Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 14 appraisals
Gut and liver
Data-Informed Intuition in Hepatology: Integrating Evidence, Context, and Clinical Reasoning
Artificial intelligence and data-driven models are changing hepatology, but expert clinical judgment remains essential. Liver diseases are complex and evolve over time, requiring reasoning that links numerical data with clinical context. We propose data-informed intuition (DII), a conceptual framework bridging evidence-based medicine with clinical experience and reflective reasoning. Instead of presenting a validated prediction model, it proposes DII as an integrative scaffold for clinical reasoning that can be examined and revised. DII is viewed as a trainable skill that improves with data feedback, not mere guesswork. Clinicians continually calibrate their judgment as patient information accumulates. In hepatology, DII helps interpret disease trajectories, adapt predictive scores to context, and handle uncertainty in liver transplantation, hepatocellular carcinoma, acute liver failure, and related conditions. The DII framework describes eight axes (time, rate, magnitude, pattern, context, causality, integration, and uncertainty) that make visible how data and intuition interact in clinical reasoning. Integrating DII into fellowship training and artificial intelligence-assisted systems could nurture clinicians who combine algorithmic precision with human insight. This perspective summarizes the conceptual basis, clinical uses, and educational value of DII, and outlines both a research agenda for its empirical testing and a path toward data-informed professionalism in hepatology.
15 July 2026
Read appraisal →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 →Critical care explorations
Artificial Liver Support Effectively Removes Immunosuppressive Bile Acids From Circulation in Patients With Severe Liver Failure: A Proof of Concept Study
OBJECTIVE: Bile acids that induce immunosuppression through activation of the Takeda G protein-coupled receptor 5 (TGR5) have recently been identified in the circulation of patients with liver failure and sepsis. These bile acids are associated with increased susceptibility to infection and a high short-term mortality. Furthermore, TGR5 activation by bile acids has been implicated in the development of pruritus. However, therapies targeting TGR5-activating bile acids in patients have not yet been reported. This study investigates the effects of two artificial liver support systems, the Molecular Adsorbent Recirculating System (MARS) and the open albumin dialysis (OPAL). DESIGN: Proof of concept study, multicenter study. SETTING: University Hospital Jena, University Hospital Ulm, and University Hospital Münster, Germany. PATIENTS: Patients with severe liver failure, as defined by the Sequential Organ Failure Assessment hepatic sub-score (i.e., bilirubin > 12 mg/dL). INTERVENTIONS: Patients with severe liver failure were randomized to receive one session of MARS or OPAL for 8 hours, followed by crossover to the other treatment on the next day. MEASUREMENTS AND MAIN RESULTS: Bilirubin, circulating total and individual bile acids, albumin function, and TGR5 activation induced by circulating bile acids were assessed before and after each treatment session. Both OPAL and MARS significantly removed bilirubin, as well as individual and total bile acids from circulation. OPAL was superior to MARS in removing protein-bound lipophilic bile acids and restoring patients' albumin function (i.e., albumin-binding capacity, detoxification efficiency, and binding efficiency). TGR5 activation induced by circulating bile acids was reduced by 60% with OPAL compared with 39% with MARS (median values, p = 0.051). CONCLUSIONS: Artificial liver support systems effectively remove immunosuppressive bile acids from circulation. The clinical implications of bile acid reduction, however, require further study.
11 June 2026
Read appraisal →The New England journal of medicine
Stem-Cell-Derived Biologic Ventricular Assist Tissue in Heart Failure
BACKGROUND: Biologic ventricular assist tissue (BioVAT) is formulated from engineered heart muscle composed of cardiomyocytes and stromal cells derived from allogeneic induced pluripotent stem cells for cardiac remuscularization in patients with heart failure and a reduced left ventricular ejection fraction. METHODS: We conducted an open-label, phase 1-2 study of tissue-engineered heart repair by means of BioVAT transplantation. Patients with heart failure and a left ventricular ejection fraction of 35% or less and at least one hypokinetic or dyskinetic left ventricular segment were treated with BioVAT allografts, which consisted of 5, 10, or 20 engineered-heart-muscle units. All the patients received immunosuppression. Safety was assessed as adverse events related to the procedure. The primary efficacy end points were the change from baseline in the target heart-wall thickness, the left ventricular ejection fraction, and the Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS). RESULTS: A total of 20 patients were treated in the study. Three patients died during the study (1 each from vasoplegia, coronavirus disease 2019, and aortic dissection). One patient underwent heart transplantation. Immunosuppression was discontinued in 4 patients because of implantation of a left ventricular assist device (in 2 patients), renal failure (in 1 patient), and urothelial carcinoma (in 1 patient). Of the 16 patients who were treated with the safe maximal dose (20 engineered-heart-muscle units), 12 patients completed the prespecified 3-month interim follow-up. The least-squares mean increase in the target-wall thickness was 4.5 mm (90% confidence interval [CI], 3.7 to 5.4; P<0.001), the increase in the left ventricular ejection fraction was 3.9 percentage points (90% CI, 0.9 to 6.8; P = 0.04), and the increase in the KCCQ-OSS was 6.7 points (90% CI, 1.0 to 12.5; P = 0.06). All the patients had at least one adverse event. CONCLUSIONS: In this interim analysis, cardiac remuscularization with BioVAT was associated with an increase in the target heart-wall thickness, left ventricular ejection fraction, and KCCQ-OSS at 3 months; all the patients had at least one adverse event. Longer-term follow-up and further clinical investigation are warranted. (Funded by the German Center for Cardiovascular Research and Repairon; BioVAT-HF ClinicalTrials.gov number, NCT04396899.).
30 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 →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 →Circulation journal : official journal of the Japanese Circulation Society
Association of Lipid Core Burden Index With Early Progression of Cardiac Allograft Vasculopathy in Patients After Heart Transplantation
BACKGROUND: The association of the lipid-core burden index (LCBI), measured using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), with early progression of cardiac allograft vasculopathy remains unclear. METHODS AND RESULTS: We prospectively examined 12 consecutive heart transplant recipients who underwent NIRS-IVUS and IVUS. Patients were stratified according to the median maximum LCBI in a 4-mm segment (maxLCBI4 mm) of 223 at 1 month. The magnitude of maximal intimal thickness (MIT) progression was greater in the higher maxLCBI4 mmgroup. CONCLUSIONS: Patients with a higher maxLCBI4 mmat baseline exhibited greater MIT progression during the first post-transplant year.
26 May 2026
Read appraisal →Hepatology communications
Midodrine versus placebo in patients with acute-on-chronic liver failure with ascites-A randomized trial (MIDAS trial)
BACKGROUND: Ascites is common in patients with acute-on-chronic liver failure (ACLF) and can complicate the course of ACLF due to circulatory dysfunction and hemodynamic compromise. Oral midodrine has been variably reported to improve hemodynamics and reduce complications of ascites in patients with decompensated cirrhosis, but its role in patients with high MELD ACLF remains unknown, which we aimed to assess. METHODS: In this single-center, double-blind, randomized trial, patients with ACLF were assigned 1:1 to receive midodrine (5-7.5 mg tid) or a placebo for 30 days, alongside standard care. Transplant-free survival (TFS) at 1 month was the primary outcome, while secondary outcomes included TFS at 3 months, the proportion of patients achieving ascites control, changes in mean arterial pressure (MAP) and plasma renin activity at 1 month, the incidence of cirrhosis complications, and diuretic-related complications. RESULTS: One hundred thirty patients with ACLF were enrolled. Midodrine use was not associated with improvement in TFS at 1 (HR, 0.99 [95% CI: 0.37-2.65]) and 3 months (HR, 0.93 [95% CI: 0.48-1.8]). Ascites control at day 30 (placebo: 9.2% [95% CI: 3.5-19] vs. midodrine: 20% [95% CI: 12.3-33.5]; p=0.08) and 90 (placebo: 44.6% [95% CI: 32.2-57.5] vs. midodrine: 53.8% [95% CI: 41-66.3]; p=0.29) was comparable. Midodrine increased the MAP (1.9 vs. 6.9 mm Hg; p=0.003) with an insignificant reduction in plasma renin activity levels (delta change: 0.22±1.6 vs. -1.6±2.2; p=0.09). Cirrhosis-related and diuretic-related complications were similar in both groups. CONCLUSIONS: Midodrine increases MAP in patients with ACLF and high MELD scores without TFS benefit and does not reduce the rate of ascites-related complications.
25 May 2026
Read appraisal →Journal of medical Internet research
Human-AI Interaction in Kidney Transplant Decision Support Systems: Qualitative Study of Patient and Support Person Expectations
BACKGROUND: Artificial intelligence (AI) is increasingly applied in medicine, including clinical decision-making. AI-based decision support systems (DSS) can enhance early risk detection and treatment optimization. However, the perspectives of patients and their support persons on AI-assisted DSS in clinical care, particularly regarding shared decision-making (SDM), remain underexplored. OBJECTIVE: This study investigates the expectations, informational needs, and perceptions of patients who underwent kidney transplantation and their support persons regarding AI-assisted DSS and its influence on SDM in posttransplant care. METHODS: In a longitudinal qualitative study, 36 semistructured interviews were conducted with patients who underwent kidney transplantation and their support persons at a German kidney transplant center. Participants were asked about their views on AI's role in follow-up care, its impact on communication, trust, and decision-making, as well as their informational needs regarding AI-assisted DSS. Interviews were transcribed, pseudonymized, and analyzed using framework analysis. RESULTS: Participants recognized AI's potential to support clinicians by identifying risks of transplant loss, rejection, and infection, and by providing data-driven treatment recommendations. However, they emphasized that final decisions should remain with physicians. A majority of participants (n=28, 78%) expressed concern that AI might depersonalize care and diminish physician-patient communication due to a lack of "human touch." Participants demonstrated limited understanding of AI-based DSS functionality and highlighted the need for simple, accessible educational materials (eg, leaflets) explaining AI operations. While most doubted AI could replicate human empathy, some acknowledged that AI might be perceived as more attentive than time-pressured physicians, offering consistent monitoring and support. Participants consistently stressed that AI should augment, not replace, clinical decision-making. CONCLUSIONS: Patients who underwent kidney transplantation and support persons endorse the integration of AI in follow-up care when it enhances clinical decision-making without supplanting the physician's role. Acceptance and trust depend on transparency, accountability, and preserving the "human touch" in care. The development of educational tools to communicate AI functions and limitations is crucial to empower patients and support persons in SDM processes and to ensure AI complements, rather than undermines, patient-centered care.
23 May 2026
Read appraisal →Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Respiratory Syncytial Virus Vaccination in Solid Organ Transplant Recipients: Interim Findings From a Phase 3 Trial of mRNA-1345
BACKGROUND: Solid organ transplant (SOT) recipients are at increased risk for severe respiratory syncytial virus (RSV) disease due to chronic immunosuppression. METHODS: In this ongoing, open-label, phase 3 trial, adults ≥18 years with a history of liver, kidney, or lung transplant received 2 doses of mRNA-1345 RSV vaccine (50 µg) 56 days apart. Primary endpoints were tolerability, safety, and RSV-A/RSV-B neutralizing antibody (nAb) responses on Day 85; secondary endpoints included immunogenicity on Days 29 and 181. Cell-mediated immunity was an exploratory endpoint assessed in a subset of participants. RESULTS: 146/150 participants (median: age, 57 years; time since transplant, 4.7 years) received both doses. Reactogenicity was mild to moderate and transient. No vaccine-related discontinuations, deaths, adverse events of special interest (AESIs), or events of transplant rejection were reported within 28 days after any dose. One dose was immunogenic across all SOT types, with 4.9- and 3.4-fold increases in RSV-A/RSV-B nAb GMTs by Day 29, respectively. A second dose resulted in modest additional increases over baseline (RSV-A, 7.1-fold; RSV-B, 5.2-fold). Added benefit of the second dose was more apparent in participants with kidney and lung transplant, <2 years post-transplant, and on mycophenolate. Responses remained above baseline through Day 181. Polyfunctional CD4⁺ T-cell responses were robust and sustained; CD8⁺ responses were also observed. CONCLUSIONS: mRNA-1345 was well tolerated and immunogenic in SOT recipients. A single dose induced nAb responses across subgroups, with potential additional benefit from a second dose in specific groups. Durable antibody and cellular responses support mRNA-1345 as a preventive strategy for RSV in this vulnerable population. CLINICAL TRIALS REGISTRATION: NCT06067230.
22 May 2026
Read appraisal →Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
Modified Frailty Index-11 (mFI-11) measured frailty as a predictor of post-transplant outcomes in non-Hodgkin's lymphoma patients undergoing hematopoietic stem cell transplantation: a retrospective analysis of National Inpatient Sample database
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a critical treatment for non-Hodgkin lymphoma (NHL) but involves significant post-transplant risks. Frailty, measured by the Modified Frailty Index-11 (mFI-11), may influence outcomes. METHODS: We analyzed NHL patients undergoing autologous or allogeneic HSCT from the Nationwide Inpatient Sample (2016-2020). Frailty was defined by mFI-11, and outcomes included in-hospital mortality, unfavorable discharge, prolonged length of stay (LOS), complications, and costs. Multivariable regression models with stratification by age and Charlson Comorbidity Index were applied. RESULTS: Of 2807 patients (ages 18-85), frail patients were older and had more comorbidities. In autologous HSCT, frailty was linked to higher mortality (2.02% vs. 0.27%, p < 0.001), increased unfavorable discharges (19.75% vs. 10.80%, p < 0.0001), and prolonged LOS (15.92% vs. 7.75%, p < 0.0001). Similar trends were observed in the allogeneic cohort. CONCLUSIONS: Frailty predicts worse post-transplant outcomes in NHL patients undergoing HSCT, emphasizing the need for pre-transplant frailty screening.
10 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 →The Cochrane database of systematic reviews
Lung transplant in people with cystic fibrosis and nontuberculous mycobacteria infection
RATIONALE: Cystic fibrosis (CF) is an inherited multi-organ disorder. People with CF (pwCF) experience recurrent and chronic lung infections and a progressive loss of lung function. PwCF with poor and rapidly declining lung function may be considered for lung transplantation (LTx), which may improve their quality of life and survival. Nontuberculous mycobacteria (NTM) can cause pulmonary disease in pwCF, and NTM infection is a poor prognostic factor in LTx. Guidelines recommend NTM infection should not automatically preclude LTx. It is important to evaluate the evidence base for LTx in pwCF and NTM pulmonary disease. OBJECTIVES: To evaluate clinical outcomes in pwCF and with NTM infection (NTM infection alone or with NTM pulmonary disease) who undergo LTx by comparing: 1. pwCF with current NTM lung infection who undergo LTx versus those with NTM infection who do not undergo LTX; 2. pwCF with current NTM lung infection who undergo LTx versus those without NTM undergoing LTx. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, CENTRAL, MEDLINE, Embase, and PubMed as well as two ongoing trials registries. We checked references. The latest search date was 17 February 2026. ELIGIBILITY CRITERIA: We considered non-randomised studies of pwCF (any age) with or without NTM lung infection or disease being considered for LTx as well as studies of pwCF and NTM who either did or did not undergo LTx. OUTCOMES: Our critical outcomes were mortality, disseminated NTM infection post-LTx, time to chronic lung allograft dysfunction (CLAD), and quality of life at any time points reported. We additionally planned to report lung function, hospitalisations for pulmonary exacerbations, and nutritional parameters in the review. RISK OF BIAS: We assessed the risk of bias in three studies using ROBINS-I and in one study using the Joanna Briggs Institute checklist for case series. SYNTHESIS METHODS: We could only report results narratively. We used GRADE to assess the certainty of the evidence. INCLUDED STUDIES: We included four single-centre retrospective studies (388 adults). Sample sizes ranged from nine to 177 participants. Mycobacteria abscessus was the most common NTM species identified, and all studies reported infection with other pathogens. All studies compared pwCF and NTM infection to pwCF without NTM infection, all undergoing LTx. Each study reported mortality and disseminated NTM infection post-LTx; two studies recorded CLAD. No study reported quality of life, specific lung function measures (although one study commented briefly on lung function in general), hospitalisations for pulmonary exacerbations, or nutritional parameters. SYNTHESIS OF RESULTS: We analysed all NTM infections together for practical reasons and were not able to undertake a planned subgroup analysis by subspecies, but acknowledge that the prognosis and clinical trajectory of pwCF infected with different NTM may not be similar. We downgraded the certainty of the evidence due to non-randomised study design and serious risk of bias across all studies. We assessed all identified evidence as of very low certainty, such that lung transplant may have little to no effect on any of the outcomes listed below, but the evidence is very uncertain. Mortality Two studies (18 participants with NTM) reported similar survival data between NTM-positive LTx recipients and matched controls without NTM. Another study (9 participants) reported that two of five participants NTM-positive at LTx died within a few months post-LTx, whilst one of four NTM-negative participants died three years post-LTx due to chronic rejection. One study (177 participants) found that pwCF who had positive NTM cultures pre-LTx had a longer median survival duration than those who had negative cultures. This study additionally reported on survival of participants with post-LTx NTM infection, finding that the five participants who had post-LTx NTM disease had a longer mean survival duration than the 141 participants without post-LTx NTM disease. Disseminated NTM infection post-LTx In the largest study, of the 18 pwCF with NTM at the time of LTx, seven had at least one positive NTM culture, and four developed NTM disease post-LTx. Conversely, 79 of the 89 pwCF without NTM remained so post-LTx; 10 participants recorded a positive NTM culture, but none developed NTM disease. For the 39 participants without a baseline NTM culture, three participants recorded positive NTM cultures post-LTx, and one developed NTM disease. Of the remaining small studies, one reported that NTM was isolated in four of 13 participants at LTx and in three of these post-LTx. A second study reported that one out of five pwCF had NTM infection post-LTx (all were positive at LTx). The third study reported that five out of nine participants had NTM disease at LTx, and two of these five remained NTM-positive post-LTx. CLAD Two studies assessed CLAD. One study reported that none of the five NTM-positive LTx recipients developed CLAD, stating that the risk of CLAD appeared to be similar between the NTM and the comparator group. The second study stated that three out of nine LTx recipients with NTM disease developed chronic rejection or graft dysfunction. AUTHORS' CONCLUSIONS: There are no randomised trials to guide clinicians and patients or their families when making decisions regarding LTx in pwCF with NTM. The available data come from observational studies and registry data, often with few people with NTM reported. It has not been possible to pool the available data in meta-analysis, and we are very uncertain of the effect of NTM on pwCF undergoing LTx on the risk of developing NTM disease post-LTx, survival after LTx, and the development of CLAD. The studies were small and at times contradictory. In the era of highly effective modulator treatments, as some centres do not offer LTx to people with a history of NTM, there is an urgent need for more data to guide decision-making. FUNDING: This review is part of a suite of reviews on NTM funded jointly by the CF Foundation and the CF Trust. REGISTRATION: Protocol registration (2024): www.crd.york.ac.uk/PROSPERO/view/562682.
23 Apr 2026
Read appraisal →The European respiratory journal
A European multicentre, randomised controlled trial of pirfenidone in bronchiolitis obliterans syndrome after bilateral lung transplantation
BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a major obstacle to improving outcomes after lung transplantation. Bronchiolitis obliterans syndrome (BOS), characterised by progressive decline in forced expiratory volume in 1 s (FEV1) due to fibrotic scarring of the small airways, accounts for most CLAD cases. Pirfenidone, an antifibrotic agent used for idiopathic pulmonary fibrosis, was assessed for treating progressive BOS. METHODS: An investigator-initiated, international, multicentre, randomised, double-blind, placebo-controlled phase II trial was conducted in nine European lung transplant centres. Adults with bilateral lung transplants and progressive BOS were randomised (1:1) to receive pirfenidone 2403 mg·day-1 or placebo with standard care for 26 weeks. The primary end-point was change in FEV1 from baseline to week 26, with imputation for missing values. FINDINGS: From 1 May 2015 to 1 December 2019, 477 patients were screened, and 90 were randomised to pirfenidone (n=48) or placebo (n=42). Both groups showed continued decline in FEV1 from baseline to week 26, with no significant difference in intention to treat (ITT), ITT with imputation, or per-protocol analyses. Secondary end-points (graft loss, death, re-transplantation) were similar between groups. Treatment-related serious adverse events were distributed equally. INTERPRETATION: Pirfenidone did not show superiority over placebo and standard care in this exploratory trial. It cannot be recommended for treating BOS. Further research is needed to explore other treatments for CLAD to improve long-term outcomes after lung transplantation.
4 Apr 2026
Read appraisal →