Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 6 appraisals
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Clinical applications of artificial intelligence in autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder leading to kidney failure. Recent advancements in artificial intelligence (AI) are transforming the diagnosis, risk stratification, management and prognostication in ADPKD by enabling more accurate assessments and individualized care. AI-powered imaging tools enhance the measurement of total kidney volume (TKV), improving the precision and efficiency of monitoring disease progression and more reliable assessment of therapeutic response. Machine learning algorithms can integrate genetic, imaging and clinical data to predict kidney function decline, facilitating personalized treatment strategies. In addition, AI is being used to identify genetic variants and to refine genotype-phenotype relationships, offering deeper insights into disease variability. AI-enabled monitoring technologies can support longitudinal tracking of TKV measurements obtained through magnetic resonance imaging or computed tomography, thereby improving clinical decision-making and management. Furthermore, AI can optimize clinical trial design by improving patient selection, prediction of treatment responses and safety monitoring. Despite these promising developments, integrating AI into the clinical practice remains controversial and may pose several challenges. This review highlights the emerging clinical applications of AI in ADPKD, emphasizing its potential to advance precision medicine and improve patient outcomes.
1 July 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
Accurate identification of sickle cell disease cases in a large genotyped cohort using electronic health record data
The US Food and Drug Administration recently approved sickle cell disease (SCD) gene therapies that require a contemporaneous cohort to compare their outcomes with those of individuals who did not receive gene therapy. Previously, we developed an automated algorithm to create a contemporaneous cohort of children and adults with SCD using electronic health record data. We tested the hypothesis that the updated Vanderbilt University Medical Center (VUMC) algorithm can identify individuals with SCD with sensitivity and specificity of >95%. In the VUMC health care system, we identified a cohort of 33 141 adults and children of primarily African ancestry who underwent β-globin gene sequencing, with a 1.4% prevalence of SCD (473/33 141). For SCD, the performance of the VUMC algorithm using International Classification of Diseases (ICD) and laboratory data showed a sensitivity of 97.6% (462/473), specificity of 99.9% (32 663/32 668), positive predictive value of 98.9% (462/467), and negative predictive value of 99.9% (32 663/32 674). Three SCD phenotypes account for 98.5% of the individuals in the cohort. The cohort had sensitivities of 96.8% (272/281), 93.7% (136/145), and 85% (34/40) for hemoglobin SS (HbSS)/Hb Sβ0-thalassemia (HbSβ0), HbSC, and HbSβ+, respectively. The cohort had a specificity of 99.9% across all 3 phenotypes: HbSS/HbSβ0, HbSC, and HbSβ+, respectively. We have developed an updated algorithm using ICD and laboratory data that accurately identifies individuals with SCD within a large health care system, and distinguishes HbSS/HbSβ0, HbSC, and HbSβ+.
9 June 2026
Read appraisal →Journal of medical Internet research
Benchmarking Large Language Models and Prompt Engineering Strategies in Microsatellite Instability Cancers: Evaluation Study
BACKGROUND: The reliability of general-purpose large language models (LLMs) for complex clinical tasks in specialized domains such as microsatellite instability (MSI) cancers remains critically uncharacterized. The absence of a domain-specific benchmark to evaluate and guide the optimization of their capabilities across diverse clinical tasks poses unevaluated risks to patient safety. OBJECTIVE: This study aimed to develop and validate Microsatellite Instability Cancer Benchmark (MSIC-Bench), a novel, two-tiered benchmark for MSI cancer, covering both consensus and frontier knowledge. Using this framework, we aimed to systematically assess LLM performance across various prompting strategies, identify task-specific weaknesses, and reveal effective pathways for performance improvement. METHODS: We developed MSIC-Bench, a 511-question benchmark derived from clinical guidelines and a curated knowledge base. Three state-of-the-art LLMs (GPT-4o, [OpenAI], Gemini 2.5 Pro [Google], and Claude Opus 4 [Anthropic]) were evaluated using 4 prompting strategies, including vanilla, chain-of-thought, reflection of thoughts, and retrieval-augmented generation (RAG), under both multiple-choice and open-ended modalities. Performance was assessed on accuracy, safety (honesty), error composition, and token usage. RESULTS: LLMs demonstrated a significant "scaffolding effect," with accuracy dropping substantially in open-ended scenarios. For non-RAG strategies, the primary failure mode was an internal knowledge deficit. The integration of RAG proved to be the most effective intervention. A domain-aligned RAG strategy not only significantly improved accuracy in complex decision-making tasks but also fundamentally shifted the system's primary bottleneck from knowledge deficits to retrieval failures. In terms of safety, RAG induced a favorable shift from high-risk fabrications to safer refusals, though this introduced a safety-utility trade-off in the form of false refusals. Notably, our hybrid-RAG configuration, which combined both knowledge sources, demonstrated the most robust and generalizable performance across all tasks. CONCLUSIONS: Current LLMs lack the specialized knowledge required for reliable application in MSI oncology. A well-designed RAG architecture is the pivotal intervention to address this gap. However, its success is not automatic; it transforms the nature of system failure, making retrieval precision and knowledge base quality the new critical determinants of performance and safety. Our findings establish a clear directive for developing trustworthy clinical artificial intelligence: focus must shift toward optimizing the retrieval component and curating high-quality, comprehensive knowledge sources. MSIC-Bench provides a robust framework to guide these future efforts.
22 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 →Journal of neurology
Effect of exercise training on clinical and physiological variables in adults with myotonic dystrophy type 1: a systematic review and meta-analysis
Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disorder characterized by muscle weakness, fatigue, reduced endurance, and impaired quality of life. This systematic review and meta-analysis aimed to evaluate the effects of exercise training on clinical and physiological outcomes in adults with DM1. Six databases were searched for studies published between 2003 and 2023. Randomized controlled trials, quasi-experimental studies, and longitudinal cohort studies involving adults with DM1 undergoing aerobic or resistance training were included, and risk of bias was assessed. Meta-analyses used standardized mean differences with fixed- or random-effects models based on heterogeneity. Fourteen studies were included. Most studies demonstrated low risk of bias. Only one study reported any adverse events, and the incidence of these events was similar in occurrence between the intervention and standard care only groups. Meta-analysis demonstrated a moderate improvement in strength (p = 0.022). Endurance showed a large but non-significant pooled effect (p = 0.14). Meta-analyses for fatigue (p = 0.49) and sleep (p > 0.05) were inconclusive. Narrative synthesis indicated improvements in most clinical and physiological outcomes, while sleep outcomes showed minimal or inconsistent changes across studies. Exercise training appears safe and provides moderate benefits for strength and selected clinical and physiological outcomes in adults with DM1. Future well-powered trials with standardized protocols are needed to optimize exercise prescription.
12 Apr 2026
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