation of ICI dosing strategies and may enhance global access.
21 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor-Positive/HER2-/PIK3CA Wild-Type Advanced Breast Cancer
PURPOSE: Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant. METHODS: This phase III randomized trial (VIKTORIA-1; ClinicalTrials.gov identifier: NCT05501886) evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective. RESULTS: A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade ≥3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients. CONCLUSION: The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor-positive/HER2-, PIK3CA WT advanced breast cancer.
21 Apr 2026
Read appraisal →Medicine
Drug-induced neutropenia: A comprehensive pharmacovigilance study of the FAERS database.
Drug-induced neutropenia (DIN) deserves both clinicians' and researchers' attention for the serious clinical consequences. This study aimed to conduct an exploratory analysis of DIN reports in the United States Food and Drug Administration Adverse Event Reporting System database to identify drugs associated with neutropenia. A disproportionality analysis of DIN was conducted using reports submitted to the United States Food and Drug Administration Adverse Event Reporting System from the first quarter of 2004 to the fourth quarter of 2024. Both the reporting odds ratio algorithms and the information component were applied to identify an association between target drugs and DIN events. A total of 223,736 DIN cases were found, and 254 drugs were identified as potentially associated with neutropenia. The top-ranked drug categories were "monoclonal antibodies and antibody-drug conjugates," "other antineoplastic agents," "protein kinase inhibitors," "direct-acting antivirals," "antimetabolites," "alkylating agents," and "immunosuppressants." The top 5 drugs ranked by number of cases were clozapine, lenalidomide, rituximab, palbociclib, and carboplatin. The top 5 drugs ranked by reporting odds ratio signal strength were calcium levofolinate, vinorelbine, gemtuzumab ozogamicin, fludarabine, and daunorubicin. This comprehensive pharmacovigilance study identified drugs potentially associated with neutropenia, which can help clinicians and researchers further understand DIN.
20 Apr 2026
Read appraisal →Medicine
Drug-associated insomnia: A pharmacovigilance study based on FDA adverse event reporting system.
Insomnia has become an increasingly serious public health issue with complex causes, among which medications act as a significant factor. This study aims to systematically detect and evaluate drug adverse event signals associated with insomnia risk using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The analysis utilized data from the FAERS database covering January 2004 to December 2024. Disproportionality analysis was conducted using 4 algorithms: reporting odds ratio, proportional reporting ratio, information component (IC), and empirical Bayes geometric mean. Potential risk signals were deemed significant only when all 4 algorithms simultaneously met their thresholds. Subgroup analyses were further performed, stratified by age and sex, to assess the robustness of signals across different populations. From 2004 to 2024, there were 179,697 adverse event reports of insomnia in FAERS in which one or more medications were designated as the primary suspect. The top 30 medications with the strongest signal strength were predominantly nervous system medicines (18 types, 60%), followed by respiratory system medicines (3 types, 10%), and genitourinary system and sex hormones (3 types, 10%). The top 3 medications with the highest reporting frequency were mefloquine, viloxazine, and flibanserin. Subgroup analyses revealed distinct drug signal profiles across age groups and genders, with pediatric cases dominated by nervous system and anti-infective agents, adults and the elderly showing additional endocrine or hormonal signals, and sex specific signals such as finasteride in males and flibanserin in females. This pharmacovigilance study identifies insomnia risk signals across multiple drug classes, underscoring the need for clinical vigilance regarding drug-related sleep disturbances. Further prospective research is required to confirm these associations.
20 Apr 2026
Read appraisal →PloS one
Treatment sequence patterns of urate-lowering therapy in Korean patients with gout: A common data model-based study
BACKGROUND: A treat-to-target strategy involving treatment modification improves outcomes in gout, but evidence remains limited regarding the optimal approach when initial urate-lowering therapy (ULT) fails. This study aimed to investigate real-world ULT sequence patterns and evaluate treatment retention based on the initial agent, modification type, and comorbidities. METHOD: We analyzed electronic health record data collected from 2010 to 2022 from the common data model databases of two hospitals. Adults aged 18 years or older diagnosed with gout who initiated ULT and were followed for at least 2 years were included. Outcomes included the frequency and sequence of ULT prescriptions. Treatment modification, defined as switching to another ULT or adding an additional agent, was considered the end of retention for the previous regimen. Subgroup analyses were performed based on comorbidity. RESULTS: Among 2220 patients, febuxostat was the most common first-line agent (51.4%), with 90.9% maintaining therapy. Among those who modified febuxostat therapy, switchers and add-on users continued treatment similarly (91.5% vs. 86.8%, P = 0.33). Of allopurinol initiators, 55.8% changed therapy, mainly switching to febuxostat or benzbromarone rather than adding another agent (51.4% vs. 4.1%, P < 0.001), with similar retention rates (91.5% vs. 86.8%, P = 0.33). Among benzbromarone initiators, 57.2% changed therapy (switchers, 56.7%; add-on users, 0.5%; P < 0.001), and retention rates were 90.5% and 100%, respectively (P = 1.00). Chronic kidney disease was associated with low variability in ULT sequence. CONCLUSIONS: ULT demonstrated durable retention when used as first- or second-line treatment, with switching being more common than add-on therapy and maintaining similar retention rates.
19 Apr 2026
Read appraisal →mAbs
Multi-modal feature learning to prioritize ADCs with favorable half-life in mice
Favorable pharmacokinetic (PK) properties of antibody-drug conjugates (ADCs) enable higher systemic exposure and are associated with improved clinical efficacy, yet ADC PK optimization remains largely empirical and resource-intensive. We developed an in silico framework to predict half-lives of monoclonal antibodies (mAbs) and ADCs in C57BL/6 mice using multi-modal feature learning. To address structural complexity of ADCs, each compound was deconvoluted into three components: (1) antibody features represented using sequence descriptors, AlphaFold-based structural properties, or protein language model (PLM) embeddings; (2) conjugation-related features, including drug-to-antibody ratio and conjugation sites; and (3) physicochemical properties of linker-payloads. XGBoost models were trained using experimental half-life data from 118 mAbs and ADCs. Structure-based and PLM approaches achieved strong cross-validation (Pearson's r = 0.76), outperforming sequence-only models. In temporal validation of 32 mAbs and ADCs, the structure-based models demonstrated robust generalization (r = 0.79). PLM embeddings achieved comparable rank ordering (Spearman's ρ up to 0.81 for ESM-2), but lower quantitative accuracy relative to structure-based models. Overall, our study presents a scalable machine learning framework for early PK screening of mAbs and ADCs prior to synthesis and in vivo testing.
19 Apr 2026
Read appraisal →Pharmaceutical biology
Valeriana species and insomnia: multi-organ mechanisms and translational perspectives.
CONTEXT: Insomnia is a common sleep disorder that substantially impairs quality of life. Conventional treatments, including cognitive behavioral therapy and pharmacological agents, are often limited by side effects and insufficient long-term safety data. Valeriana species, such as Valeriana officinalis L. and Valeriana jatamansi Jones, have been traditionally used for their sedative and neuroprotective properties. OBJECTIVE: This review evaluates the therapeutic potential of Valeriana species for insomnia, emphasizing their pharmacological mechanisms, multi-organ effects, and evidence from preclinical and clinical studies. METHODS: A systematic literature search was performed in databases including PubMed and Web of Science. Studies addressing Valeriana-induced sleep regulation, neurotransmitter modulation, oxidative stress reduction, and neural, hepatic, and gastrointestinal interactions were included to assess efficacy and safety. RESULTS: Valeriana species modulate neurotransmission, mitigate oxidative stress, and influence hepatic and gastrointestinal functions. Preclinical studies support their sedative and neuroprotective effects, while clinical outcomes vary with formulation, dosage, and individual response. Overall, safety profiles are favorable, though inconsistencies remain. CONCLUSION: Valeriana species represent a promising multi-target strategy for insomnia, integrating neural and peripheral pathways. Future research should clarify the mechanisms underlying multi-organ effects, optimize formulations, and conduct rigorous clinical trials to establish standardized, effective, and safe interventions.
19 Apr 2026
Read appraisal →Open heart
Non-invasive endotyping improves treatment satisfaction and prescribing appropriateness in patients with angina and no obstructive coronary artery disease.
BACKGROUND: Patients with angina and no obstructive coronary artery disease (ANOCA) frequently receive empirical antianginal therapy that fails to target underlying pathophysiological mechanisms. Whether stress perfusion cardiac magnetic resonance (CMR)-guided endotyping and stratified medical therapy improves treatment satisfaction and appropriate medication prescribing in this population is uncertain. METHODS: In the Coronary Microvascular Angina CMR Imaging Trial, 250 patients with suspected ANOCA, who had undergone invasive coronary angiography demonstrating no obstructive disease, were enrolled and underwent stress perfusion CMR with quantification of myocardial blood flow. Participants were randomised 1:1 to CMR-guided management (intervention) or angiography-guided management (control). Treatment satisfaction was assessed using the validated Treatment Satisfaction Questionnaire for Medication (TSQM-9) at baseline, 6 months and 12 months. Medication prescriptions were documented at these time points. RESULTS: Stress CMR imaging led to diagnostic reclassification in 53.0% of patients, with microvascular angina diagnosed in 51.0%. At 12 months, global treatment satisfaction was significantly higher in the intervention group compared with controls (adjusted difference, 19.30 units (95% CI 13.89 to 24.71); p<0.001), with consistent improvements across the effectiveness and convenience domains. CMR-guided management was associated with more appropriate prescribing, including higher use of preventive therapies (85.5% vs 67.5%; p=0.001), and more targeted antianginal prescribing, including calcium channel blockers (43.5% vs 27.0%; p=0.008) and long-acting nitrates (56.5% vs 32.5%; p<0.001). CONCLUSIONS: In patients with ANOCA, non-invasive CMR-guided endotyping substantially improves treatment satisfaction and enables more appropriate, mechanism-targeted pharmacotherapy compared with angiography-guided care. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID NCT04805814.
19 Apr 2026
Read appraisal →Breast cancer research and treatment
Oral selective estrogen receptor degraders in hormone receptor-positive, HER2-negative advanced breast cancer: a systematic review and meta-analysis
PURPOSE: The development of endocrine resistance is frequent in hormone receptor-positive, HER2-negative advanced breast cancer (HR + /HER2-ABC), particularly after CDK4/6 inhibitor exposure. Next-generation oral selective estrogen receptor degraders (SERDs) have been developed to improve estrogen receptor blockade; however, randomized trials have yielded heterogeneous results with uncertain clinical benefit. METHODS: A PRISMA 2020 compliant systematic review and meta-analysis with PROSPERO registration was conducted. PubMed, Embase, and Cochrane CENTRAL were searched through October 2025 for phase II-III randomized trials comparing oral SERDs with standard endocrine therapy (ET) in HR + /HER2-ABC after prior ET. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and treatment-related adverse events (TRAEs). Treatment effects were pooled using random effects models with prespecified subgroup analyses by ESR1 mutation status and key clinical characteristics. RESULTS: Six randomized trials, including 2808 patients, were analyzed. Oral SERDs improved PFS versus standard ET in the overall population (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.70 to 0.89). ORR was higher with oral SERDs (odds ratio [OR] 1.67; 95% CI 1.23 to 2.28), corresponding to absolute response rates of approximately 21% versus 14%. An OS improvement was observed (HR 0.72; 95% CI 0.57 to 0.90), although follow-up was limited. Benefit was concentrated in ESR1-mutated tumors (PFS, HR 0.57; 95% CI 0.48 to 0.67) with no significant PFS advantage in ESR1 wild-type disease. Gastrointestinal adverse events were more frequent with oral SERDs compared with the control ET. CONCLUSIONS: Pooled randomized evidence supports a clinically meaningful benefit of oral SERDs over standard ET after endocrine progression in HR + /HER2-ABC, with the strongest and most consistent efficacy observed in ESR1-mutated disease.
18 Apr 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Recurrent Resistance Mutations to Lirafugratinib Inform Treatment Sequencing in FGFR2-Driven Tumors
PURPOSE: The use of reversible fibroblast growth factor receptor 2 (FGFR) inhibitors leads to the emergence of "undruggable" FGFR2 kinase domain mutations, hampering sequential treatment strategies. Lirafugratinib and futibatinib are irreversible FGFR inhibitors with the most promising clinical activity against FGFR2-driven tumors. EXPERIMENTAL DESIGN: We characterized resistance to lirafugratinib with circulating tumor DNA, tissue whole-exome sequencing, and bulk RNA sequencing in 30 patients with FGFR2-driven cancers, treated in the phase I/II ReFocus trial (NCT04526106) and enrolled in the UNLOCK program at Gustave Roussy. RESULTS: Among the 30 patients included, 18 (60%) had intrahepatic cholangiocarcinoma and 12 (40%) had other tumor types. Twenty-two patients (73%) were FGFR inhibitor-naïve. Among those experiencing primary resistance to lirafugratinib, we identified potential resistance mechanisms in five of six pretreatment samples. Patients with acquired lirafugratinib resistance manifested an unprecedented emergence of FGFR2 mutations in the M538 and/or L618 residues of the kinase domain, documented in 11 of 16 cases (69%). Compared with futibatinib resistance, FGFR2 molecular brake (N550) and gatekeeper (V565) mutations were rare. Leveraging the spectrum of FGFR2 kinase domain mutations at resistance to lirafugratinib and futibatinib, respectively, we identified the complementarity of the two irreversible inhibitors. On the basis of viability assays in FGFR2::BICC1-dependent Ba/F3 models and in vivo studies on patient-derived xenografts, we propose treatment sequences with the two agents. After lirafugratinib progression, three patients received futibatinib and experienced prolonged disease response. CONCLUSIONS: The complementary activity of lirafugratinib and futibatinib against FGFR2 kinase domain mutations supports their sequential use when precise resistance mutations are detected in patients.
17 Apr 2026
Read appraisal →The American journal of cardiology
Mavacamten and Aficamten in Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis of Randomized Trials
Myosin inhibitors represent a novel therapeutic class for hypertrophic cardiomyopathy (HCM). While both mavacamten and aficamten have been evaluated in randomized trials, comparative evidence across the 2 agents remains limited. We performed a systematic review and meta-analysis of 8 randomized controlled trials of myosin inhibitors in HCM. Outcomes included improvement in the New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), postexercise and resting left ventricular outflow tract (LVOT) gradients, mean rest LVOT peak gradient, mean Valsalva LVOT peak gradient, change in left ventricular ejection fraction (LVEF), peak oxygen uptake, N-terminal pro-B-type natriuretic peptide (NT-proBNP), treatment-emergent adverse events, and serious adverse events. Pooled effects were estimated twice using random-effects models, once stratified by drug and once pooled altogether. Results showed that myosin inhibitors improved clinical and hemodynamic outcomes versus placebo. Both mavacamten and aficamten yielded improvements in New York Heart Association functional class and KCCQ-CSS, while reducing LVOT gradients and proBNP levels. Effect magnitudes were generally larger with mavacamten; aficamten demonstrated concordant but smaller effects and was the only agent to increase peak oxygen uptake. Safety was favorable for both agents, with pooled estimates indicating a marginally more favorable safety profile for aficamten. In conclusion, myosin inhibitors improve functional status, quality of life, and hemodynamics in HCM with an acceptable safety profile. Mavacamten generally demonstrates more robust benefits, while aficamten appears to have a more favorable safety profile. Additional trials directly comparing these agents are warranted to better clarify relative efficacy and safety.
17 Apr 2026
Read appraisal →Signal transduction and targeted therapy
HDAC inhibitor tucidinostat and metronomic capecitabine plus endocrine therapy for patients with HR-positive HER2-negative advanced breast cancer after CDK4/6 inhibitors treatment: clinical findings and exploratory circulating tumor cell and ctDNA biomarker analyses of a multicenter, phase 2 study (SYSUCC-020 trial)
Treatment options for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that progresses after CDK4/6 inhibitor (CDK4/6i) continue to evolve, and no single regimen has been established as the preferred standard of care. We conducted a phase 2 trial (SYSUCC-020, NCT05411380) to investigate the efficacy and safety of a novel combination of tucidinostat and metronomic capecitabine (mCAP) with endocrine therapy (ET) in patients following progression on CDK4/6i. This trial adopted a Simon two-stage design: eligible patients received tucidinostat plus metronomic capecitabine together with either an aromatase inhibitor (Cohort 1) or fulvestrant (Cohort 2), selected according to prior ET. Seventy-two female patients were screened and sixty-six patients were included in the efficacy and safety analyses. The median follow-up was 13.88 months (Interquartile range, 8.67-20.67) and the objective response rate was 25.8%, with 17 partial responses. The median progression-free survival (PFS) was 5.39 months (95% CI, 4.07-7.69), namely 6.93 months (95% CI, 4.76-12.22) in Cohort 1 and 3.98 months (95% CI, 2.79-7.59) in Cohort 2. Most patients (93.9%) experienced at least one adverse event. In addition, exploratory analyses of biomarkers indicated that the baseline TP53 mutation status (Wild type vs. mutated, 7.64 months vs. 3.55 months) and circulating tumor cell (CTC) status (CTC-negative vs. CTC-positive, 7.59 months vs. 3.78 months) were associated with the median PFS. Our study demonstrated that tucidinostat combined with mCAP and ET is efficacious and well-tolerated in patients with HR-positive HER2-negative ABC previously treated with CDK4/6i.
17 Apr 2026
Read appraisal →The Cochrane database of systematic reviews
Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease
RATIONALE: Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline. OBJECTIVES: To assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. We included both parallel-group and cluster designs. OUTCOMES: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid-related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any-cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment. RISK OF BIAS: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance. SYNTHESIS METHODS: We meta-analysed results for each outcome within each comparison using the inverse variance method and the random-effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high. INCLUDED STUDIES: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months. The 17 studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months. All studies were funded by the pharmaceutical industry. SYNTHESIS OF RESULTS: Below, we report the results of the studies at 18 months. Cognitive function Compared to placebo, amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) scale (standardised mean difference (SMD) -0.11, 95% confidence interval (CI) -0.16 to -0.06; 13 studies, 9895 participants; moderate certainty). Dementia severity Amyloid-beta-targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR-SB (Clincal Dementia Rating Sum of Boxes) scale (SMD -0.12, 95% CI -0.24 to -0.00; 9 studies, 8053 participants; low certainty). Functional ability Amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS-ADL-MCI (Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty). Adverse events Amyloid-beta-targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty). Three studies assessing any ARIA H showed heterogeneous results (I2 = 81%), which prevented pooled analysis. At 18 months, amyloid-beta-targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty). We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects). AUTHORS' CONCLUSIONS: The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action. FUNDING: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia-Romagna, Bologna, Italy. The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health. REGISTRATION: Protocol (2025): PROSPERO registration number CRD420251114325.
17 Apr 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Camonsertib, an ATRi, in Combination with Low-Dose Gemcitabine in Solid Tumors with DNA Damage Response Aberrations: Preclinical and Phase Ib Results.
PURPOSE: The utility of combination treatment with gemcitabine and camonsertib, an ataxia telangiectasia and Rad3-related kinase inhibitor, in mediating tumor cell death was assessed in preclinical models, prompting clinical investigation. The phase Ib TRESR study (NCT04497116) aimed to evaluate the safety, tolerability, and preliminary efficacy of the combination in patients with advanced solid tumors harboring DNA damage repair (DDR) gene alterations. PATIENTS AND METHODS: Cell lines and tumor xenografts were tested across a range of dose levels and schedules. Patients (N = 76) harboring tumors with DDR gene alterations received camonsertib (80-120 mg) and de-escalating gemcitabine (1,000-100 mg/m2) in 21- or 28-day cycles on an intermittent dosing regimen. Safety, tolerability, and preliminary efficacy were assessed to identify an optimal dosing regimen. RESULTS: In preclinical models, low-dose camonsertib (1/3 maximum tolerated dose) and gemcitabine led to tumor regression and was well tolerated with minimal body weight loss observed. In patients, synergistic toxicities were observed, primarily myelosuppression, resulting in gemcitabine de-escalation. The introduction of a 1 week on/1 week off schedule in combination with low-dose gemcitabine allowed for spontaneous neutrophil recovery, fewer dose modifications, and improved tolerability. Tumor responses were primarily observed in patients with gynecologic cancers, with tumor control maintained for greater than 1 year in some patients. CONCLUSIONS: Camonsertib and low-dose gemcitabine demonstrated preliminary clinical activity, but due to challenging tolerability, further evaluation is warranted to identify the optimal dosing regimen and subset of patients who may benefit most from this combination.
17 Apr 2026
Read appraisal →PloS one
Assessing the real-world safety of vutrisiran for transthyretin-mediated amyloidosis with polyneuropathy: Based on WHO-VigiAccess and FAERS databases
BACKGROUND: Vutrisiran is a double-stranded siRNA targeting transthyretin mRNA, primarily for the treatment of transthyretin-mediated amyloidosis (ATTR) with polyneuropathy. Understanding its safety in real-world settings is crucial for achieving optimal treatment outcomes for patients. METHODS: This study assessed the safety of vutrisiran for clinical use by analyzing all adverse drug reaction (ADR) reports in WHO-VigiAccess and U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) databases with vutrisiran as the primary suspected drug and by using four disproportionality analysis and Bayesian information component. Weibull distribution was also utilized to predict the time of occurrence of ADR. RESULTS: During the research process, WHO-VigiAccess reported 721 adverse reaction reports related to vutrisiran, while FAERS documented 732 ADR reports. The analysis revealed that: this study not only demonstrated known adverse reactions such as injection site reactions, such as redness, pain, or swelling at the injection site; systemic reactions like fatigue and myalgia; pain in extremity; and potential risks associated with reduced vitamin A levels, but also detected potential safety signals related to drug such as night blindness and cardiac pacemaker insertion. Furthermore, it was observed that in both the WHO-VigiAccess and FAERS databases, the highest reporting rates of ADR were found in the category of general disorders and administration site conditions. It also confirms the importance of monitoring the occurrence of adverse reactions within one year after drug treatment. CONCLUSION: The study identified several known ADRs and detected potential positive signals that may be associated with the drug. These research results provide clinicians with more information to consider and monitor adverse reactions in patients with ATTR-related polyneuropathy after treatment with vutrisiran, offering more evidence for its safety in real-world settings.
16 Apr 2026
Read appraisal →Cancer immunology, immunotherapy : CII
Hematological toxicities and thrombosis risk associated with immune checkpoint inhibitors: a pharmacovigilance study from 2014 to 2024
BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in a wide range of cancers but may also induce hematological toxicities and thrombosis risk. This study comprehensively evaluated hematological and thrombotic adverse events (AEs) associated with ICIs in real-world settings using the FDA Adverse Event Reporting System (FAERS) database, aiming to characterize their clinical features. METHODS: Data were extracted from the FAERS database (Q1 2014 to Q4 2024) for disproportionality analysis. AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). Associations between ICIs and hematological/thrombotic AEs were assessed via the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) methods. Clinical characteristics of affected patients were analyzed, and time-to-onset across ICI regimens was further evaluated. RESULTS: We identified 14,753 ICI-associated hematological toxicities and thrombotic events. Among reports with available sex information, a higher reporting frequency was observed in men (50.90%) than in women (40.11%). The most frequent AEs were anemia (2963 cases, 16.62%), thrombocytopenia (1961, 11.00%), febrile neutropenia (1935, 10.85%), neutropenia (1392, 7.81%), myelosuppression (979, 5.49%), pancytopenia (739, 4.14%), lymphadenopathy (475, 2.66%), disseminated intravascular coagulation (DIC; 468, 2.62%), leukopenia (468, 2.62%), and deep vein thrombosis (DVT; 213, 1.19%). The median time-to-onset for ICI monotherapy-associated AEs was 28 days (IQR 11-79), with 78.22% occurring within 3 months. Notably, DIC and DVT had the highest mortality proportion among the top 10 AEs. CONCLUSION: Hematological and thrombotic AEs associated with ICI therapy show notable reporting frequencies in FAERS. Combination regimens demonstrated stronger reporting signals for certain events. These AEs frequently showed early reporting and notable mortality proportions, highlighting the importance of clinical vigilance. Further studies are needed to confirm these findings.
16 Apr 2026
Read appraisal →Clinical cancer research : an official journal of the American Association for Cancer Research
Becotatug Vedotin in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Multicenter, Phase IIa Trial
PURPOSE: This multicenter, phase IIa trial (NCT04868162) investigated the efficacy and safety of becotatug vedotin, an anti-epidermal growth factor receptor (EGFR) antibody-drug conjugate, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who have limited therapeutic options. PATIENTS AND METHODS: Patients with R/M SCCHN who progressed after platinum-based chemotherapy and/or programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, including those with multiple lines of prior therapy, were administered intravenous becotatug vedotin at either 2 or 2.3 mg/kg every 3 weeks. The primary endpoint was the objective response rate (ORR). RESULTS: Sixty-seven patients were enrolled (35 received 2 mg/kg and 32 received 2.3 mg/kg). The ORR was 20.9% [14/67, 95% confidence interval (CI), 11.9-32.6], with a median duration of response (DoR) of 10.9 months (95% CI, 2.6-15.1). The median progression-free survival (PFS) was 2.9 months (95% CI, 1.8-3.9), and the median overall survival (OS) was 6.7 months (95% CI, 5-8.9). Treatment-related adverse events (TRAE) were reported in 91% (61/67) patients, most commonly being rash (26.9%), pruritus (25.4%), constipation (23.9%), and anemia (20.9%). CONCLUSIONS: Becotatug vedotin demonstrated promising antitumor activity with a manageable safety profile in previously heavily treated R/M SCCHN, particularly at the recommended dose of 2.3 mg/kg, among patients who had failed platinum-based chemotherapy and PD-1/PD-L1 inhibitors (≤2 prior lines of therapy).
16 Apr 2026
Read appraisal →Cancer cell
HS-20093, a B7-H3-targeted antibody-drug conjugate in lung cancer: Results from the ARTEMIS-001 phase 1a/b trial
This phase 1a/b study (NCT05276609) evaluated the safety, pharmacokinetics, and efficacy of B7-H3-targeted antibody-drug conjugate HS-20093 (GSK5764227) in 306 patients with previously treated advanced solid tumors. In phase 1a, 12.0 mg/kg was established as the maximum tolerated dose. Among 236 lung cancer patients who received 8.0 or 10.0 mg/kg HS-20093, the most frequent grade ≥3 treatment-related adverse events (AEs) included decreased neutrophil (25.5% vs. 50.5%) and white blood cell counts (19.7% vs. 42.4%), and anemia (16.8% vs. 34.3%), respectively. Treatment-related interstitial lung disease and AEs leading to death occurred in 3.4% and 3.8% of patients, respectively. Among response-evaluable patients, the confirmed objective response rate was 52.3% (95% CI: 39.5, 64.9) for extensive-stage SCLC (ES-SCLC, N = 65) and 22.4% (95% CI: 16.0, 29.8) for non-small cell lung cancer (NSCLC, N = 152) patients, with comparable rates between 8.0 mg/kg and 10.0 mg/kg dose cohorts across both groups. These results support further development of HS-20093, with 8.0 mg/kg selected for phase 3 trials.
16 Apr 2026
Read appraisal →Signal transduction and targeted therapy
STRATEGIC-1: multiple-line, randomized, open-label GERCOR-PRODIGE-39 phase III trial in unresectable RAS/BRAF wild-type metastatic colorectal cancer
Managing unresectable metastatic colorectal cancer (mCRC) requires a comprehensive strategy. While chemotherapy, anti-angiogenic, and anti-epidermal growth factor receptor (EGFR) agents are available, strategy trials are needed to optimize their use and sequencing. The STRATEGIC-1 phase III trial (NCT01910610) was designed to determine the optimal treatment sequence in patients with untreated, unresectable wild-type RAS/BRAFV600E mCRC. Patients were randomized (1:1) to FOLFIRI-cetuximab then mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab then FOLFIRI-bevacizumab followed by EGFR monoclonal antibody +/- irinotecan (arm B). The primary endpoint was the duration of disease control (DDC). Secondary endpoints were overall survival (OS), time to failure of strategy (TFS), progression-free survival (PFS), overall response rate (ORR), salvage surgery rate, safety, and health-related quality of life (HRQoL). Overall, 263 patients (arm A:131, arm B:132) were randomized. After 68.4 months of median follow-up (95% CI, 76.5-98.0), the median DDC was 22.8 months (95% CI, 20.4-28.8) in arm A and 23.5 months (95% CI, 17.9-26.3) in arm B (HR = 1.01, 95% CI, 0.76-1.34; log-rank P = 0.945). The median OS was 40.4 months (95% CI, 32.4-51.1) in arm A and 34.4 months (95% CI, 27.5-42.2) in arm B (HR = 1.30, 95% CI, 0.99-1.72). The ORR was higher in arm A (82.4% versus 65.4%) in the first-line group but not in the second-line group (20.7% versus 16.4%). Adverse events were consistent with the well-known safety profiles. STRATEGIC-1 did not meet its primary endpoint and was inconclusive in identifying the optimal treatment strategy in wild-type RAS/BRAFV600E mCRC.
16 Apr 2026
Read appraisal →Cancer
A phase 1 study of ASTX727 plus talazoparib in patients with triple-negative or hormone resistant/HER2-negative metastatic breast cancer
BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) is recruited to DNA damage sites along with epigenetic factors such as DNA methyltransferase 1 (DNMT1). Inhibitors of DNMT modulate reactive oxygen species (ROS)-cyclic adenosine monophosphate (cAMP)/Protein Kinase A signaling and induce a "BRCAness phenotype" that further sensitizes cells to PARPi. In preclinical studies, combined DNMTi + PARPi therapy was effective in both triple-negative (TNBC) and hormone resistant (HRBC) models with intact BRCA. METHODS: The authors conducted a phase 1 study combining the oral DNMTi ASTX727 with the PARPi talazoparib in patients with previously treated TNBC or HRBC. Patients with deleterious mutations of BRCA were excluded. A classical 3+3 design guided dose escalation/de-escalation, and 28 days constituted each cycle. Serial peripheral blood mononuclear cells (PBMCs) were analyzed for changes in methylation using the Infinium Methylation EPIC BeadChip and LINE1 sequencing. RESULTS: Thirty-four evaluable patients were enrolled and treated in eight dose cohorts. Myelosuppression was common with grade >3 neutropenia in 42% and grade 3 anemia and thrombocytopenia in 13%. Dose-limiting toxicity was limited to neutropenia. Efficacy was assessed in 29 patients. There were no objective responses, six patients had stable disease persisting for >4 months in three patients. LINE1 demethylation ranged from ∼2%-10% and immune-specific CpGs (methylation in immune cells) changed 1%-5% at day 15. Methylation changes were not dose-dependent. CONCLUSIONS: ASTX727 plus talazoparib produces significant myelosuppression without other adverse events. Modest methylation changes in PBMCs were detected. There were no objective responses, but some heavily pretreated patients had stable disease for >4 months despite the attenuated doses.
15 Apr 2026
Read appraisal →International immunopharmacology
Multicentre development and validation of a risk model integrating immunotherapy and coagulation biomarkers for thrombosis in autoimmune neurological disorders
PURPOSE: Patients with Autoimmune Neurological Disorders (ANDs) require routine immunomodulatory therapy, which inherently increases thrombosis risk. Despite this recognised association, reliable tools for thrombosis prediction remain limited, highlighting the need for accurate risk stratification to inform targeted prevention strategies. PATIENTS AND METHODS: This multicentre retrospective study developed a machine learning-based thrombosis risk prediction model using data from 786 patients with ANDs receiving immunomodulatory therapy. The model was trained on data from three centres and externally validated on an independent fourth centre, evaluating six algorithms based on the area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), and Brier score. Feature selection and Shapley Additive Explanations (SHAP) analysis were applied to ensure model interpretability. RESULTS: Among all algorithms tested, XGBoost (XGB) demonstrated the best performance. On the external validation set, the XGB model achieved an AUROC of 0.949, AUPRC of 0.544, and Brier score of 0.045, significantly outperforming the traditional Padua score. SHAP analysis identified the top three thrombotic risk factors: elevated D-dimer levels, prolonged immobilisation, and advanced age. The total doses of intravenous immunoglobulin and glucocorticoid were also confirmed as significant contributors. The model further enabled stratification into low-, intermediate-, and high-risk groups, offering a practical tool for individualised thromboprophylaxis. CONCLUSION: This study presents a high-performing, interpretable model for early thrombosis risk prediction in patients with ANDs, which facilitates timely clinical decision-making and targeted preventive strategies to reduce thromboembolic complications.
15 Apr 2026
Read appraisal →Journal of molecular modeling
HopWD-DTA: a novel framework for drug-target affinity prediction fusing multi-hop neighborhoods and deep features
CONTEXT: Accurate prediction of drug-target affinity (DTA) is crucial for accelerating drug discovery, but it remains a significant challenge. While deep learning methods have shown promise, many existing models struggle with representing long-range protein relationships within protein-protein interaction (PPI) networks, often suffering from performance degradation as graph neural network layers deepen. To overcome this limitation, we developed HopWD-DTA, a novel framework designed to effectively capture both local and global protein features. The core innovation lies in integrating multi-hop neighborhood information from PPI networks with deep structural features of proteins and drugs. Comprehensive evaluations on the Davis, KIBA, and Human benchmark datasets demonstrate that HopWD-DTA achieves state-of-the-art performance, significantly improving DTA prediction accuracy over existing cutting-edge solutions. METHODS: The HopWD-DTA framework consists of separate branches for protein and drug feature extraction. For proteins, structural features from residue contact maps are first encoded using a Graph Convolutional Network (GCN). These features, along with InterPro annotations, are then embedded into a PPI network. We introduce a multi-hop neighborhood serialization technique, which generates a sequence of feature matrices representing different neighborhood scopes. This sequence is processed by a Variational Autoencoder (VAE) to learn a robust protein representation. For drugs, molecules are represented as graphs from SMILES strings and encoded via a GCN, followed by a novel Wide-and-Deep Path (WDPATH) module to capture both macroscopic and microscopic features. The final protein and drug features are concatenated and fed into a multilayer perceptron for affinity prediction. The model was implemented using PyTorch and RDKit.
15 Apr 2026
Read appraisal →Blood advances
Targeting Aurora kinase A to prevent GVHD and relapse after myeloablative allogeneic hematopoietic cell transplantation
The success of posttransplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has driven efforts to optimize partner therapies that balance GVHD and relapse prevention. We report phase 1 dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, after myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). Results from murine and in vitro studies informed the development of the novel drug combination. In the phase 1 trial, patients aged 18 to 60 years received myeloablative conditioning, followed by PTCy (50 mg/kg; days +3/+4), SIR (from day +5; target 8-12 ng/mL), and VIC-1911 (25, 50, or 75 mg twice daily; days +5 to +45). The primary end point was achieving <54% phosphorylated histone H3 serine 10 expression in CD4+ T cells by day +21. Preclinical models show that combining SIR with AURKA inhibition suppresses signaling downstream of CD28, enhancing GVHD prevention while leveraging the antileukemia activity of AURKA inhibition. In the phase 1 trial, the optimal VIC-1911 dose achieving target pathway inhibition without dose-limiting toxicities was 75 mg twice daily. Clinical outcomes included no grade 3 to 4 acute GVHD through day 180 (0%) and low rates of moderate/severe chronic GVHD (6%) and relapse (0%) through 1 year (5/16 received maintenance). The 1-year overall survival for this cohort was 94%. VIC-1911 at 75 mg twice daily, combined with PTCy and SIR, effectively suppressed AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes. The trial was registered at www.clinicaltrials.gov as NCT05120570.
15 Apr 2026
Read appraisal →Toxicology mechanisms and methods
Introducing AutoML framework for drug-drug interaction prediction: application of AutoGluon.
Drug-drug interactions (DDIs) remain a major concern in medication safety. Although advanced artificial intelligence methods such as deep learning have improved DDI prediction, their adoption is limited by the need for specialized expertise and complex model development. This study introduces the first application of the AutoGluon AutoML framework to DDI prediction using molecular features, aiming to automate and simplify model development. A curated subset of 100,000 drug pairs from DrugBank was used, employing three molecular representations: 2D molecular descriptors, 2048-bit Morgan fingerprints, and their combination. Models were trained using AutoGluon-Tabular with no manual hyperparameter tuning. The descriptor-only model achieved the best performance, with 84.4% test accuracy and an AUC of 0.916, outperforming fingerprint-based and hybrid models. Feature importance analysis identified key physicochemical and topological descriptors-such as drug-likeness, electrotopological indices, and hydrophobic surface area-as critical predictors of DDIs. These results demonstrate that AutoML can extract chemically meaningful patterns while reducing technical barriers. Overall, our results validate AutoGluon as a scalable approach to DDI prediction that provides chemically meaningful, feature-level interpretability, and lay the groundwork for future applications involving larger datasets and more complex chemical representations.
15 Apr 2026
Read appraisal →ChemMedChem
Structure- and Ligand-Based Discovery of Novel 3-Chymotrypsin-Like Protease Nonpeptidomimetic Hits
The SARS-CoV-2 3-chymotrypsin-like (3CLpro) protease is a key target for the development of COVID-19 therapeutics. While ensitrelvir and nirmatrelvir are approved drugs for treatment, the continuous research and development for new antiviral drugs is necessary to combat the emergence of variants and other related viruses. This study employed structure- and ligand-based computer-assisted approaches to identify new 3CLpro nonpeptidomimetic inhibitors. Using data from COVID Moonshot, NCATS, and the literature, computational methods such as shape-based, ensemble docking, and machine learning (ML) techniques were developed, achieving robust validation metrics: AUC = 87%, EF = 7, BEDROC = 60% for shape-based; AUC = 87%, EF = 7.03, BEDROC = 62% for ensemble docking, and ACC = 81%, MCC = 62% for ML models, combing Random forest + ECFP4 fingerprint. These models were utilized in virtual screening (VS) campaigns using the H3D and ChemBridge libraries, from which six promising hits with IC50 values ≤80 µM were identified, including LabMol-499 with an IC50 of 13.71 µM and a Ki of 21.74 µM. Moreover, we found that LabMol-499 acts as a noncompetitive, reversible inhibitor of 3CLpro. These findings provide a foundation for hit-to-lead optimization of new nonpeptidomimetic 3CLpro inhibitors.
15 Apr 2026
Read appraisal →Blood advances
RNA interference therapy targeting coagulation factor XI: a first-in-human trial of RBD4059 (vortosiran)
Inhibiting coagulation factor XI (FXI) activity has emerged as a promising strategy to prevent intravascular thrombosis. Here, we describe the first-in-human trial with an N-acetylgalactosamine-conjugated small interfering RNA (siRNA), RBD4059, targeting FXI. In this phase 1 single ascending dose study (NCT05653037), healthy volunteers were randomized to receive either active drug or placebo (6 + 2), administered subcutaneously, in 4 consecutive dose cohorts ranging from 50 mg to 600 mg. The primary end point was safety and tolerability up to day 169 after dose. Secondary end points included pharmacokinetic and pharmacodynamic (PD) parameters. Single ascending doses of RBD4059 were well tolerated, and no apparent safety concerns were identified. RBD4059 was associated with a dose-dependent and durable suppression of FXI activity up to >90%. Modeling of the available PD data supports clinical dosing schemes of 3 to 6 months to achieve a robust antithrombotic effect. Altogether, these observations support further clinical development of RBD4059 to provide an siRNA-based therapeutic option targeting FXI for patients inadequately treated with or contraindicated for current available thrombosis prophylaxis. This trial was registered at www.clinicaltrials.gov as #NCT05653037.
15 Apr 2026
Read appraisal →Food & function
Metabolic and inflammatory effects of oleuropein and olive leaf extract: a systematic review and meta-analysis
Background: Olive leaves, a by-product of olive oil production, are rich in oleuropein, a phenolic compound with antioxidant and anti-inflammatory properties. This systematic review and meta-analysis evaluated the effects of olive leaf extract (OLE) and oleuropein on glucose metabolism, lipid profile, and inflammatory markers in randomized clinical trials (RCTs). Methods: The review was registered in PROSPERO (CRD42022375615) and followed PRISMA guidelines. PubMed, Scopus, and Web of Science were searched up to January 2026 without restrictions. Eligible studies were RCTs in adults comparing OLE or oleuropein with placebo or control. Study selection, data extraction, and risk of bias (RoB 2) assessment were performed independently by two reviewers; certainty of evidence was assessed with GRADE. Meta-analyses were conducted when at least two trials reported suitable data. Results: Eleven RCTs were included (4 short-term and 7 continuous-intake trials). Short-term crossover studies showed heterogeneous effects on postprandial glycemia and insulin responses, precluding meta-analysis. In continuous-intake, parallel-design RCTs, pooled analyses demonstrated no statistically or clinically significant effects on glycemic or lipid outcomes. Evidence regarding inflammatory markers was scarce and of low certainty. Conclusion: The current evidence does not support clinical recommendations for OLE supplementation aimed at health benefits. Data from methodologically consistent and robust trials indicate no statistically significant metabolic or inflammatory effects under usual human consumption patterns, whereas evidence from other study designs remains inconclusive. Further high-quality RCTs are required to clarify potential metabolic benefits.
15 Apr 2026
Read appraisal →Blood advances
Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi in R/R marginal zone lymphoma: phase 1/2 BRUIN study.
Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies with a remitting and relapsing course. For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy or in combination with chemotherapy (chemoimmunotherapy), with second-line options including covalent Bruton tyrosine kinase inhibitors (cBTKi). However, management of relapsed and refractory (R/R) MZL remains challenging. Pirtobrutinib, a highly selective, noncovalent BTKi has shown promising efficacy and tolerability in poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here, we report the safety and efficacy of pirtobrutinib in MZL from the phase 1/2 BRUIN study. Endpoints included investigator-assessed objective response rate (ORR) by Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 36 patients with R/R MZL (extranodal [n = 6]; nodal [n = 17]; splenic [n = 13]), median age was 68 years (range, 22-83) and median prior lines of therapy were 3 (range, 2-10). The ORR was 55.6% (95% confidence interval [CI], 38.1- 72.1), including 3 (8.3%) complete responses and 17 (47.2%) partial responses. Median DOR was 17.8 months (95% CI, 7.4 to nonestimable [NE]), and median PFS was 16.6 months (95% CI, 9.0-22.1). With median follow-up of 32.4 months (IQR, 28.0-41.3), median OS was NE (95% CI, 29.5-NE). The ORR for patients with prior cBTKi therapy was 53.8% (95% CI, 33.4-73.4). Pirtobrutinib was well tolerated with dose reductions in 4 patients (11.1%) and permanent discontinuation due to treatment emergent adverse events in 4 patients (11.1%). Pirtobrutinib showed promising efficacy and safety in patients with heavily pretreated R/R MZL, including prior cBTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.
15 Apr 2026
Read appraisal →Hepatology communications
Seladelpar in patients with primary biliary cholangitis and compensated cirrhosis: Efficacy and safety from RESPONSE and ASSURE studies
BACKGROUND: Treatment options are limited for patients with primary biliary cholangitis (PBC) and cirrhosis. Seladelpar, a first-in-class delpar (selective PPAR-δ agonist), had generally similar efficacy and safety among patients with versus without compensated cirrhosis in the phase 3 RESPONSE study. Here we provide additional data on seladelpar in patients with compensated cirrhosis from the phase 3 program. METHODS: In RESPONSE, patients with PBC and an inadequate response or intolerance to UDCA were randomized 2:1 to seladelpar 10 mg or placebo for 1 year. Upon completion, patients rolled over into the open-label (seladelpar 10 mg) phase 3 ASSURE study, which also enrolled patients from earlier seladelpar legacy PBC studies. Here, we assessed the composite endpoint [alkaline phosphatase (ALP) <1.67×upper limit of normal (ULN), ALP decrease ≥15%, and total bilirubin ≤ULN], other laboratory changes, and safety in all patients with cirrhosis from RESPONSE and an interim analysis of the ongoing ASSURE study through January 2024. RESULTS: Twenty-seven patients with compensated cirrhosis enrolled in RESPONSE (18 seladelpar, 9 placebo). At month 12, 38.9% and 22.2% of patients in the seladelpar and placebo groups, respectively, met the composite endpoint; mean percent change from baseline in ALP was -37.1% and -10.1%, respectively. Upon rollover to ASSURE (13 seladelpar, 6 placebo), ALP declines were maintained for up to 18 months. An additional 35 patients with compensated cirrhosis in ASSURE from legacy studies had similar reductions in ALP with up to 2 years of treatment. Bilirubin remained overall stable. No treatment-related serious adverse events occurred. Variceal bleeding and/or ascites developed in 3 patients after ≥9 months. CONCLUSIONS: Seladelpar decreased markers of cholestasis and was overall safe and well-tolerated in patients with PBC and compensated cirrhosis.
15 Apr 2026
Read appraisal →Journal of chemical information and modeling
AI-MedCraft: A Strategy-Driven AI Platform for Multi-Objective Molecular Design
Small-molecule drug discovery requires balancing potency, selectivity, solubility, safety, and synthetic feasibility, among other interdependent properties. Yet most computational workflows address these properties sequentially or collapse them into fixed weighted scores. Although artificial intelligence has accelerated molecular design, many platforms struggle to handle explicit multiobjective trade-offs. Here, we present AI-MedCraft, a strategy-driven molecular design framework that applies adaptive, Pareto-guided reinforcement learning to optimize multiple objectives concurrently within a unified workflow. When structural information is available, physics-aware scoring is incorporated to support binding-competent designs. In a structure-based benchmark on the solubility rescue of the BTK inhibitor GDC-0834, AI-MedCraft achieves broader Pareto-front coverage than the scalar-reward reinforcement learning framework REINVENT 4 under matched objectives and computational cost. In a second case study, AI-MedCraft redesigns Efavirenz to retain HIV-1 reverse transcriptase engagement while reducing predicted 5-HT2A off-target binding, demonstrating its use in multiconstraint molecular optimization.
14 Apr 2026
Read appraisal →Journal of chemical information and modeling
Compressing Chemistry Reveals Functional Groups
We introduce the first formal large-scale assessment of the utility of traditional chemical functional groups as used in chemical explanations. Our assessment employs a fundamental principle from computational learning theory: a good compression of data should reveal a good explanation. We introduce an unsupervised learning algorithm based on the Minimum Message Length (MML) principle that searches for substructures that compress around three million biologically relevant molecules. We demonstrate that the discovered substructures contain most human-curated functional groups as well as novel larger patterns with more specific functions. We also run our algorithm on 24 specific bioactivity prediction data sets to discover data set-specific functional groups. Fingerprints constructed from data set-specific functional groups are shown to significantly outperform other fingerprint representations, including the MACCS and Morgan fingerprint, when training ridge regression models on bioactivity regression tasks.
14 Apr 2026
Read appraisal →Journal of chemical information and modeling
ToxPLTC: Peptide Toxicity Prediction by Integrating Pretrained T5 Protein Language Model and Text Convolutional Neural Network
Peptide-based therapeutics show promising potential in treating a range of diseases, such as diabetes, cancer, and chronic pain. However, critical challenges, including peptide toxicity, immunogenicity, and stability deficiencies of peptides, have become major obstacles to their direct clinical application. Traditional toxicity testing methods based on a wet lab are not only costly but also time-consuming. In contrast, the classification model based on deep learning provides a new technical path for the efficient identification of peptide toxicity. In this study, we propose a deep learning framework called ToxPLTC, which employs the ProtT5 protein language model based on the Transformer architecture for pretraining peptide sequences, adopts the borderline SMOTE algorithm to handle an imbalanced training set data, and utilizes a text convolutional neural network combined with a fully connected layer for classification. Additionally, visualization analysis, motif analysis, and mutation-scan analysis are performed to understand the function of each module and enhance the interpretability of our model. The applicability domain is constructed based on the K-NN strategy to define the effective prediction range of our model to ensure the reliability of model predictions. The ToxPLTC model achieves a balanced accuracy of 93.02% on independent test set 1 and 88.04% on independent test set 2. Experimental results demonstrate that our model outperforms existing models on independent test sets and has good generalization ability. The ToxPLTC model possesses great potential as a valuable and robust tool for peptide-based drug development. The source data sets and codes can be available at the following GitHub repository: https://github.com/yunyunliang88/ToxPLTC.
14 Apr 2026
Read appraisal →Journal of chemical information and modeling
EviCYP: In Silico Prediction of Cytochrome P450 Substrates Based on Vector Quantization and Evidential Deep Learning
The accurate identification of cytochrome P450 (CYP) substrates is crucial in drug discovery and safety assessment, as these enzymes mediate the metabolism of most clinical drugs. However, existing computational models are often limited by data quality issues and lack the ability to quantify prediction uncertainty, hindering their reliable application. To address these challenges, we present EviCYP, a novel prediction framework that integrates evidential deep learning with vector quantization (VQ). We first constructed a high-quality data set by curating 4388 substrates and 2880 nonsubstrates from 1629 publications, and supplemented it with 3728 pseudonegative samples, resulting in 10,996 samples spanning nine major CYP isoforms. The EviCYP architecture processes multimodal molecular representations and enzyme sequences through dedicated encoders, compresses features via VQ to reduce redundancy, and employs an evidential layer to output both class probabilities and an uncertainty estimate. On an internal test set, EviCYP achieved an average AUROC of 0.9500. Notably, the model's uncertainty quantification is highly reliable, with high-uncertainty predictions strongly correlating with classification errors. This work provides a robust and trustworthy computational tool for CYP substrate prediction.
14 Apr 2026
Read appraisal →Lancet (London, England)
Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention: 10-year follow-up of the HOST-EXAM trial
BACKGROUND: The long-term clinical outcomes of clopidogrel monotherapy versus aspirin monotherapy after percutaneous coronary intervention (PCI) remain uncertain. We conducted a 10-year follow-up of the HOST-EXAM trial to assess the very long-term effects of clopidogrel versus aspirin monotherapy in this setting. METHODS: In HOST-EXAM, patients who had completed dual antiplatelet therapy without clinical events for 6-18 months after PCI were randomly assigned to receive clopidogrel 75 mg once daily or aspirin 100 mg once daily. This study is an investigator-initiated 10-year extended follow-up of the HOST-EXAM trial. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium type ≥3 bleeding. The primary analysis was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov (NCT02044250) and is complete. FINDINGS: From March 26, 2014, to May 29, 2018, 5530 patients were enrolled and 5438 were randomly assigned to the aspirin group (n=2728) or the clopidogrel group (n=2710). Clinical follow-up status was ascertained on May 1, 2025, resulting in a median follow-up duration of 10·5 years (IQR 9·4-11·4) after PCI and a completion rate of 92·8%. Clopidogrel was associated with a lower rate of the primary composite endpoint than aspirin (Kaplan-Meier estimate 25·4% for the clopidogrel group vs 28·5% for the aspirin group; hazard ratio 0·86 [95% CI 0·77-0·96]; log-rank p=0·0050). Clopidogrel was also associated with a lower rate of the thrombotic endpoint (17·3% vs 20·0%; log-rank p=0·0024) and bleeding endpoint (9·1% vs 10·8%; log-rank p=0·020). All-cause mortality was similar between groups. INTERPRETATION: During 10 years of follow-up, clopidogrel monotherapy, compared with aspirin monotherapy, was associated with lower rates of the primary composite, ischaemic, and bleeding outcomes, but not all-cause mortality after PCI. These findings support consideration of clopidogrel as an alternative to aspirin for long-term antiplatelet monotherapy during the chronic maintenance phase after PCI. FUNDING: Ministry of Health & Welfare, South Korea.
14 Apr 2026
Read appraisal →Journal of chemical information and modeling
Multiscale-Aware Graph Embedding Approach Uncovers LC-61, a Potent Anti-Leishmania infantum Compound
Visceral leishmaniasis caused by Leishmania infantum remains a lethal disease with few therapeutic options, necessitating innovative computational methods and approaches to accelerate drug discovery. Here, we present a graph neural network (GNN) framework incorporating well-established multiscale mechanisms to improve the identification of novel antileishmanial compounds. Across two classificatory antileishmanial data sets, our GNNs demonstrated significant improvements in predictive performance, with area under the receiver operating characteristic curve (AUC) increases of 2.2-29.2% on the imbalanced data set (activity cutoff: 1 μM) and 3.4-22.5% on the balanced data set (activity cutoff: 10 μM) compared to default GNNs. Subsequently, the framework was applied to screen a library of approximately 1.3 million compounds, pinpointing LC-61 as a potent antileishmanial agent with nanomolar activity against intracellular L. infantum (IC50 = 0.076 μM) and minimal cytotoxicity to macrophages (THP-1 CC50 = 157 μM). A comprehensive in vitro ADME profiling revealed that LC-61 combines high solubility at both acidic and physiological pH (>28 μg/mL), balanced lipophilicity (eLogD = 4.07), and favorable passive permeability (PAMPA = 4.86 × 10-6 cm/s), while exhibiting lower microsomal stability. Overall, our GNN framework effectively accelerated the discovery of LC-61, a novel and biologically validated hit suitable for hit-to-lead optimization.
14 Apr 2026
Read appraisal →Signal transduction and targeted therapy
Deutenzalutamide, a novel androgen receptor inhibitor, after progression on docetaxel and abiraterone in metastatic castration-resistant prostate cancer: results from the randomized phase III HC-1119-04 trial
Metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel and androgen receptor signaling inhibitors (ARSIs) has limited treatment options. Although enzalutamide has shown activity after abiraterone and docetaxel, robust evidence from randomized phase III trials is lacking. Deutenzalutamide, a novel derivative with slower metabolism and improved pharmacokinetics, may offer enhanced safety and efficacy. This phase III, double-blind trial conducted at 36 centers in China enrolled patients whose disease progressed on or who were intolerant to abiraterone and docetaxel, or who were ineligible for docetaxel. Patients were randomized (2:1) to receive deutenzalutamide 80 mg once daily or placebo until progression or unacceptable toxicity; the primary endpoint was radiographic progression-free survival (rPFS). Of 417 patients (276 deutenzalutamide; 141 placebo), all had previously received abiraterone, and 68% had also received docetaxel. Deutenzalutamide significantly improved rPFS (HR, 0.58; P = 0.0001), reducing the risk of progression by 42%. Although the initial OS analysis was not significant (HR, 0.95), sensitivity analyses adjusting for subsequent therapies showed significant OS benefits (HR, 0.65-0.73). Treatment-related grade 3 or higher adverse events occurred in 22.3% of patients treated with deutenzalutamide, compared with 15.0% with placebo. The most common treatment-related adverse event was anemia, reported at any grade in 21.2% versus 17.9%, with grade 3/4 anemia in 6.6% versus 2.9%, respectively. Notably, no seizures or falls were reported. In summary, deutenzalutamide significantly prolonged rPFS and, after adjustment, showed a potential OS benefit with a favorable safety profile, supporting its promise as a new treatment option for mCRPC. Clinical trial registration: NCT03851640.
13 Apr 2026
Read appraisal →Cardiovascular toxicology
A Real-World Disproportionality Analysis of Drug-Induced Heart Failure: Integrating FAERS Database and AHA Statement
Heart failure (HF), the advanced stage of diverse cardiac conditions, poses a significant public health challenge. This study analyzes adverse event (AE) signals associated with HF within the FDA Adverse Event Reporting System (FAERS) database, offering critical insights to guide rational medication use in clinical settings. Adverse event reports (AERs) associated with HF in the FAERS database, spanning from the first quarter of 2004 to the fourth quarter of 2024, were analyzed. The potential HF risk of drugs was assessed using the disproportionality analysis, with findings juxtaposed against the American Heart Association (AHA) drug list. Drug-induced HF cases showed equivalent distribution between male and female, and high rates of rehospitalization and mortality. Prominent hypoglycemic drugs associated with HF included rosiglitazone, pioglitazone, and saxagliptin. Combination therapies, such as metformin/saxagliptin and metformin/rosiglitazone, also demonstrated elevated risks. In the context of pulmonary hypertension, drugs like macitentan, selexipag, and epoprostenol were particularly notable. Analysis against the AHA drug list confirmed stronger signal strength and frequency among Class A drugs, validating our results. Furthermore, drugs not flagged as positively signaling in the AHA registry, such as amiodarone, aliskiren, and testosterone, merit closer scrutiny due to their potential for adverse reactions. Our analysis of the FAERS database has identified medications associated with potential HF risks, providing valuable evidence to inform clinical decision-making and promote the safe use of medications.
13 Apr 2026
Read appraisal →European journal of clinical pharmacology
Clozapine prescribing in treatment-resistant schizophrenia - an updated systematic literature review of barriers and facilitators among clinicians
BACKGROUND: Increased rates of clozapine prescribing are essential to improving timely patient access within treatment-resistant schizophrenia (TRS) management. The extent of geographical variation in its use suggests it is possible to develop interventions to increase clinician engagement. To inform intervention development, a contemporary review of barriers and facilitators to increased clozapine prescribing is required. We aimed to conduct a systematic review of research addressing barriers and facilitators to clozapine prescribing among clinicians within TRS management. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, CINAHL, and PsycINFO were searched from inception to July 2025. Results were synthesized qualitatively. RESULTS: Fifteen studies were included. Barriers related to clinicians, patients and carers, and healthcare institutions. Primary clinician-related barriers included insufficient knowledge of, and confidence in, managing clozapine treatment and the associated administrative burden. Primary patient-related barriers included concerns regarding patients' willingness to consistently adhere to clozapine treatment and associated monitoring requirements. A lack of dedicated systems of care to facilitate clozapine initiation and shared community care were the leading institutional barriers. Major facilitators included improved education for clinicians, access to point-of-care testing, and increased availability of dedicated clozapine clinics. CONCLUSION: Most barriers to systematically increasing clozapine prescribing rates are beyond the influence of individual prescribers. Instead, structural interventions focusing on (i) reducing the administrative burden associated with establishing clozapine treatment, (ii) increasing access to standardised training and supervision opportunities, and (iii) providing longitudinal support to clinicians when managing clozapine treatment, are required.
13 Apr 2026
Read appraisal →International journal of pharmaceutics
From permeability to prediction: evolving strategies for evaluating oral drug absorption
Oral drug administration, preferred for patient compliance and convenience, encounters significant bioavailability challenges arising from complex physicochemical, physiological, and formulation-related barriers. Traditional models for evaluating absorption exhibit limitations in physiological relevance and predictive accuracy. This review critically examines evolving methodologies for oral drug absorption assessment, from classical permeability assays to emerging predictive platforms, emphasizing integration of mechanistic research with predictive modeling to advance intelligent platforms and clinical translation. While classical permeability models including parallel artificial membrane permeability assay (PAMPA), Caco-2, Ussing chambers, and intestinal perfusion remain indispensable for early screening, their limited physiological relevance and inability to elucidate mechanistic pathways constrain predictive accuracy. Mechanistic approaches such as lymphatic transport studies and advanced tracking techniques using fluorescence, Single Photon Emission Computed Tomography (SPECT), or Positron Emission Tomography (PET) imaging reveal critical biological pathways but suffer from scalability challenges. Emerging platforms provide transformative potential, as organoid-on-a-chip offer physiologically relevant and high-throughput alternatives, while integrated computational modeling enables multiscale prediction, from molecular interactions to systemic pharmacokinetics. Future oral absorption assessment requires converging in vitro biomimetics, computational modeling, and Artificial intelligence (AI) within unified platforms. Achieving this requires standardized in vitro models, robust data integration, and alignment with regulatory to accelerate translational drug development.
12 Apr 2026
Read appraisal →PDA journal of pharmaceutical science and technology
The European Qualified Person: Legal Accountability, Quality Leadership, and AI Integration in Modern Pharmaceutical Manufacturing: Navigating Complex Therapies and AI-Supported Oversight to Safeguard Patient Safety
The European Qualified Person (QP) holds unique legal responsibility for certifying batch release, ensuring patient safety, and maintaining regulatory compliance. Modern pharmaceutical manufacturing-especially in biologics, advanced therapy medicinal products (ATMPs), and personalized medicines-generates complex, multi-site, data-rich environments that challenge traditional oversight. Artificial Intelligence (AI) offers predictive analytics, anomaly detection, and trend recognition to support decision-making but cannot currently replace the QP's scientific judgment or legal accountability. The forthcoming Annex 22 introduces Human-in-the-Loop (HITL) frameworks that embed human oversight within AI-supported processes, aligning technological advancement with regulatory control. This review explores evolving QP responsibilities, core and emerging competencies, AI integration within Quality Risk Management (QRM) and Good Manufacturing Practice (GMP) frameworks, and ethical considerations, illustrated with practical case studies. By developing AI literacy and applying HITL oversight, QPs can more effectively translate technological potential into transparent, science-based, and patient-centered batch-release decisions.
12 Apr 2026
Read appraisal →Journal of medical Internet research
Large Language Model-Based Analysis of Statin Therapy Discussions and Sentiment on Social Media: Cross-Sectional Observational Study
BACKGROUND: Statin therapy, despite proven cardiovascular benefits, remains underused. Social media platforms may capture patient perspectives that are less visible in clinical encounters. OBJECTIVE: This study aimed to characterize themes, sentiment, and decision-making factors related to statin therapy through large language model (LLM)-based analysis of Reddit discussions. METHODS: This cross-sectional observational study analyzed English-language Reddit posts and comments mentioning statins from January 2022 to May 2025, identified via keyword-based Reddit application programming interface searches (≤1000 posts per keyword). A total of 5328 retrieved discussions (n=1661, 31.2% posts and n=3667, 68.8% keyword-containing comments) from public subreddits were included. Themes, sentiments (positive, neutral, or negative), guideline-informed clinical relevance, information-seeking behavior, adverse effect mentions, decision factors, and adherence-related content were extracted using an LLM-based pipeline. RESULTS: Among 5328 discussions, prominent topics included adverse effects (n=1697, 31.9%), decision-making references related to laboratory results and physician advice (n=2767, 51.9% and n=2034, 38.2%, respectively), and alternative approaches (n=2485, 46.6%). Overall sentiment was neutral in 34% (n=1812) of discussions, negative in 30.9% (n=1646), and positive in 16.9% (n=900); the remainder were mixed or unclear. Statin-directed sentiment was neutral in 44.1% (n=2350) of discussions, negative in 25.2% (n=1343), and positive in 12.5% (n=666); the remainder did not express statin-directed sentiment. High clinical relevance was identified in 12.6% (n=672) of discussions. Adherence-related issues were mentioned in 29.8% (n=1587) of discussions. Among adverse effect mentions, muscle pain (n=129, 7.6%) and fatigue (n=110, 6.5%) were common. CONCLUSIONS: LLM-enabled analysis of Reddit discourse highlights substantial negative sentiment, adherence-related concerns, and adverse effect narratives surrounding statin therapy. These findings suggest opportunities for patient-centered communication and shared decision-making strategies that address symptom attribution, uncertainty, and information needs in digital information environments.
12 Apr 2026
Read appraisal →Medicine
Comparative evaluation of human T lymphocytes in HIV patients treated with lamivudine + zidovudine combined with nevirapine versus efavirenz
This study aimed to explore the efficacy of lamivudine + zidovudine plus nevirapine and efavirenz in the treatment hf human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). A total of 100 patients with HIV/AIDS admitted to our hospital from June 2021 to September 2024 were selected and randomly assigned into nevirapine and efavirenz groups (n = 50 per group). The nevirapine group was treated with lamidudine plus zidovudine combined with nevirapine, and the efavirenz group was treated with lamidudine plus zidovudine plus efavirenz. The primary outcomes measured were the changes of lymphocyte count and adverse effects after 3 months of treatment. There was no statistical difference in baseline information between the 2 groups. After treatment, CD3 + and CD4 + levels were higher in the nevirapine group than in the efavirenz group (P <.05, 95% CI: 45.2-98.7 for CD3 + and 32.8-76.4 for CD4+), and CD8 + levels were lower in the nevirapine group than in the efavirenz group (P <.05); the overall incidence of adverse effects in the nevavirapine group was significantly lower than that in the efavirenz group (P <.05). In HIV/AIDS patients, treatment with lamivudine + zidovudine combined with nevirapine resulted in significantly improved CD4 + T cell counts, enhanced immune function, and fewer adverse reactions compared to treatment with lamivudine + zidovudine plus efavirenz, suggesting superior clinical value of the nevirapine-containing regimen.
12 Apr 2026
Read appraisal →Medicine
Real-world safety profile of anifrolumab: An observational disproportionality analysis of the FAERS database
Anifrolumab is a type I interferon receptor antagonist approved for the treatment of moderate-to-severe systemic lupus erythematosus. While its efficacy has been demonstrated in clinical trials, its long-term safety remains understudied in the real world. This study extracted relevant data from the FDA Adverse Event Reporting System (FAERS) to evaluate the post-marketing safety profile of anifrolumab in real-world clinical practice and to identify potential safety signals. We analyzed 1293 reports involving 3542 adverse events (AEs) from the FAERS database (Q3 2021-Q1 2025) using disproportionality analysis. Reports in which anifrolumab was designated as the "primary suspect" drug were included. Safety signals were identified using the reporting odds ratio and the Bayesian confidence propagation neural network, with a signal defined as positive only if it met both criteria: a lower limit of the reporting odds ratio's 95% confidence interval > 1 and the 95% lower credibility interval for the information component of the Bayesian confidence propagation neural network > 0. Additionally, multivariable logistic regression analyses were performed for key AEs to rule out potential confounding. The study identified 97 positive safety signals associated with anifrolumab. In addition to the labeled AEs, such as infusion-related reactions and infections, several unexpected AEs were also identified, including renal-related, cardiovascular-related, and neurological AEs. Multivariable logistic regression analyses for key AEs showed that concomitant immunosuppressants, comorbidities, and disease severity were not significant independent predictors (all P > .05), supporting the robustness of the identified signals. This pharmacovigilance study provides hypothesis-generating evidence on the post-marketing safety profile of anifrolumab and highlights several potential safety signals that warrant further evaluation. It is crucial to emphasize that these findings are derived from the FAERS, a spontaneous reporting database that cannot establish causality due to inherent limitations, such as underreporting, missing data, and lack of exposure information. Therefore, these results require confirmation in well-designed observational studies and clinical trials. Clinicians should be aware of these potential associations and consider appropriate monitoring.
12 Apr 2026
Read appraisal →PDA journal of pharmaceutical science and technology
Bridging Guidance and Regulation: Interpreting the Draft Annex 22 on Artificial Intelligence in GMP Manufacturing
This paper builds upon Stassen et al. (2025), "Recommendations for Artificial Intelligence Application in Continued Process Verification," to provide a detailed interpretation of the European Medicines Agency (EMA) Draft Annex 22-Artificial Intelligence (July 2025 draft) within the context of GMP-regulated pharmaceutical manufacturing. The draft annex introduces a structured, risk-based framework for artificial intelligence (AI) adoption, defining expectations for intended use, validation, life cycle management, explainability, and human-in-the-loop (HITL) oversight. This manuscript examines the alignment between Annex 22 provisions and continued process verification (CPV) recommendations, identifies convergence, operational challenges, and areas for future development, and proposes a roadmap for compliant AI implementation. Conceptual frameworks and workflow illustrations depict the harmonization of CPV principles, life cycle management, and emerging regulatory expectations. This review supports harmonized AI governance and readiness for Annex 22 compliance across the pharmaceutical sector.
12 Apr 2026
Read appraisal →Signal transduction and targeted therapy
Irinotecan with trifluridine/tipiracil and bevacizumab for second-line metastatic colorectal cancer: a phase II multicenter study
Patients diagnosed with metastatic colorectal cancer (mCRC) face a constrained therapeutic landscape following the failure of initial treatment. This multicenter, single-arm, phase II trial (NCT06202001) aimed to assess the efficacy and safety of a novel second-line regimen comprising trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab. Patients with mCRC resistant to prior fluoropyrimidine and oxaliplatin-based chemotherapy were enrolled. Based on a preceding phase I trial, patients received biweekly cycles of oral TAS-102 (30 mg/m² twice daily, days 1-5), intravenous irinotecan (150 mg/m²), and intravenous bevacizumab (5 mg/kg). The primary outcome measure was the objective response rate (ORR). From October 2023 to August 2024, 60 patients were enrolled. As of December 2024, the ORR was 18.3% (2 complete and 9 partial responses), and the disease control rate (DCR) was 83.3%. The median progression-free survival (PFS) was 6.6 months (95% CI, 4.39-8.81), and the median overall survival (OS) was 17.3 months (95% CI, 13.55-21.05). Subgroup analyses indicated that prior resection of the primary tumor was associated with significantly longer median OS (21.9 vs. 16.2 months; p = 0.048) and PFS (8.9 vs. 5.2 months; p = 0.004). The most frequently reported treatment-related adverse events (TRAEs) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The predominant grade 3/4 TRAEs included neutropenia (48.3%), febrile neutropenia (8.3%), and diarrhea (6.7%). In conclusion, the combination of irinotecan, TAS-102, and bevacizumab shows encouraging efficacy and a manageable safety profile as a second-line therapy for mCRC, meriting further investigation.
11 Apr 2026
Read appraisal →Journal for immunotherapy of cancer
Simlukafusp alfa (FAP-IL2v) plus atezolizumab with or without bevacizumab in unresectable, metastatic renal cell carcinoma: a randomized, open-label phase Ib study
BACKGROUND: Simlukafusp alfa (FAP-IL2v) was engineered to preferentially activate CD8+ T and natural killer (NK) cells in tumor microenvironments overexpressing fibroblast activation protein (FAP). Checkpoint inhibitors combined with antiangiogenic agents are standard therapy for metastatic renal cell carcinoma (mRCC), which overexpresses FAP. Here, we explored the efficacy, safety, and pharmacodynamic effects of FAP-IL2v in combination with atezolizumab with or without bevacizumab in patients with mRCC. METHODS: Patients with treatment-naïve or pretreated clear cell and/or sarcomatoid mRCC were eligible. Dose escalation explored FAP-IL2v every 2 weeks (Q2W) with atezolizumab Q2W (doublet, arm A), and with atezolizumab and bevacizumab Q2W (triplet, arm B) in patients treated with up to one prior systemic therapy. Dose extension explored in untreated patients the recommended FAP-IL2v dose administered Q2W (doublet, arm A; and triplet, arm B) or 3-weekly (doublet, arm C; and triplet, arm D). Primary objectives were the recommended FAP-IL2v dose and antitumor activity. Secondary objectives included safety, pharmacodynamics, and exploratory biomarkers in peripheral blood and paired biopsies. RESULTS: By the data cut-off date (31 August, 2021), 66 patients were enrolled. The median duration of treatment was 11.0 months. Objective response rates (ORRs) were 25% for the doublet and 47% for the triplet, and median progression-free survival was 6.3 and 18.3 months, respectively. Safety profiles were consistent with the individual drugs, including expected interleukin-2 (IL-2) class-specific adverse events (AEs). Two deaths were recorded caused by AEs related to study treatment (acute kidney injury, n=1; pancytopenia, n=1). Expansion and activation of NK and T cells, but not regulatory T cells, was observed in peripheral blood, leading to increased tumor infiltration and inflammation in paired biopsies. The addition of bevacizumab led to a reduced angiogenesis signature score and reduced vessel density. CONCLUSION: The combination of FAP-IL2v plus atezolizumab with or without bevacizumab was consistent with the known safety profile of the individual drugs. The maximum tolerated dose was not reached, with a recommended FAP-IL2v dose of 10 mg. ORR was higher among patients receiving the triplet therapy compared with the doublet. Pharmacodynamic results were consistent with the mechanism of action of IL-2, supporting further research in this field.
11 Apr 2026
Read appraisal →Open heart
Sex differences in risk factor control and medication adherence post-ACS: insights from the TEXTMEDS randomised clinical trial
INTRODUCTION: Poor adherence to risk factor control and life-saving medications is a key factor affecting long-term patient prognosis. Evidence indicates that sex plays a significant role in the uptake of both pharmacological and non-pharmacological interventions, ultimately influencing long-term outcomes. This study aimed to quantify sex differences in risk factor management and medication adherence following acute coronary syndrome (ACS). METHODS: This is a secondary analysis of the TEXTMEDS randomised clinical trial - a single-blind, multicentre randomised controlled trial of patients post-ACS. We compared sex differences in achieving clinical and lifestyle targets for secondary prevention, namely blood pressure control (<140/90 mm Hg), low-density lipoprotein cholesterol (LDL-C) (<1.8 mmol/L), healthy body mass index (BMI) (<25 kg/m²), regular physical activity (Global Physical Activity Questionnaire score ≥600), smoking status and adherence to cardioprotective medications (aspirin, beta blockers, ACE/angiotensin receptor blockers, statins, antiplatelets), using adjusted logistic regression models. Medication adherence was defined as taking ≥80% of prescribed doses in the month prior to follow-up, across all five drug classes, unless contraindicated. RESULTS: Of 1379 patients (mean age 58.5±10.7 years; 1095 (79.4%) male), females were less likely than men to achieve LDL-C targets (adjusted OR (aOR): 0.61, 95% CI 0.45 to 0.82) and engage in regular physical activity (aOR: 0.61, CI 0.47 to 0.80), but more likely to achieve a healthy BMI (aOR: 1.47, CI 1.04 to 2.06). Female patients are less likely to adhere to their medication compared with male counterparts (aOR: 0.68, CI 0.50 to 0.92). However, this association weakened and lost statistical significance after further adjustment for socio-economic factors (aOR: 0.71, CI 0.50 to 1.03). There were no significant interactions between sociodemographic or clinical factors and sex in relation to overall medication adherence (P-interactions >0.05). CONCLUSION: This study reveals that female patients are less likely to achieve LDL-C targets and engage in physical activity but more likely to maintain a healthy BMI. Although females showed lower medication adherence, this association weakened after adjusting for socio-economic factors. These findings highlight the importance of sex-sensitive strategies focusing on risk factor control and medication adherence for improving cardiovascular health outcomes. TRIAL REGISTRATION NUMBER: ACTRN12613000793718.
11 Apr 2026
Read appraisal →Blood
A decade of ibrutinib for CLL with and without TP53 aberration: final report on an investigator-sponsored phase 2 study
Bruton tyrosine kinase inhibitors improve outcomes for patients with chronic lymphocytic leukemia (CLL). Long-term data with continuous therapy are limited. With a median follow-up of 10.0 years, we report final results on 84 patients with TP53 aberrations (deletion of chromosomal arm 17p or TP53 mutation) or ≥65 years of age treated with 420 mg of single-agent ibrutinib daily until progression or unacceptable toxicity. A total of 52 (61.9%) patients were previously untreated; 56 (66.7%) had unmutated immunoglobulin heavy-chain variable region; and 53 (63.1%) had TP53 aberrations, including 34 treatment naïve patients. As of 31July 2024, 9 (10.7%) patients continued ibrutinib, 39 (46.4%) discontinued ibrutinib for progressive disease, 31 (36.9%) for adverse events, and 5 (5.9%) withdrew consent. The median progression-free survival (PFS) was 7.2 years; median overall survival (OS) was not reached. In patients with and without TP53 aberrations, median PFS was 5.6 years and not reached, and 10-year OS was 51.3% and 75.3%, respectively. The estimated 10-year PFS and OS for patients with TP53-aberrant CLL treated in first line was 38.6% and 65.7%, respectively. Minimal residual disease (MRD) was quantified by peripheral blood flow cytometry annually. Undetectable MRD (uMRD; at 10-4) was achieved in 13 (15.5%) patients after a median of 5 years. Twelve patients maintained uMRD, the longest observation ongoing at 8.0 years. Seventeen (42.5%) patients with best response of high MRD (>10-2) remained progression-free for >5 years. These results highlight durable benefits and deepening responses with ibrutinib, including in high-risk CLL. Whether patients maintaining uMRD for years can safely discontinue therapy should be assessed prospectively. This trial was registered at www.clinicaltrials.gov as NCT01500733.
10 Apr 2026
Read appraisal →Blood
A phase 3 study of intensive chemotherapy with or without dasatinib in core-binding factor acute myeloid leukemia
Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT. We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multikinase inhibitor dasatinib in adult patients with CBF-AML. Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg daily on days 8 to 21 in induction, and on days 6 to 28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg daily. Primary end point was event-free survival (EFS). Secondary end points included overall survival, relapse-free survival, and cumulative incidence of relapse. A total of 202 patients were randomly assigned to the standard arm (n = 102) and to the dasatinib arm (n = 100). Median age was 49 years (range, 18-77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); and 58 (28.7%) patients had a KIT comutation. There was no statistically significant difference in EFS (hazard ratio, 0.92; 95% confidence interval, 0.63-1.33; P = .66) or secondary end points between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%). In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.ClinicalTrials.gov as NCT02013648.
10 Apr 2026
Read appraisal →Journal of medicinal chemistry
Rational Design of Broad-Spectrum Non-Nucleoside Reverse Transcriptase Inhibitors via Pharmacophore-Oriented Generative Artificial Intelligence
Guided by the pharmacophore-oriented molecular generation platform PhoreGen, we employed rilpivirine (RPV) as a lead compound to generate 300 structurally diverse analogs that preserve key pharmacophoric features. Subsequent drug-likeness evaluation, molecular docking score, and synthetic feasibility led to the identification of compound No.102 (A19), which displayed potent inhibition activity against WT HIV-1 (EC50 = 3.15 nM) and low cytotoxicity (CC50 > 335 μM). Subsequent structure-activity relationship optimization identified A24, which demonstrated robust activity against clinically relevant drug-resistant HIV-1 mutants (EC50 = 2.07-28.8 nM). Notably, compared to RPV, A24 exhibited significantly reduced cytotoxicity (CC50 = 82.3 μM vs. 3.98 μM) and enhanced potency against the Y188L (EC50 = 28.8 nM vs. 79.4 nM) and F227L + V106A (EC50 = 19.0 nM vs. 81.6 nM) mutants. Pharmacokinetic evaluations revealed that A24 exhibited attenuated CYP enzyme inhibition (IC50 ≥ 1.88 μM), reduced hERG-related toxicity (IC50 = 2.633 μM), and improved metabolic stability (human t1/2 = 39.1 min). Collectively, these favorable properties position A24 as a promising NNRTI for further development.
10 Apr 2026
Read appraisal →Chemical communications (Cambridge, England)
Innovative integration of molecular docking and machine learning for drug discovery: from virtual screening to nanomolar inhibitors
This review highlights our group's systematic approach to integrating molecular docking, pharmacophore modeling, and machine learning methodologies for the rational discovery of bioactive leads. We describe innovative strategies including docking-based data augmentation, ligand-receptor contact fingerprints, genetic algorithm-guided feature selection, and SHAP-based model interpretation. These approaches have enabled the discovery of nanomolar inhibitors against multiple therapeutic targets including STAT3, TTK, LSD-1, and HER2. The presented workflow demonstrates how machine learning (ML) can be synergistically combined with traditional computer-aided drug design methods to achieve efficient scaffold hopping and identify novel chemotypes with potent biological activities.
10 Apr 2026
Read appraisal →Lupus science & medicine
Efficacy and safety of anifrolumab in patients with systemic lupus erythematosus without prior immunosuppressant use: post hoc analysis of phase 3 TULIP-1 and TULIP-2 trials
OBJECTIVE: Although current treatment recommendations for systemic lupus erythematosus (SLE) provide the option for biologic agents without prior failure of immunosuppressants (IS), data on this treatment approach are limited. This study evaluates the efficacy and safety of anifrolumab by IS exposure. METHODS: Pooled data from the Phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials were analysed post hoc to compare patients with moderate-to-severe SLE treated with intravenous anifrolumab 300 mg or placebo alongside standard therapy by reported IS use. Efficacy outcomes by IS use included Definition of Remission in SLE (DORIS) remission and Lupus Low Disease Activity State (LLDAS) attainment, analysed using a stratified Cochran-Mantel-Haenszel approach; all p values are nominal. Safety was summarised descriptively. RESULTS: In this analysis, 257 patients had no reported IS use (IS-inexperienced; anifrolumab 300 mg, n=127; placebo, n=130), and 469 were IS-experienced (anifrolumab 300 mg, n=233; placebo, n=236). At Week 52, DORIS remission and LLDAS attainment rates were higher with anifrolumab versus placebo in both IS subgroups (DORIS, IS-inexperienced, 16.2% vs 6.0%, p=0.0242; IS-experienced, 14.6% vs 7.3%, p=0.0304; LLDAS, IS-inexperienced, 34.0% vs 26.2%, p=0.1718; IS-experienced, 27.7% vs 16.2%, p=0.0038). Anifrolumab was well tolerated, regardless of reported IS history; safety was more favourable among IS-inexperienced versus IS-experienced patients. CONCLUSIONS: This post hoc analysis of pooled TULIP-1/TULIP-2 data supports the efficacy and tolerability of anifrolumab in patients with moderate-to-severe SLE regardless of IS treatment history.
10 Apr 2026
Read appraisal →Proceedings of the National Academy of Sciences of the United States of America
Reconstruction of human metabolic models with large language models
Genome-scale metabolic models (GEMs) have become essential tools for understanding human metabolism. Here, we introduce Human2, a consensus human GEM with enhanced precision and biological relevance, which leverages large language models (LLMs) and GitHub Action checks to streamline automated, efficient, and collaborative curation. Human2 supports the reconstruction of tissue- and organ-specific models tailored to sex- and age-specific human groups. By integrating transcriptomic, proteomic, and kinetic data, we reveal distinct metabolic features across these groups, such as significant differences in arachidonic acid and leukotriene metabolism. The specific models were integrated into a dynamic whole-body framework, marking an enzyme-constrained dynamic model that simulates interorgan metabolite exchanges under varying nutritional states, from feeding to fasting. Our work highlights the transformative role of LLMs in GEM reconstruction and introduces a whole-body dynamic simulation that integrates kinetic data, offering a powerful resource for multiscale human metabolism modeling.
10 Apr 2026
Read appraisal →PloS one
Deep learning for adaptive chemotherapy: A DDPG-based approach to optimizing tumor-immune dynamics
In this article, we propose a deep reinforcement learning based chemotherapy regulation framework to realize personalized and dynamic optimization of cancer treatment. We use a nonlinear dynamic system to model the dynamic evolution of the tumor microenvironment including tumor cell, normal cell and immune cell interactions, with drug concentration serving as the control input variable. The Deep Deterministic Policy Gradient (DDPG) algorithm makes agents can study optimal dosing strategy in a continuous space of movement to inhibit tumor growth effectively and minimize damage to normal tissues. To make the strategy more stable, Gauss noise is added to the model to simulate physiological oscillations and uncertainties in the treatment reaction. Experimental results show that it can control the growth of tumor in various initial scenarios and the accumulation of the drug concentration with high flexibility and safety. Our technique provides a feasible technical way for precision, low toxicity adaptive chemotherapy.
9 Apr 2026
Read appraisal →The New England journal of medicine
Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer
BACKGROUND: The KRAS p.G12D variant occurs in 5% of patients with non-small-cell lung cancer (NSCLC) and is the most common substitution variant in pancreatic ductal adenocarcinoma, occurring in 40% of patients, but no targeted therapies directed against this variant are currently approved for clinical use. Setidegrasib (ASP3082) is a first-in-class KRAS G12D-targeted protein degrader. METHODS: We conducted this phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. The primary objectives were to evaluate the safety profile, as indicated by dose-limiting toxic effects and adverse events (the primary end points), and to determine the phase 2 dose. Setidegrasib was administered intravenously once weekly at doses of 10 to 800 mg. RESULTS: Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as the phase 2 dose, adverse events occurred during treatment in all the patients, with events of grade 3 or higher in 42%. Treatment-related adverse events occurred in 93% of the patients; the most common were transient infusion-related reactions (in 80%) and nausea (in 30%). Adverse events led to discontinuation in 2 patients. Among the 45 patients with NSCLC who received the 600-mg dose, 36% (95% confidence interval [CI], 22 to 51) had a partial response, the median progression-free survival was 8.3 months (95% CI, 4.1 to could not be estimated), and the estimated 12-month overall survival was 59% (95% CI, 40 to 74). Among the 21 patients with metastatic pancreatic ductal adenocarcinoma who received the 600-mg dose as second- or third-line treatment (of whom 67% received setidegrasib as third-line treatment), 24% (95% CI, 8 to 47) had a response, the median progression-free survival was 3.0 months (95% CI, 1.4 to 6.9), and the median overall survival was 10.3 months (95% CI, 4.2 to 13.0). CONCLUSIONS: Setidegrasib was associated with antitumor activity and a low incidence of treatment discontinuation due to adverse events in patients with previously treated advanced KRAS p.G12D-mutated NSCLC or pancreatic ductal adenocarcinoma. (Funded by Astellas Pharma; ClinicalTrials.gov number, NCT05382559.).
9 Apr 2026
Read appraisal →The New England journal of medicine
A Phase 2 Randomized Trial of Mezagitamab in Primary Immune Thrombocytopenia
BACKGROUND: Immune thrombocytopenia (ITP) is a disorder of increased platelet destruction and reduced platelet production and is associated with an increased bleeding risk and a compromised quality of life. Available therapies are ineffective in at least 20% of cases. Mezagitamab is an anti-CD38 antibody that targets plasma cells, plasmablasts, and natural killer cells. METHODS: We conducted this multicenter, double-blind, randomized, placebo-controlled trial to assess the safety and efficacy of mezagitamab at a dose of 100 mg, 300 mg, or 600 mg, as compared with placebo, administered subcutaneously once weekly for 8 weeks in adults with persistent or chronic ITP (mean platelet count on ≥2 measurements, <30,000 per microliter). The primary end point was adverse events. A key secondary efficacy end point was a platelet response (defined by a platelet count of ≥50,000 per microliter and ≥20,000 per microliter above the baseline value) on at least two visits at any time through week 16. RESULTS: In the combined mezagitamab groups (28 participants), the mean age was 50 years (range, 24 to 88) and the mean number of previous ITP therapies was 4 (range, 1 to 9); in the combined placebo groups (13 participants), the mean age was 39 years (range, 20 to 65) and the mean number of previous ITP therapies was 4 (range, 1 to 13). The mean baseline platelet count was 19,100 and 17,300 per microliter, respectively. Adverse events were reported in 19 of 28 participants (68%) in the combined mezagitamab groups and in 9 of 13 participants (69%) in the combined placebo groups; adverse events of grade 3 or higher in 5 of 28 participants (18%) and in 3 of 13 participants (23%), respectively; and serious adverse events in 4 of 28 participants (14%) and in 1 of 13 participants (8%). Through week 16, a platelet response was observed in 10 of 11 participants (91%) in the mezagitamab 600-mg group and in 3 of 13 participants (23%) in the combined placebo groups. CONCLUSIONS: Treatment with mezagitamab led to increased platelet counts, with a safety profile that appeared to be similar to that of placebo among participants with persistent or chronic ITP. (Funded by Takeda Development Center Americas; ClinicalTrials.gov number, NCT04278924.).
9 Apr 2026
Read appraisal →The New England journal of medicine
Intensive LDL Cholesterol Targeting in Atherosclerotic Cardiovascular Disease
BACKGROUND: Despite guideline recommendations, evidence from randomized trials evaluating the appropriate low-density lipoprotein (LDL) cholesterol target for secondary prevention in patients with atherosclerotic cardiovascular disease remains limited. METHODS: In this open-label superiority trial conducted in South Korea, we randomly assigned patients with atherosclerotic cardiovascular disease in a 1:1 ratio to a target LDL cholesterol level of less than 55 mg per deciliter (1.4 mmol per liter) (intensive-targeting group) or less than 70 mg per deciliter (1.8 mmol per liter) (conventional-targeting group). The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina at 3 years. Safety was also assessed. RESULTS: Of 3048 patients who underwent randomization, 1526 were assigned to the intensive-targeting group and 1522 to the conventional-targeting group. The median follow-up was 3.0 years. The median LDL cholesterol level during the trial was 56 mg per deciliter (1.4 mmol per liter) in the intensive-targeting group and 66 mg per deciliter (1.7 mmol per liter) in the conventional-targeting group. A primary end-point event occurred in 100 patients (Kaplan-Meier estimate of cumulative incidence, 6.6%) in the intensive-targeting group and in 147 patients (Kaplan-Meier estimate of cumulative incidence, 9.7%) in the conventional-targeting group (hazard ratio, 0.67; 95% confidence interval, 0.52 to 0.86; P = 0.002). The incidence of prespecified safety end points was similar in the two trial groups, except for a lower incidence of creatinine elevation in the intensive-targeting group. CONCLUSIONS: Among patients with atherosclerotic cardiovascular disease, targeting an LDL cholesterol level of less than 55 mg per deciliter resulted in a lower risk of cardiovascular events at 3 years than targeting a level of less than 70 mg per deciliter. (Funded by the Cardiovascular Research Center and Yuhan; Ez-PAVE ClinicalTrials.gov number, NCT04626973.).
9 Apr 2026
Read appraisal →Microbiology spectrum
Evaluation of contezolid's cerebrospinal fluid concentration and safety in tuberculous meningitis patients
Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) with high mortality. This study evaluated the cerebrospinal fluid (CSF) concentration and safety of the novel oxazolidinone contezolid compared to linezolid in TBM patients. In this randomized prospective study, 10 TBM patients received either a linezolid-containing (n = 5) or contezolid-containing (n = 5) anti-TB regimen. CSF and blood concentrations were measured at 2 and 6 h post-dose. Peak (2 h) and trough (6 h) concentrations, area under the concentration-time curve (AUC), and safety were assessed. Contezolid CSF concentrations exceeded the Mycobacterium tuberculosis (Mtb) MIC (0.5 μg/mL) at 2 h (median: 1.0806 μg/mL, range: 0.9295-1.3165 μg/mL) but declined by 6 h (median: 0.7920 μg/mL, range: 0.1867-1.0194 μg/mL). Linezolid CSF concentrations were significantly higher than contezolid at both 2 h (median: 3.251 μg/mL, range: 1.9545-4.9636 μg/mL; P = 0.008) and 6 h (median: 1.623 μg/mL, range: 0.941-1.765 μg/mL; P = 0.016), remaining above MIC in all samples at 6 h. The mean CSF AUC for contezolid (4.637 μg·h/mL, 95% CI: 3.599-5.675) was significantly lower than that for linezolid (12.537 μg·h/mL, 95% CI: 7.8797-17.277; P = 0.008). Blood concentrations were higher than CSF for both drugs at all time points. No serious drug-related adverse events occurred. Contezolid effectively penetrates the blood-CSF barrier in TBM patients, achieving CSF concentrations above the MIC for Mtb. Although its CSF exposure was significantly lower than linezolid, its demonstrated penetration and safety profile suggest contezolid warrants further investigation as a potential treatment option for drug-resistant TBM.IMPORTANCETuberculous meningitis (TBM) is the deadliest form of tuberculosis, especially difficult-to-treat drug-resistant TBM. Finding new, effective, and safe medicines is critical. This study provides evidence in TBM patients that a newer antibiotic, contezolid, successfully reaches the infection site in cerebrospinal fluid (CSF) at levels expected to kill Mycobacterium tuberculosis. While linezolid achieved higher levels in CSF, contezolid still reached concentrations predicted to be effective and caused no serious side effects in our study. This is important because contezolid might offer a safer alternative to linezolid, which can have significant long-term toxicity. These promising results suggest contezolid could become a valuable new weapon against refractory drug-resistant TBM, potentially saving lives where current options are limited or too toxic.
9 Apr 2026
Read appraisal →Analytica chimica acta
Point-of-need and portable sensing strategies for quality and safety assessment of Traditional Chinese Medicine products: A critical analytical review.
Sensor technology has emerged as a transformative tool for point-of-need and portable quality control and safety assessment of Traditional Chinese Medicine (TCM) products. Although separation and detection technologies have improved, there is still a strong need to critically evaluate the entire analytical workflow from sample preparation to data interpretation to meet regulatory and routine monitoring requirements. This review critically evaluates the complete analytical workflow, from sample pretreatment to intelligent data interpretation, necessary to bridge the gap between laboratory prototypes and real-world deployment. Additionally, it provides a systematic summary of the mechanisms and applications of common types of sensors, utilising nanomaterials and molecular recognition elements to overcome the specific challenge of complex TCM matrices. A particular focus is placed on the emerging roles of Artificial Intelligence (AI) and Machine Learning (ML) in resolving high-dimensional spectral data and enhancing pattern recognition accuracy. Furthermore, we critically analyze current bottlenecks, including matrix interference, the lack of standardized validation protocols, and the reliability of portable devices in uncontrolled environments. Future directions are highlighted towards the development of self-validating, cloud-integrated (IoT), and eco-friendly sensing systems, aiming to support the global standardization and safety assurance of TCM products.
9 Apr 2026
Read appraisal →BMJ open
Identification of immunomodulators associated with atrial fibrillation reporting to better understand AF immunologic mechanisms: a Vigibase retrospective disproportionality analysis and a literature review
OBJECTIVES: Growing evidence exists about the pivotal role of immune mechanisms in the physiopathology of atrial fibrillation (AF). Drugs that modulate the immune system (immunomodulators) may contribute to the development of AF. We aimed to identify immunomodulators that are associated with AF to better define their safety profile, and elucidating their mechanisms of action could yield novel insights into AF's immune physiopathology. DESIGN: A descriptive and disproportionality analysis of claims data. SETTINGS: World pharmacovigilance database VigiBase until 1 March 2025. PRIMARY AND SECONDARY OUCTOMES: First, we ascertained the association of immunomodulators with AF over-reporting with a disproportionality analysis evaluating the multivariable-adjusted reporting odds ratio (aROR) for AF reporting performed for 141 immunomodulators in VigiBase. Then, a literature review was done to explore the underlying mechanisms of AF through immunomodulator mechanisms. RESULTS: A total of 6 148 556 reports encompassing at least one of the 141 immunomodulators were identified in Vigibase. Our primary analysis revealed 20 immunomodulators associated with AF over-reporting. The three immunomodulators with the greatest signal were: recombinant interleukin-11 with an aROR=20.91 (99.96% CI 12.08 to 36.17), efgartigimod alfa with an aROR=6.75 (99.96% CI 3.96 to 11.52) and recombinant interleukin-2 with an aROR=6.15 (99.96% CI 3.62 to 10.45). A derivative literature review posited a hypothetical immune 'vicious circle' promoting AF, involving T helper cells, macrophages and natural killer cells which could lead to electrophysiologic and histologic atrial remodelling. CONCLUSIONS: Twenty Food and Drug Administration (FDA)-labelled immunomodulators are associated with AF overreporting in Vigibase with a substantial signal on recombinant IL-11. These data contribute substantively to the prevailing understanding of the safety profile of these immunomodulators. Moreover, these findings support a multidirectional interaction between the immune system and AF development and might lead to considering future therapeutic targets. TRIAL REGISTRATION NUMBER: NCT06095791.
9 Apr 2026
Read appraisal →Neurology
Efficacy of Pyridostigmine in Myasthenia Gravis: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial
BACKGROUND AND OBJECTIVES: Pyridostigmine, an acetylcholinesterase inhibitor, is a symptomatic drug approved for the treatment of myasthenia gravis (MG), but no randomized controlled trials substantiate its widespread use. We aimed to assess the efficacy and cost utility of pyridostigmine in patients with anti-acetylcholine receptor-positive MG (AChR MG). METHODS: A randomized, double-blind, placebo-controlled crossover trial was conducted at Leiden University Medical Center, a tertiary center for the treatment of MG in the Netherlands. Main eligibility criteria were current use of pyridostigmine and a stable dose of other MG treatments. Participants were assigned to a sequence of 2 treatment periods for 5 days separated by a 2-day washout, in which patients either first received placebo and then pyridostigmine, or vice versa. Pyridostigmine dosing matched each participant's prestudy regimen. The primary outcome was change in the Myasthenia Gravis Impairment Index (MGII) score. Secondary efficacy outcome measures included the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale, the Quantitative Myasthenia Gravis (QMG) score, and the revised 15-item Myasthenia Gravis Quality of Life (MG-QOL15r) questionnaire. For the post hoc cost-utility analysis, a mathematical model was developed to translate the observed study results into long-term annual effect on societal costs and quality-adjusted life years (QALYs). RESULTS: A total of 19 patients (median age 59 years, 58% female) were recruited between March 23, 2023, and February 21, 2024. The estimated mean difference in the MGII score between pyridostigmine and placebo interventions was 5.3 (95% CI 1.9-8.7, p = 0.004). Secondary efficacy outcome measures showed estimated mean differences of 1.4 (95% CI 0.5-2.3) for the QMG score, 1.2 (95% CI 0.5-1.8) for the MG-ADL score, and 2.0 (95% CI 0.03-3.91) for the MG-QoL15r score. The post hoc cost-utility analysis showed lower annual societal costs (€6,565, 95% CI €328-€15,945) and annual improved QALYs (0.106, 95% CI 0.019-0.210) for patients using pyridostigmine. DISCUSSION: This trial showed that, in patients with AChR MG chronically treated with pyridostigmine, pyridostigmine demonstrated benefit over placebo across all efficacy outcome measures and substantially reduced societal costs. TRIAL REGISTRATION INFORMATION: The trial was registered at EudraCT (2021-004110-20, registration date: July 12, 2022) and ClinicalTrials.gov (NCT05919407, registration date: June 16, 2023). First patient enrolled: March 23, 2023. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, in adults with AChR ab-positive ocular or generalized MG on stable standard-of-care therapy and currently using pyridostigmine, pyridostigmine improves MG symptoms compared with placebo.
9 Apr 2026
Read appraisal →Signal transduction and targeted therapy
Anti-PD-1 antibody penpulimab plus chemotherapy for recurrent or metastatic nasopharyngeal carcinoma: a randomized, double-blind phase 3 study
In this phase 3 trial, penpulimab combined with chemotherapy was assessed against a regimen of placebo plus chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC). 291 patients were randomised and allocated in a 1:1 ratio in order to receive penpulimab (n = 144; 200 mg) or placebo (n = 147; 200 mg), plus chemotherapy (cisplatin/carboplatin and gemcitabine) every 3 weeks. Patients followed by maintenance therapy with penpulimab or placebo after 6 cycles. The primary endpoint of this study was progression-free survival (PFS) according to RECIST v1.1, and a significantly longer median PFS in the penpulimab arm versus the placebo arm (9.63 versus 7.00 months; hazard ratio 0.45, 95% CI: 0.33-0.62, P < 0.0001) was demonstrated in this prespecified interim analysis. The key secondary endpoint was the overall survival (OS). However, the OS data were still immature, and the median OS was not achieved (hazard ratio, 0.94; 95% CI: 0.63-1.40). The occurrence of treatment-related adverse events (grade ≥ 3) was 89.0% and 85.9% in two arms, with the most common being reduced the quantity of neutrophil (56.2% vs. 62.0%), reduced the quantity of white blood cell (54.1% vs. 54.9%), and anemia (45.2% vs. 38.7%). In the penpulimab arm, 6 patients (4.1%) experienced immune-related adverse events (grade ≥ 3). Adding penpulimab to chemotherapy led to a notable enhancement in PFS for the first-line R/M NPC treatment, alongside a safety profile that was both manageable and tolerable. ClinicalTrials.gov identifier NCT04974398.
8 Apr 2026
Read appraisal →JMIR research protocols
Enhancing Continuous Medication Safety Through e-Prescription and Clinical Decision Support Systems in Outpatient Practices and Pharmacies: Protocol for a Multiperspective Study (eRIKA Study)
BACKGROUND: Increased life expectancy is associated with increasing multimorbidity and polypharmacy, leading to a heightened risk of drug-drug interactions and adverse events, especially when multiple health care providers are involved. To address the urgent need for safer medication management in this population, tools such as medication plans (MP), electronic prescriptions (e-prescriptions), and clinical decision support systems (CDSS) offer valuable support. These instruments have the potential to enhance medication safety by providing physicians and pharmacists with a comprehensive overview of a patient's overall medication regimen and by assisting health care professionals in making informed prescribing decisions. OBJECTIVE: This study aims to improve medication therapy safety by combining e-prescriptions, the use of claims data, MPs, CDSS, and interprofessional communication. To comprehensively evaluate this complex intervention, a holistic multiphase study will be conducted, examining (1) the effectiveness of the intervention and (2) health-economic and (3) implementation-related aspects. METHODS: A multiphase study design is used. In the first phase, the intervention is implemented in selected outpatient practices (n=10) and pharmacies (n=10) in 2 regions in Germany as part of a cluster-randomized controlled trial to assess process-related outcomes. The primary outcome is the congruence between the MP and claims data. In phase 2, the intervention is scaled up in 3 regions and evaluated in a quasi-experimental study. The required sample size for the intervention group is 3528 patients, with a synthetic control group matched from existing claims data. The primary outcome is a combined end point of all-cause mortality and hospitalization within 3 months of an index prescription. Quantitative methods (descriptive, regression-based methods using claims data, calculation of the incremental cost-effectiveness ratio, and survey-based analyses of implementation-related aspects) and qualitative methods (interviews and focus groups to capture experiences of health care professionals and patients) are used. RESULTS: In phase 1, a total of 187 patients were recruited (74 in the intervention group and 113 in the control group) by June 2025. Phase 2 is currently ongoing, with data collection continuing through December 31, 2025. Final analyses are planned by March 2027. CONCLUSIONS: Medication safety in polypharmacy remains a critical challenge in Germany. This study provides multiperspective evidence supporting the nationwide implementation of the eRIKA (e-prescription as an element of interprofessional care pathways for continuous medication therapy management [eRezept als Element interprofessioneller Versorgungspfade für kontinuierliche AMTS]) intervention.
8 Apr 2026
Read appraisal →Neurology
Efficacy and Safety of Amifampridine in Myasthenia Gravis: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial
BACKGROUND AND OBJECTIVES: Amifampridine, a short-acting potassium-channel blocker, is the first-line treatment for Lambert-Eaton myasthenic syndrome. Its benefit as add-on to pyridostigmine in acetylcholine receptor (AChR)-positive myasthenia gravis (MG) has been proposed, but no randomized controlled trials have been conducted. We aimed to evaluate the efficacy and safety of amifampridine in AChR-MG with insufficient symptom control on pyridostigmine. METHODS: A randomized, double-blind, placebo-controlled crossover trial was conducted at Leiden University Medical Center, a tertiary center for the treatment of MG in the Netherlands, as part 2 of the IMPACT-MG trial. Eligible patients had either completed part 1 (pyridostigmine vs placebo) or failed the initial 2-day pyridostigmine washout, and had an Myasthenia Gravis Impairment Index (MGII) score >10. Participants were randomized (1:1:1) to 1 of 3 treatment sequences. Each treatment period lasted 5 days, with a 2-day washout between treatments, during which participants received either 30 mg or 60 mg of amifampridine modified release, or placebo. The primary outcome was the difference in MGII score between the 2 amifampridine dosages and placebo. Pharmacokinetics, safety, and tolerability were assessed throughout the trial. RESULTS: Between March 2023 and April 2024, 20 patients were enrolled (median age 60 years, 55% female). For the MGII score, the estimated mean differences were -1.0 (95% CI -4.1 to 2.0, p = 0.681) for amifampridine 30 mg vs placebo and -1.7 (95% CI -4.7 to 1.4, p = 0.379) for amifampridine 60 mg vs placebo. No statistically significant association was observed between pharmacokinetic parameters and the MGII. No serious adverse events were reported. Adverse events were more common with amifampridine 30 mg (12 patients [60%]) and 60 mg (15 patients [75%]), compared with placebo (6 patients [30%]), with paresthesia, fatigue, numbness, dizziness, and sleep disturbances most frequently reported. Three patients discontinued amifampridine early due to adverse events. DISCUSSION: The addition of amifampridine to pyridostigmine was not superior to treatment with pyridostigmine alone and was associated with a higher incidence of adverse events. TRIAL REGISTRATION INFORMATION: The trial was registered at EudraCT (2021-004110-20, registration date: July 12, 2022) and ClinicalTrials.gov (NCT05919407, registration date: June 16, 2023). First patient enrolled: March 23, 2023. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with AChRAb+ MG, the addition of amifampridine to pyridostigmine was not superior to treatment with pyridostigmine alone and was associated with a higher incidence of adverse events.
8 Apr 2026
Read appraisal →Journal of the American Heart Association
Left Atrial Volume Index and Left Ventricular Mass Index Determine the Benefits of Spironolactone in Patients With Heart Failure With Preserved Ejection Fraction
BACKGROUND: It is unclear whether patients with heart failure with preserved ejection fraction respond to spironolactone based on cardiac structure or function. METHODS: A post hoc analysis was performed among participants with left ventricular (LV) ejection fraction ≥50% and evidence of abnormal LV diastolic function or filling pressures in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial). Log-rank tests and Cox regression models were used for comparison between groups. RESULTS: Totally, 757 subjects were qualified and stratified by parameters on cardiac structure or function. In patients with increased left atrial volume index, spironolactone reduced cardiovascular mortality (adjusted hazard ratio [HR], 0.48 [95% CI, 0.24-0.98]; P=0.042, log-rank; interaction P=0.045). Meanwhile, in patients with increased LV mass index, spironolactone decreased heart failure hospitalization (adjusted HR, 0.51 [95% CI, 0.32-0.80]; P=0.009, log-rank; interaction P=0.041) and the composite outcome of cardiovascular mortality, heart failure hospitalization, and aborted sudden death (adjusted HR, 0.63 [95% CI, 0.43-0.93]; P=0.045, log-rank; interaction P=0.029). Then, in participants with increased left atrial volume index and LV mass index, who matched at 1:1 ration by propensity score matching, spironolactone reduced cardiovascular mortality (adjusted HR, 0.31 [95% CI, 0.11-0.92]; P=0.039, log-rank), heart failure hospitalization (adjusted HR, 0.26 [95% CI, 0.10-0.68]; P=0.005, log-rank), and the composite outcome (adjusted HR, 0.33 [95% CI, 0.15-0.72]; P=0.006, log-rank). CONCLUSIONS: Spironolactone reduced cardiovascular mortality, heart failure hospitalization, or the composite outcome of cardiovascular mortality, heart failure hospitalization, and aborted sudden death in patients with heart failure with preserved ejection fraction with increased left atrial volume index or LV mass index.
8 Apr 2026
Read appraisal →Journal of the American Heart Association
Ex Vivo Effect of Apixaban on Hemostatic Biomarkers in Children With Heart Disease: A SAXOPHONE Trial Substudy
BACKGROUND: The SAXOPHONE (Safety of Apixaban on Pediatric Heart Disease on the Prevention of Embolism) trial demonstrated the safety of apixaban for thromboprophylaxis in children with heart disease. Included a priori in the trial design was an exploratory biomarker substudy to evaluate the effects of apixaban on surrogate biomarkers of efficacy, thrombin generation capacity, and hemostatic proteins. The study assessed changes in d-dimer, thrombin generation assay parameters, factor VIII, fibrinogen, protein C, and protein S in children receiving apixaban compared with standard-of-care vitamin K antagonists (VKAs) or low-molecular-weight heparin. METHODS: SAXOPHONE participants aged >1 year (n=182) had blood samples for biomarkers collected at baseline, week 2, or month 6. Participants were randomized to apixaban (n=123) or standard of care (VKA or low-molecular-weight heparin; n=59). Subgroup analyses accounted for prior VKA exposure. RESULTS: d-dimer levels decreased at month 6 in all treatment groups and remained stable during VKA-to-apixaban bridging. Apixaban significantly prolonged thrombin generation assay lag time and time to peak compared with VKAs and decreased peak thrombin similarly to VKAs in anticoagulant-naïve participants. Apixaban was associated with decreased fibrinogen and factor VIII at month 6, with no effect on protein C or S. Prior VKA exposure produced carryover effects, suppressing baseline d-dimer, thrombin generation assay parameters, and proteins C and S. CONCLUSIONS: Apixaban reduced hypercoagulability, as shown by decreased d-dimer levels and prolonged lag time, and preserved endogenous thrombin potential in thrombin generation assay, changes consistent with adult data. These findings align with SAXOPHONE's primary outcomes, supporting apixaban's favorable risk-benefit profile as a thromboprophylaxis option in children with heart disease.
8 Apr 2026
Read appraisal →Journal of the American Heart Association
Impact of Atrial Fibrillation Pattern on Edoxaban Antithrombotic Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease: A Secondary Analysis of the EPIC-CAD Randomized Clinical Trial
BACKGROUND: Paroxysmal atrial fibrillation (AF) is associated with a risk of stroke or systemic embolism similar to nonparoxysmal (persistent or permanent) AF. However, whether the optimal antithrombotic strategy in patients with AF and stable coronary artery disease differs by AF pattern remains uncertain. METHODS: This prespecified substudy of the EPIC-CAD (Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease) trial compared edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with AF and stable coronary artery disease. Stratified analyses were performed by AF pattern. The primary outcome was net adverse clinical events, defined as a composite of all-cause death, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, major bleeding, or clinically relevant nonmajor bleeding within 12 months. RESULTS: Among 1040 patients, 575 (55.3%) had paroxysmal and 465 (44.7%) had nonparoxysmal AF. The 12-month primary outcome rate was similar between paroxysmal and nonparoxysmal AF (10.3% versus 12.2%; adjusted hazard ratio [HR], 1.15 [95% CI, 0.79-1.68]). Edoxaban monotherapy was associated with a significantly lower risk of the primary outcome than dual antithrombotic therapy in both paroxysmal AF (4.6% versus 16.2%; adjusted HR, 0.23 [95% CI, 0.12-0.42]) and nonparoxysmal AF (9.3% versus 15.0%; adjusted HR, 0.56 [95% CI, 0.32-0.87]). No significant interaction was observed between antithrombotic strategy and AF pattern (P for interaction=0.10). CONCLUSIONS: In patients with AF and stable coronary artery disease, edoxaban monotherapy significantly reduced net adverse clinical events at 12 months compared with dual antithrombotic therapy, irrespective of AF pattern. REGISTRATION: URL: https://www.ClinicalTrials.gov; Unique identifier: NCT03718559.
8 Apr 2026
Read appraisal →Pulmonology
Low-dose theophylline in mild to moderate Chronic Obstructive Pulmonary Disease: A randomized clinical trial in China
BACKGROUND: Low-dose theophylline has anti-inflammatory effects, but its efficacy in mild to moderate COPD remains controversial. RESEARCH QUESTION: Is low dose theophylline effective and safe in patients with mild to moderate COPD? METHODS: In this prospective, parallel-group, randomised, double-blind, placebo-controlled trial across ten centres in China, subjects with mild to moderate COPD were randomized 2:1 to oral low-dose theophylline sustained-release tablets (100 mg twice daily) or matching placebo for 12 months. Primary endpoints were between-group differences in pre-bronchodilator FEV1 change from baseline to 12 months and annual exacerbation rate. FINDINGS: 734 subjects were randomized; 615 completed the study. Compared with placebo, low-dose theophylline significantly ameliorated FEV1 before bronchodilator use by 30 ml [95% CI, 3 to 57 ml] (p = 0.031) at month 12, with a between-group difference in mean change from baseline of 28 ml/year [95% CI, -2 to 58 ml/year] (p = 0.063). The annual exacerbation rate did not differ between groups (0.46 ± 0.03 vs 0.43 ± 0.04 per patient-year; RR, 1.07 [95% CI, 0.84 to 1.36]; p = 0.607). In addition, the incidence of adverse events was comparable between both groups. INTERPRETATION: In mild to moderate COPD, low-dose theophylline was well-tolerated but did not reduce exacerbation rates. A modest improvement in pre-bronchodilator FEV1 was observed, though its magnitude was limited. Larger trials are needed to further evaluate its potential to improve lung function in this population. What is already known on this topic:The efficacy of low-dose theophylline specifically in the mild to moderate COPD population remains unclear.What this study adds:Our study indicated that low-dose theophylline treatment alone was associated with a significant improvement in pre-bronchodilator FEV1 and demonstrated good tolerability in patients with mild to moderate COPD.How this study might affect research, practice or policy:What we found in this study presented promising opportunities for intervention with theophylline alone in patients with mild to moderate COPD.
8 Apr 2026
Read appraisal →EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology
Ischaemic and bleeding events after complex versus non-complex PCI: a systematic review and meta-analysis
BACKGROUND: Complex percutaneous coronary intervention (PCI) is increasingly performed among patients undergoing myocardial revascularisation. AIMS: We conducted a systematic review and meta-analysis to evaluate the association between complex PCI and the risk of ischaemic and bleeding outcomes. METHODS: Hazard ratios (HRs) were pooled using a random-effects model within a Bayesian framework. The primary analysis was restricted to studies providing adjusted risk estimates, whereas the secondary analysis included unadjusted risk estimates. The primary outcomes were myocardial infarction and major bleeding. The secondary outcomes were all-cause death, stent thrombosis, cardiovascular death, target lesion or vessel revascularisation, and stroke. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework for prognostic studies was used to determine the level of certainty in the association between complex PCI and the risk of events. RESULTS: We included 290,039 patients, of whom 94,633 (33%) underwent complex PCI. Compared with non-complex PCI, patients undergoing complex PCI had a higher risk of myocardial infarction (adjusted HR 1.71, 95% credible interval [CrI]: 1.49-1.96), major bleeding (adjusted HR 1.24, 95% CrI: 1.14-1.35), all-cause death (adjusted HR 1.21, 95% CrI: 1.12-1.32), cardiovascular death (adjusted HR 1.29, 95% CrI: 1.15-1.46), stent thrombosis (adjusted HR 1.76, 95% CrI: 1.49-2.14), target lesion or vessel revascularisation (adjusted HR 1.99, 95% CrI: 1.58-2.50), and stroke (adjusted HR 1.21, 95% CrI: 1.03-1.42). The posterior probability of a higher risk associated with complex versus non-complex PCI was >99% for all study outcomes. Except for stroke (which was low certainty), the certainty of evidence was moderate to high for all other outcomes. Secondary analysis, including unadjusted risk estimates, provided consistent results. CONCLUSIONS: Patients undergoing complex PCI have an increased risk of both ischaemic and bleeding events compared with patients undergoing non-complex PCI (PROSPERO: CRD420250656254).
8 Apr 2026
Read appraisal →Journal of computer-aided molecular design
Computer-aided discovery of CDK16 inhibitors: a docking-augmented machine learning regression modelling approach
Cyclin-dependent kinase 16 (CDK16), a serine/threonine protein kinase, is a critical regulator of cell cycle progression, vesicle trafficking, and apoptosis. Its dysregulation is implicated in the progression of aggressive cancers, including triple-negative breast, lung, and prostate cancer, where its overexpression correlates with poor prognosis. Despite its therapeutic promise, CDK16 remains an understudied kinase lacking selective inhibitors, underscoring the need for innovative discovery approaches. This study introduces a novel computational framework that leverages multiple docked poses to augment datasets for regression-based machine learning (ML) models targeting CDK16 inhibition. This data augmentation strategy incorporated docking scores, ligand-receptor contact fingerprints (LRCFs), and conformation-sensitive physicochemical descriptors as input features. To our knowledge, this is the first application of docked pose augmentation for a regression-based drug discovery model. A systematic evaluation of eight ML algorithms across multiple docking score consensus levels identified Gradient Boosted Trees as the optimal learner. The Genetic Function Algorithm was integrated to select a minimal set of descriptors, which improved model generalizability. The resulting validated ML-QSAR model guided the generation of a robust pharmacophore model, which was used for virtual screening of the NCI and OpnMe databases. Subsequent in vitro LanthaScreen kinase assays confirmed two novel and potent CDK16 inhibitors: compound H_28 (OpnMe code: BI-831266) with an IC50 of 3.5 µM, and H_33 (OpnMe code: BI-1282) with an IC50 of 5.8 µM. These findings highlight the efficacy of integrating docked pose augmentation with regression modeling and experimental validation, offering a robust framework for accelerating the discovery of targeted anticancer agents.
7 Apr 2026
Read appraisal →Journal of ethnopharmacology
Unveiling the genus Taraxacum: From folk medicine to chemodiversity-driven pharmacological and toxicological outcomes-A systematic review
ETHNOPHARMACOLOGICAL RELEVANCE: The genus Taraxacum (dandelion), belonging to the Asteraceae family, encompasses over 2800 species predominantly found in temperate to subtropical regions of the Northern Hemisphere. Dandelion has a long history as a functional food and traditional medicine in numerous countries, including China, Turkey, Spain, Italy, etc. Traditional application records indicate that dandelion might be used extensively to treat kidney stones, constipation, eczema, ulcers, inflammation, etc. However, the therapeutic application of different Taraxacum species varies significantly across regions, which may be influenced by local cultural and medical traditions. AIM OF THE REVIEW: This review provides a comprehensive summary of recent advancements in traditional applications, phytochemistry (highlighting 184 newly identified compounds), pharmacology, and toxicology, offering novel insights into both genus-wide characteristics of Taraxacum (covering 55 species) and species-specific differences. MATERIALS AND METHODS: A comprehensive search for relevant data was conducted using keywords such as "Taraxacum", "dandelion", "Taraxaci Herba", "pu gong ying", and others across multiple scientific databases, including Google Scholar, Web of Science, PubMed, ScienceDirect, Baidu Scholar, CNKI, online ethnobotanical databases, ethnobotanical monographs, The Plant List, Dictionary of Chinese Ethnic Medicine and considered data from 1972 to 2025. World Flora Online (http://www.worldfloraonline.org/) was utilized for confirming the correct species names of Taraxacum genus. The gathered information on the ethnobotanical usages, phytochemistry, pharmacology, and toxicology is comprehensively summarized in this paper. RESULTS: The literature review indicates that dandelion, a medicinal and edible plant, has been extensively utilized in traditional Chinese medicine since the 7th century. In Europe, its edible and medicinal properties began to be acknowledged and applied during the Middle Ages. In ethnomedical practice, dandelion has been used as diuretic, laxative, anti-inflammatory remedy, digestive aid, etc. Building on the 197 compounds reported from T. officinale, this review highlights over 180 newly identified compounds from 19 Taraxacum species, expanding the genus-wide catalog to more than 380 constituents. Recent toxicological and safety evaluations corroborate that T. officinale F.H.Wigg., T. mongolicum Hand.-Mazz., and T. lacistrum Sahlin possess a favorable safety profile. CONCLUSIONS: The genus Taraxacum is a promising medicinal and edible plant, exhibiting a range of biological activities, including anti-cancer, anti-inflammatory, and antioxidant effects. These properties align with its ethnobotanical usages, confirming its traditional use as diuretic, laxative, anti-inflammation, and digestive aid. However, research on its effects on neurodegenerative and cardiovascular diseases remains limited. Future studies should focus on in vivo experiments to explore the material basis and mechanisms underlying the therapeutic effects of dandelion species. Furthermore, current phytochemical and pharmacological research has overlooked several Taraxacum species with well-documented traditional uses. Investigating these understudied species is essential to fully elucidate the potential therapeutic value of the genus Taraxacum.
6 Apr 2026
Read appraisal →Journal of ethnopharmacology
Efficacy of Yuxintong capsule on cardiorespiratory fitness in patients with stable coronary heart disease: A multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial
ETHNOPHARMACOLOGICAL RELEVANCE: Yuxintong capsule, a traditional Chinese patent medicine, has been widely used in the treatment of coronary heart disease (CHD). However, whether it can improve cardiopulmonary fitness (CRF) in patients with CHD remains unclear. AIM OF THE STUDY: To evaluate the efficacy and safety of Yuxintong capsule in CRF in patients with stable CHD. MATERIALS AND METHODS: A multicentre, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in 13 hospitals in China from March 2021 to November 2021, and 404 patients with stable CHD were randomly assigned to receive either Yuxintong capsule and conventional Western medicine (Yuxintong group) or placebo and conventional Western medicine (placebo group) in a 1:1 ratio for 12 weeks (ChiCTR2000041293, December 23, 2020). The primary outcomes were peak oxygen uptake (VO2peak) and anaerobic threshold (AT). The secondary outcomes were metabolic equivalents (METs), duration and onset time of 1-mm ST-segment depression on electrocardiography (ECG), and 36-Item Short Form Health Survey (SF-36) scores. The main safety indicators included complete blood count, urinalysis, liver function, renal function, coagulation function, and 12-lead electrocardiogram. And adverse events were recorded throughout the trial. RESULTS: 369 patients, 187 in the Yuxintong group and 182 in the placebo group, were finally included for analysis. Compared with placebo group, 12-week treatment with Yuxintong showed an improvement in AT (0.98 ± 2.88 vs. 0.12 ± 2.79 mL kg-1·min-1; LSMD, 0.80 [95 % CI: 0.28 to 1.32]; P < 0.025), and general health (13.61 ± 15.13 vs. 8.29 ± 14.14; LSMD 5.30, [95 % CI: 2.33 to 8.31]; P < 0.05) and vitality scores (12.46 ± 11.32 vs. 6.01 ± 11.41; LSMD 6.43, [95 % CI: 4.13 to 8.31]; P < 0.05) on SF-36 scale. The other outcomes did not significantly differ between the two groups. The adverse events were similar between the two groups. CONCLUSIONS: Yuxintong capsule, as an adjunctive therapy to conventional treatment, improved AT, and general health and vitality scores on SF-36 scale in patients with stable CHD. However, the improvements in VO2peak, METs, and the duration and onset time of 1-mm ST-segment depression on ECG were not statistically significant.
6 Apr 2026
Read appraisal →Journal of ethnopharmacology
Efficacy and safety of Qiliqiangxin capsule as adjunctive therapy in heart failure with reduced ejection fraction: A systematic review and meta-analysis of randomized controlled trials
ETHNOPHARMACOLOGICAL RELEVANCE: The Qiliqiangxin (QLQX) capsule is a prominent traditional Chinese medicine formulation developed based on the collateral disease theory, specifically for the treatment of heart failure (HF). Its composition includes 11 medicinal botanicals, such as Huang Qi, Ren Shen, and Dan Shen, and is designed to tonify qi, activate blood circulation, and promote diuresis. Supported by over 20 years of extensive clinical application, modern pharmacological research, and stringent quality control, QLQX has been incorporated into the national heart failure guidelines in China. AIM OF THE STUDY: This study evaluates the efficacy and safety of QLQX as adjunctive therapy for heart failure with reduced ejection fraction (HFrEF). METHODS: We systematically searched seven databases until February 24, 2025, for randomized controlled trials (RCTs) evaluating QLQX in patients with HFrEF. Two independent researchers screened trials, extracted data, and assessed the risk of bias using the Cochrane RoB 2.0 tool. Meta-analyses were conducted for efficacy and safety outcomes, with evidence quality evaluated through the GRADE framework. RESULTS: Twenty-four RCTs (n = 5580) were included. Compared with conventional treatments (CTs) alone, QLQX adjunctive therapy significantly reduced the risk of cardiovascular death (RR = 0.82, 95 %CI [0.69, 0.96], P = 0.02), hospitalization for HF (RR = 0.78, 95 %CI [0.67, 0.91], P = 0.001), and composite cardiovascular events by 18 % (RR = 0.82, 95 %CI [0.73, 0.92], P = 0.0005), with evidence quality rated as moderate. QLQX significantly improved cardiac function parameters compared to controls: increased left ventricular ejection fraction (MD = 7.14, 95 % CI [6.75, 7.54], P < 0.05), reduced left ventricular end-diastolic diameter (MD = -5.25, 95 % CI [-5.75, -4.75], P < 0.05), improved NYHA class (RR = 1.19, 95 %CI [1.14, 1.25]), decreased NT-proBNP (SMD = -2.01, 95 %CI [-2.26, -1.95], P < 0.05), and increased 6-min walking distance (MD = 44.80, 95 %CI [42.37, 47.22], P < 0.05). CONCLUSION: QLQX adjunct therapy effectively reduces cardiovascular death and HF hospitalization while improving cardiac function in HFrEF, with favorable safety. Large-scale multicenter RCTs with extended follow-up are required to confirm long-term benefits and address existing study limitations.
6 Apr 2026
Read appraisal →Journal of ethnopharmacology
Evaluation of the association of pseudoaldosteronism with licorice-containing herbal medicine using the Japanese adverse drug event report (JADER) database
ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicine in Japan is known as Kampo preparation, a traditional medicine that combines multiple medicinal herbs and is widely used in medical practice. Pseudoaldosteronism is an issue associated with herbal medicines that contain licorice. However, the relationship between licorice intake and pseudoaldosteronism is not fully understood and is debatable. AIM OF THE STUDY: This study evaluates the association between herbal medicine preparations containing licorice and pseudoaldosteronism using data from the Japanese Adverse Drug Reaction Reporting System (JADER) database. MATERIALS AND METHODS: The JADER database contained 961,171 reports published between April 2004 and December 2024. The association between herbal medicines and pseudoaldosteronism was evaluated using the pharmacovigilance index as the reporting odds ratio (ROR) and logistic regression models. RESULTS: There were 537 cases of pseudoaldosteronism (PT code: 10037113). The reporting ratio of pseudoaldosteronism was higher in the licorice-containing herbal medicines group than in the overall herbal medicines group. The RORs of the top 20 herbal medicines with the highest number of pseudoaldosteronism reports, all of which contained licorice, exceeded one, and a signal was detected. The risk of pseudoaldosteronism increased with increasing licorice intake. According to the receiver operating characteristic (ROC) curve for pseudoaldosteronism (area under the curve (AUC) = 0.71, sensitivity = 0.8493, 1-specificity = 0.5530), the cutoff value was 1.125 g/day. CONCLUSIONS: This study is the first to clarify the association between licorice intake from herbal medicines and pseudoaldosteronism using Japan's spontaneous adverse event-reporting database. These findings will be useful and informative for medical professionals considering treatments with herbal medicines.
6 Apr 2026
Read appraisal →Journal of computer-aided molecular design
Identification of potential inhibitors of 3‑mercaptopyruvate sulfurtransferase with a deep-learning based screening of natural products
3-Mercaptopyruvate sulfurtransferase (3-MST), a key enzyme in sulfur metabolism, has recently gained attention as a potential anticancer target. However, reported 3-MST inhibitors remain limited, motivating the exploration of new scaffolds such as natural products. In this study, a library of 3744 natural products was virtually screened against human 3-MST using DiffDock (diffusion-model-based docking) followed by AutoDock Vina docking. Top-ranking candidates were further analyzed via molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area binding free energy calculations. Methylophiopogonanone A (4), Daphnoretin (5), and L-asarinin (9) exhibited stable binding with favorable energetics, displaying binding free energies comparable to the reference ligand 7NC301. Binding mode analyses revealed that Methylophiopogonanone A primarily engaged in hydrophobic interactions, whereas Daphnoretin and L-asarinin formed extensive polar contacts, accompanied by higher desolvation penalties. In vitro cytotoxicity assays showed that Methylophiopogonanone A and L-asarinin reduced HCT116 cell viability by 40.3% and 26.3% at 25 µM, which is consistent with their inhibitory of 3-MST with IC50 = 5.83 ± 0.69 µM and IC50 = 19.11 ± 3.37 µM, respectively. These results suggested that the natural products identified in this study represent promising scaffolds for further optimization as potential 3-MST inhibitors. This work provides an AI-guided natural-product screening workflow for 3-MST and delivers prioritized inhibitor scaffolds for subsequent optimization and experimental validation.
6 Apr 2026
Read appraisal →The pharmacogenomics journal
Economic effectiveness of pharmacogenomics-guided prescribing for psychiatric disorders: a systematic review and meta-analysis
Pharmacogenomics (PGx)-guided prescribing is a promising approach to reduce variability in drug response, although its cost-effectiveness remains uncertain. We performed a systematic review and meta-analysis evaluating the cost-effectiveness of PGx-guided prescribing compared to standard care in psychiatry. In January 2026, we searched MEDLINE, Embase and PsycINFO for studies published between 2014 and 2025. We included any peer-reviewed study that included adults with a diagnosed psychiatric disorder, comparing PGx-guided prescribing to standard care, and reported both quality-of-life and economic outcomes. Given the lack of consensus on synthesising economic evidence, both a narrative synthesis and meta-analysis were conducted. Pooled incremental net benefit (INB) was used as the effect measure for the meta-analysis and heterogeneity measures including the I2 test were used to assess heterogeneity and determine which model to use for the meta-analysis. From an initial 1 271 records, 17 studies were included. The narrative synthesis found that 88% of studies favoured PGx-guided prescribing. Meta-analyses produced positive, though non-significant, pooled Incremental Net Benefits (INBs) for the total study groups (£1 623.14, 95% CI: -£116.50 to £3 362.79, p = 0.07, I2 = 100%), and for a statistically homogeneous subgroup (£41.54, 95% CI: -£18.27 to £101.35, p = 0.17, I2 = 0%). Our review indicates that PGx-guided prescribing can be cost-effective in psychiatry but highlights the need for increased consensus in economic modelling methods.
5 Apr 2026
Read appraisal →Medicine
Adverse events associated with the use of nivolumab in the middle-aged and older population (>45 years): A pharmacovigilance analysis based on the FAERS database.
The clinical use of nivolumab has significantly improved the prognosis for survival in patients with a wide range of advanced malignancies. Given the increased incidence of tumors, there is a need to gain insight into the true extent of adverse events (AEs) associated with the nivolumab drug in the middle-aged and elderly population. This pharmacovigilance study was based on an analysis of reports from the US Food and Drug Administration's adverse event reporting system for the period January 1, 2014 to December 31, 2024, and compared AEs of the drug nivolumab in the middle-aged and elderly populations using proportional reporting ratio, reporting odds ratio, BCPN, and multi-item gamma Poisson shrinker methods. The analyses showed the presence of AEs in a variety of systems, mainly involving several systems such as endocrine disorders, nervous system disorders, skin and subcutaneous tissue disorders. The immune-related AEs listed in the package insert were validated by us and their clinical significance warrants careful consideration to further guide clinical dosing, adjust therapeutic decision-making, and develop age-adapted dosing algorithms for population pharmacokinetic development in order to minimize potential risks to patients. With the exception of reports of an unspecified nature, a greater proportion of the sample was male (65.7%) than female (32.5%), indicating significant variations. The highest percentage of reports was observed in patients aged between 65 and 85 years and in patients with a body mass index ranging from 50 to 100 kg/m2. The primary indication was non-small cell lung cancer. The top 3 AE signals reported with nivolumab were malignant neoplasm progression, death, and pyrexia, with the majority of AE cases occurring within the first month following nivolumab initiation.
5 Apr 2026
Read appraisal →PloS one
Real-world safety of aliskiren in primary hypertension: A cross-database study
Hypertension is one of the main causes of cardiovascular diseases worldwide, affecting over one billion people. Although aliskiren offers a valuable option for inhibiting the renin-angiotensin system, its safety profile in the real world remains insufficiently explored, especially for rare or under-recognized adverse events (AEs), which have not been fully clarified. Therefore, leveraging large-scale post-marketing surveillance data is crucial for identifying rare AEs and guiding safer clinical practice. This study aims to elucidate pharmacovigilance signals associated with aliskiren (an antihypertensive drug) by systematically analyzing the characteristics of adverse events (AEs) from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and WHO-VigiAccess database, which provides a reliable scientific basis for clinical practice and regulatory decision-making. We conducted a retrospective quantitative analysis of aliskiren-related AE reports from the aforementioned two databases, employing the Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms for signal detection. The results indicate that there were 5,596 and 5,549 aliskiren-related reports in the FAERS and WHO-VigiAccess databases, respectively. The median duration of these AEs during the observation period was 62 days, with an interquartile range (IQR) of 7-282 days. In both databases, signals for aliskiren were distributed across 28 System Organ Classes (SOCs), among which investigations, cardiac disorders, renal and urinary disorders, vascular disorders, and metabolism and nutrition disorders exhibited significant signals based on specific criteria applied across the four algorithms. A total of 607 preferred terms (PTs) with significant disproportionality signals were detected using the four algorithms, including potential AEs not previously well-documented, such as palpitations, myalgia, proteinuria, muscular weakness, pulmonary edema, and pollakiuria. This study not only confirms the known adverse reactions of aliskiren but also uncovers new potential risks, highlighting the importance of strengthening drug safety monitoring to enhance therapeutic efficacy and reduce the risk of adverse reactions. It provides valuable safety insights for physicians considering the use of aliskiren in the management of primary hypertension.
5 Apr 2026
Read appraisal →Medicine
Post-marketing signal detection of fruquintinib-associated adverse events using the FAERS database
Fruquintinib, a targeted therapeutic agent approved in 2018 for the treatment of metastatic colorectal cancer, is gradually being applied in an expanding range of clinical settings. Given the complexities associated with real-world dosing, a comprehensive evaluation of its safety profile is essential for optimizing clinical decision-making. We conducted a retrospective pharmacovigilance study utilizing a spontaneous reporting system. Reports related to Fruquintinib were extracted through a standardized data cleaning process and cross-validated using 3 complementary signal detection algorithms: proportional reporting ratio, Bayesian confidence propagation neural network, and reporting odds ratio (ROR). This approach was employed to systematically assess the drug's safety and identify potential adverse event signals. A total of 92 statistically significant safety signals were identified from 1188 independent cases included in the analysis, corresponding to 1836 adverse event reports. The signal distribution exhibited organ system specificity, with gastrointestinal reactions being the most prevalent category. These reactions primarily manifested as typical drug-related toxicities, including diarrhea and nausea. Other notable complications included neurological, respiratory, dermatological, renal, and cardiovascular events. Important aes not mentioned in the instructions, such as bone marrow suppression (ROR = 11.17), peripheral neuropathy (ROR = 4.24) and dehydration (ROR = 3.98), were also discovered. This study systematically characterizes the post-marketing safety profile of Fruquintinib through a multi-algorithm synergistic analysis, confirming that its safety profile aligns with the clinically expected outcomes based on its mechanism of action. Future research should focus on analyzing drug interaction mechanisms and exploring biomarkers to develop a precise risk-benefit assessment model.
5 Apr 2026
Read appraisal →Blood
Belantamab mafodotin, lenalidomide, and dexamethasone for intermediate-fit and frail patients with newly diagnosed myeloma.
The phase 1/2 BelaRd (belantamab mafodotin [belamaf], lenalidomide, and dexamethasone) study evaluated the efficacy and safety of belamaf combined with lenalidomide and dexamethasone in unfit and frail transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Part 1 (n = 36) established a recommended belamaf phase 2 dose (RP2D) of 1.9 mg/kg every 8 weeks (median follow-up, 39.3 months). In part 2, 30 patients were randomized 1:1 in group A (n = 15), where belamaf dosing was guided by ophthalmologist-assessed ocular adverse events (OAEs), whereas in group B (n = 15), belamaf dosing was based on hematologist-led vision-related anamnestic (VRA) tool and ophthalmologist-assessed grade ≥3 OAEs. Among the RP2D patients (n = 42), overall response rate was 97.6%, median progression-free survival (PFS)/overall survival have not been reached yet, and the 18-month PFS and time to progression rates were 83.0% and 97.2%, respectively. Ocular toxicities were similar between assessments by hematologists and ophthalmologists, and no ophthalmologist withholding of a hematologist-led dosing occurred. Less than 1% of patients stopped driving/reading because of OAEs. Median time to belamaf reinfusion was 13 weeks. Overall, BelaRd is an effective regimen for transplant-ineligible patients with NDMM and warrants a phase 3 study in this setting. OAEs' impact on quality of life appears limited, and implementation of the hematologist-led VRA tool may eventually reduce the necessity for ophthalmologist assessments. This trial was registered at www.clinicaltrials.gov as #NCT04808037.
5 Apr 2026
Read appraisal →Open heart
Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR): a randomised controlled trial
IMPORTANCE: Women with angina due to suspected ischaemia referred for coronary angiography often have no obstructive coronary artery disease (ANOCA/INOCA). OBJECTIVE: To determine if intensive medical treatment (IMT) reduces major ischaemic events (major adverse cardiovascular event, MACE) among women with suspected ANOCA/INOCA. DESIGN: Randomised, prospective, blinded-outcomes evaluation. SETTING: 71 sites in the USA. PARTICIPANTS: 2476 women with suspected ANOCA/INOCA. INTERVENTIONS: IMT-high intensity statin, ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) and aspirin versus usual care (UC). MAIN OUTCOMES AND MEASURES: Primary: all cause death, myocardial infarction, stroke/transient ischaemic attack, hospitalisation for angina or heart failure (MACE). Secondary: components of the primary, quality of life and win ratio. RESULTS: Recruitment was lower than planned (n=2476), yielding an aged population (mean, 64 years) with well-controlled blood pressure and low-density lipoprotein cholesterol at baseline, and relatively high rates of statin and ACEI/ARB use. At 2.5 years, 421 events occurred (221 in IMT, 200 in UC) with no difference in the primary outcome (HR=1.13 (95% CI 0.94 to 1.37) for IMT vs UC, p=0.20) or secondary outcomes. Hospitalisations for angina were the dominant contributor to MACE. Sensitivity analysis of contamination provided an estimated HR for IMT versus UC of 0.74 95% CI (0.352 to 1.558), p=0.43. CONCLUSIONS AND RELEVANCE: Among women with suspected ANOCA/INOCA, outcomes were dominated by chest pain and IMT did not improve outcomes, although limited power precludes concluding that it may not be helpful. The findings support the need for more investigation in this population with high burden of angina hospitalisation, health resource consumption and poor quality of life. TRIAL REGISTRATION NUMBER: NCT03417388.
4 Apr 2026
Read appraisal →The Cochrane database of systematic reviews
Pharmacotherapy for mild hypertension
RATIONALE: This is an update of a Cochrane review published in 2012 of initiation of antihypertensive monotherapy or step-up therapy in people with untreated mild hypertension (systolic blood pressure 140 to 159 mmHg or diastolic blood pressure 90 to 99 mmHg, or both) and no pre-existing cardiovascular disease. The original review demonstrated no difference in the incidence of all-cause mortality, total cardiovascular events (stroke, myocardial infarction, and congestive heart failure), stroke incidence, coronary heart disease, or withdrawal due to adverse effects (WDAEs). Evidence for antihypertensive pharmacotherapy in people with mild hypertension for primary prevention remains uncertain in the literature with conflicting studies. We therefore performed an update of the original Cochrane review to reassess whether initiation of antihypertensive pharmacotherapy compared to placebo or no treatment in people with untreated mild hypertension and no pre-existing cardiovascular disease reduces the risk of all-cause mortality, total cardiovascular events, stroke, coronary heart disease, or WDAEs. OBJECTIVES: To reassess the efficacy and risks of initiating antihypertensive pharmacotherapy in adults with untreated mild hypertension and no pre-existing cardiovascular disease. The primary objective was to reassess the risk of all-cause mortality and total cardiovascular events (defined as fatal and non-fatal strokes, myocardial infarction, and congestive heart failure). The secondary objectives were to reassess the risk of stroke (fatal and non-fatal), coronary heart disease (fatal and non-fatal myocardial infarction and sudden cardiac death), and WDAEs. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to June 2024. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) of at least one-year duration comparing initiation on antihypertensive monotherapy or step-up therapy, or both, versus placebo or no treatment in participants with mild hypertension and no pre-existing cardiovascular disease. OUTCOMES: Our critical outcomes were all-cause mortality and total cardiovascular events. Important outcomes were stroke, coronary heart disease (fatal and non-fatal myocardial infarction and sudden cardiac death), and WDAEs. RISK OF BIAS: Two review authors assessed risk of bias independently and in duplicate using Cochrane's RoB 1 tool. SYNTHESIS METHODS: Two review authors performed title and abstract screening, full-text review, and data extraction independently and in duplicate. We calculated risk ratio (RR) along with 95% confidence interval (CI) for all-cause mortality, total cardiovascular events, stroke events, coronary heart disease events, and WDAEs with the Mantel-Haenszel test and a fixed-effect model. We assessed the certainty of the evidence using the GRADE approach. INCLUDED STUDIES: We included individual patient data from five trials involving a total of 9124 participants, of whom 4593 received antihypertensives and 4531 received placebo or no treatment. All five trials reported all-cause mortality; four trials reported total cardiovascular events and strokes; three trials reported coronary heart disease; and one trial reported WDAEs. SYNTHESIS OF RESULTS: There may be little to no reduction in all-cause mortality (RR 0.85, 95% CI 0.64 to 1.14; 5 trials, 9124 participants; low-certainty evidence), total cardiovascular events (RR 0.93, 95% CI 0.69 to 1.24; 4 trials, 7292 participants; low-certainty evidence), or coronary heart disease (RR 1.12, 95% CI 0.80 to 1.57; 3 trials, 7080 participants; low-certainty evidence). There may be a decreased risk of stroke (RR 0.41, 95% CI 0.20 to 0.84; 4 trials, 7292 participants; low-certainty evidence) and an increase in WDAEs (RR 4.80, 95% CI 4.14 to 5.57; 1 trial, 17,354 participants [aggregate trial-level data; individual patient data unavailable]; low-certainty evidence) with antihypertensives. We downgraded the certainty of evidence for all outcomes due to imprecision, indirectness, and risk of bias. AUTHORS' CONCLUSIONS: In people with untreated mild hypertension and no pre-existing cardiovascular disease, initiation of antihypertensive monotherapy or step-up therapy may not reduce all-cause mortality, total cardiovascular events, or coronary heart disease compared to those who received placebo or no treatment. There may be a reduction in stroke, but possibly also an increase in WDAEs. FUNDING: CIHR Grant to the Hypertension Review Group and British Columbia Ministry of Health Grant to the Therapeutics Initiative. REGISTRATION: Protocol (2007): doi.org/10.1002/14651858.CD006742. Original review (2012): doi.org/10.1002/14651858.CD006742.pub2.
4 Apr 2026
Read appraisal →The New England journal of medicine
Discontinuation of Beta-Blocker Therapy after Myocardial Infarction
BACKGROUND: The role of long-term beta-blocker therapy after a myocardial infarction in patients without left ventricular systolic dysfunction or heart failure is unclear in the era of contemporary coronary-artery reperfusion and secondary prevention interventions. METHODS: We conducted an open-label, randomized, noninferiority trial at 25 centers in South Korea. Patients whose condition remained stable after a myocardial infarction, who had a left ventricular ejection fraction of at least 40% and no heart failure, and who had received beta-blocker therapy for at least 1 year after the myocardial infarction were randomly assigned in a 1:1 ratio to discontinue or to continue beta-blocker therapy. The primary end point was a composite of death from any cause, recurrent myocardial infarction, or hospitalization for heart failure. The prespecified noninferiority margin was an upper limit of the 95% confidence interval for the hazard ratio of 1.4. RESULTS: A total of 2540 patients underwent randomization; 1246 were assigned to beta-blocker discontinuation and 1294 to beta-blocker continuation. The mean age of the patients was 63.2 years, and 12.8% were women. At a median follow-up of 3.1 years (interquartile range, 2.5 to 3.5), a primary end-point event had occurred in 58 patients (4-year Kaplan-Meier estimate, 7.2%) in the discontinuation group and in 74 patients (4-year Kaplan-Meier estimate, 9.0%) in the continuation group (hazard ratio, 0.80; 95% confidence interval, 0.57 to 1.13; P = 0.001 for noninferiority). The incidence of serious adverse events was similar in the two groups. CONCLUSIONS: Among patients who received beta-blocker therapy beyond the first year after a myocardial infarction, discontinuation of beta-blocker therapy was noninferior to continuation with respect to a composite of death from any cause, recurrent myocardial infarction, or hospitalization for heart failure. (Funded by Patient-Centered Clinical Research Coordinating Center in the Ministry of Health and Welfare, South Korea; SMART-DECISION ClinicalTrials.gov number, NCT04769362.).
4 Apr 2026
Read appraisal →Pharmacology research & perspectives
Improving Population Pharmacokinetic Modelling with Artificial Patients using Generative Artificial Intelligence
In population pharmacokinetics (PopPK), non-linear mixed effects (NLME) models are used to simultaneously describe a drug's pharmacokinetics (PK) and dynamics (PD) in a patient population using systems of ordinary differential equations. In this field, machine learning is mainly used for data preparation, hypothesis generation, predictive modeling, and model validation. Some approaches to integrate artificially generated information have already been explored, but real-world application is still limited. We therefore conducted a proof-of-concept study to analyze the ability of generative artificial intelligence (AI) to create artificial patient profiles to augment PopPK data sets and assess their influence on parameter estimates. We defined the pharmacokinetic parameters of a hypothetical drug and simulated the concentration curves of 20 patients. We then trained Wasserstein Generative Adversarial Networks (WGANs) with gradient penalty (GP) to generate artificial patients. The data distribution of original and artificial patients was statistically indistinguishable as shown by the Maximum Mean Discrepancy test. Therefore, the WGAN-GP is neither overfitted, that is producing only single instances of artificial patients, nor underfitted, that is producing unrealistic artificial patients. We then combined different shares of original and artificial patients in separate data sets to build and compare PopPK model estimates. Addition of artificial patients led to narrower confidence intervals, indicating more robust parameter estimates, and accentuated the allometric effect of weight on the volume of distribution. In conclusion, we provide a proof-of-concept that generative AI can be used to augment pharmacokinetic data sets, with preliminary evidence suggesting improved parameter estimation.
4 Apr 2026
Read appraisal →International journal of medical informatics
Automated extraction of fluoropyrimidine treatment and treatment-related toxicities from clinical notes using natural language processing.
OBJECTIVE: Fluoropyrimidines are widely prescribed for colorectal and breast cancers, but are associated with toxicities such as hand-foot syndrome and cardiotoxicity. Since toxicity documentation is often embedded in clinical notes, we aimed to develop and evaluate natural language processing (NLP) methods to extract treatment and toxicity information. MATERIALS AND METHODS: We constructed a gold-standard dataset of 236 clinical notes from 204,165 adult oncology patients. Domain experts annotated categories related to treatment regimens and toxicities. We developed rule-based, machine learning-based (Random Forest [RF], Support Vector Machine [SVM], Logistic Regression [LR]), deep learning-based (BERT, ClinicalBERT), and large language models (LLM)-based NLP approaches (zero-shot and error analysis prompting). A 5-fold cross validation were conducted to validate each model. RESULTS: Error analysis prompting achieved optimal precision, recall, and F1 scores for treatment (F1 = 1.000) and toxicities extraction (F1 = 0.965), whereas zero-shot perform moderately (treatment F1 = 0.889, toxicities extraction F1 = 0.854) Rule-based reached F1 = 1.000 for treatment and F1 = 0.904 for toxicities extraction. LR and SVM ranked second and fourth for toxicities extraction (LR F1 = 0.914, SVM F1 = 0.903). Deep learning and RF underperformed, with performance of BERT reached F1 = 0.792 for treatment and F1 = 0.837 for toxicities extraction.,ClinicalBERT reached F1 = 0.797 for treatment and F1 = 0.884 for toxicities extraction). RF reached F1 = 0.745 for treatment and F1 = 0.853 for toxicities extraction. DISCUSSION: LMM-based error analysis outperformed all others, followed by machine learning methods. Machine learning and deep learning methods were limited by small training data and showed limited generalizability, particularly for rare categories. CONCLUSION: LLM-based error analysis most effectively extracted fluoropyrimidine treatment and toxicity information from clinical notes, and has strong potential to support oncology research and pharmacovigilance.
4 Apr 2026
Read appraisal →Heart rhythm
Machine learning-enabled assessment of risk of drug-induced QT prolongation at the time of prescribing
BACKGROUND: Many medications are associated with long QTc. Current long QTc predictors have limited generalizability and/or modest performance. OBJECTIVE: This study aimed to compare the performance of machine learning-enabled approaches to drug-induced long QTc prediction with current risk scores, including Tisdale and RISQ-PATH. METHODS: We identified patients who began QTc-prolonging medications (QTdrugs) and had follow-up 12-lead electrocardiograms (ECGs) within 1 year. Using 5-fold cross-validation, we trained XGBoost (XGB), an ECG-based deep neural network, and combined models using electronic health record data and ECG traces to predict QTc of ≥500 ms within 1 year. We assessed performance using the area under the receiver operating characteristic (AUROC) curves and compared them with corresponding Tisdale and RISQ-PATH scores. RESULTS: QTdrug records were identified for 345,371 patients, 5.7% of whom had long QTc within 1 year. In the subset with baseline ECGs available (N = 182,448; 7.7% events), both the XGB and deep neural network models demonstrated high performance (AUROC 0.869 and 0.864, respectively) but their combination yielded no significant improvement (AUROC 0.874). Therefore, focusing on the XGB model, we observed superior performance vs RISQ-PATH in the overall population (AUROC 0.859 vs 0.701), as well as Tisdale in predominantly inpatients (N = 110,558; 8.8% events; AUROC 0.855 vs 0.770). Positive predictive value was 61.5% vs 28.35% and 54.0% vs 28.3% at equivalent operating points for the XGB model vs RISQ-PATH and Tisdale, respectively. CONCLUSION: Development and retrospective validation of 3 machine learning-based models for predicting drug-induced long QTc at the time of new QTdrug starts demonstrated superior performance compared with current clinical risk calculators and may be useful tools to support medical decision making when initiating new therapies.
4 Apr 2026
Read appraisal →Ophthalmology
Special AAO Report: Recommendations on Screening for Hydroxychloroquine Retinopathy (2025 Revision)
BACKGROUND: The American Academy of Ophthalmology recommendations on screening for hydroxychloroquine (HCQ) retinopathy are now a decade old. This revision provides an update based on current knowledge. Major points and changes are as follows. NATURE OF TOXICITY: The retina typically remains clinically normal for many years on HCQ, but there is an unpredictable point at which signs of toxicity may develop. PATTERN OF TOXICITY: Most eyes of patients of European heritage have a parafoveal pattern of toxicity, whereas eyes of East Asian patients tend to present with pericentral toxicity, but there are many exceptions, and screening examinations should look for both patterns. DOSAGE: The recommended daily dosage remains unchanged at ≤5.0 mg/day/kg real weight. Keep under 400 mg/day for severely obese patients. RISK FACTORS: Beyond dose and duration, concurrent renal disease and tamoxifen use increase risk, as does initiation of HCQ therapy at an older age. CLINICAL TESTS: The primary screening tool should be OCT, along with wide-pattern fundus autofluorescence (FAF). Visual field (VF) and multifocal electroretinography (mfERG) are secondary confirmatory tests. Newer VF algorithms such as 24-2C can screen parafoveal and pericentral regions simultaneously. SCREENING: A baseline screening examination, including fundus, OCT, and FAF, is advised soon after HCQ is begun, not only to rule out preexisting conditions but also for comparison with later results. Annual screening with OCT and FAF is recommended while using HCQ, but may be deferred during the first 5 years if there are no significant risk factors. PROGRESSION: Mild retinopathy is unlikely to progress after discontinuation of HCQ, but severe retinopathy may continue to worsen for many years. IMPLICATIONS OF EARLY SIGNS OF TOXICITY: With earlier recognition comes greater need to communicate with patients and their medical providers regarding options to stop HCQ or continue with cautious monitoring. NEW TECHNOLOGY: There have been experimental advances in imaging and artificial intelligence analysis for HCQ screening, but none have been validated for general use or are widely available at this time. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
1 Apr 2026
Read appraisal →Science
Deep generative models design mRNA sequences with enhanced translational capacity and stability
Despite the success of messenger RNA (mRNA) COVID-19 vaccines, extending this modality to more diseases necessitates substantial enhancements. We present GEMORNA, a generative RNA model that uses transformer architectures tailored for mRNA coding sequences (CDSs) and untranslated regions (UTRs) to design mRNAs with enhanced expression and stability. GEMORNA-designed full-length mRNAs exhibited up to a 41-fold increase in firefly luciferase expression compared with an optimized benchmark in vitro. GEMORNA-generated therapeutic mRNAs achieved up to a 15-fold enhancement in human erythropoietin (EPO) expression and substantially elicited antibody titers of COVID vaccine in mice. Additionally, GEMORNA's versatility extends to circular RNA, substantially enhancing circular EPO expression and boosting antitumor cytotoxicity in chimeric antigen receptor T cells. These advancements highlight the vast potential of deep generative artificial intelligence for mRNA therapeutics.
1 Nov 2025
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