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Governing the AI–biotech convergence:The rapid progress in and the dual-use nature of biotechnology and AI requires adaptive and resilient regulatory frameworks to address potential risks
No full textA qualitative study among guideline developers revealed challenges and strategies for rare disease guideline development
No full textObjectives:Clinical practice guideline (CPG) development for rare diseases is challenging due to scarce evidence, small expert groups, limited resources, and heterogeneity and complexity of conditions. Critical appraisals of existing rare disease CPGs reveal variable methodological quality. We aimed to gather the experiences of rare disease guideline developers to identify methodological challenges and strategies and eventually inform methodological guidance for rare disease CPGs. Study Design and Setting:We conducted semistructured interviews with 15 guideline developers from ten countries and diverse medical fields with hands-on experience in rare disease CPG development. Data were analyzed through a combined deductive and inductive approach following the structure of the GIN-McMaster Guideline Development Checklist. Results:Small rare disease expert groups, while highly dedicated, faced significant risks related to conflicts of interest, limited methodological expertise, resource constraints, and challenges in achieving interest-holder representation. Guideline developers adopted pragmatic approaches to utilize scarce and very low-certainty direct evidence and supplement it with indirect and expert-based evidence, registry data, and mechanistic reasoning. The Grading of Recommendations Assessment, Development and Evaluation methodology was valued for providing transparency, structure, and consistency, but some considered it not feasible in rare disease contexts. Topics beyond the GIN-McMaster Guideline Development Checklist included deciding whether to develop a CPG or another type of quality document and supporting the broader knowledge cycle. Conclusion:We gained insight into the most salient methodological issues and identified a need for further guidance and method development to improve guideline development processes for rare diseases.</p
Artificial intelligence and spillover prediction:aligning innovation with empirical reality in One Health surveillance – Authors' reply
No full textInfluenza A(H5N8) vaccine induces humoral and cell-mediated immunity against highly pathogenic avian influenza clade 2.3.4.4b A(H5N1) viruses in at-risk individuals
No full textFinland faced an outbreak of highly pathogenic clade 2.3.4.4b A(H5N1) avian influenza in 2023, which spread from wild birds to fur farms. Vaccinations of at-risk individuals began in June 2024 using the MF59-adjuvanted inactivated A(H5N8) vaccine (Seqirus; A/Astrakhan/3212/2020, clade 2.3.4.4b). Here, in an observational study, we assessed vaccine-induced immune responses in occupational at-risk individuals participating in the phase IV trial, including virus-specific antibody (n = 39 individuals) and T-cell (n = 18 individuals) responses. Vaccination elicited functional antibodies against the vaccine virus and two heterologous clade 2.3.4.4b strains associated with outbreaks on Finnish fur farms and dairy cattle in the United States. Among previously unvaccinated individuals, seroprotection rates against the vaccine virus were 83% (95% CI 70–97%) by microneutralization assay (titre ≥20) and 97% (90–100%) by haemagglutination inhibition assay (titre ≥40). In those previously vaccinated against avian influenza, a single dose induced seroprotection. A(H5N8)-specific memory CD4+ T-cell responses were detectable, with ~5-fold increase in IFNγ secretion after two doses. These results demonstrate that the vaccine probably provides cross-protection against circulating H5 clade 2.3.4.4b viruses. EU Clinical Trial Number 2023-509178-44-00.</p
DAPAgliflozin for renal protection in heart transplant recipients. Rationale and design of the randomized controlled DAPARHT trial
No full textBackground and aims: Heart transplantation is the preferred treatment for selected patients with end stage heart failure. Kidney function often declines after heart transplantation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) slow the decline in eGFR in different populations. However, the effect of SGLT2i on kidney function in heart transplant recipients is unknown. Methods: The Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT) trial is an investigator initiated, double blind, randomized, placebo-controlled trial designed to assess dapagliflozin's effect on kidney function in heart transplant recipients. Adults heart transplanted at least one year prior to randomization are eligible. Exclusion criteria include an estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m2, diabetes type I, and contraindication to study medication. Four hundred and thirty patients will be randomized 1:1 to receive 12 months blinded treatment with dapagliflozin 10 mg o.d. or placebo, followed by 24-months open-label treatment. The primary endpoint is the chronic slope of the eGFR from two weeks to 12 months after starting randomized treatment. The open-label phase evaluates dapagliflozin's long-term effects on kidney function, clinical outcomes, safety, and tolerability. Enrolment began in June 2022. As of December 18, 2024, 300 patients were enrolled. The mean baseline creatinine was 104 ± 28 µmol/L with corresponding eGFR of 66 ± 22 mL/min/1.73 m2. Estimated last patient visit is in September, 2028. Conclusion: The DAPARHT trial will test whether dapagliflozin improves eGFR slope compared to placebo during one year of follow-up, providing the first randomized evidence of the efficacy of SGLT2i in heart transplant recipients.Trial Registration: Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT), NCT05321706, clinicaltrials.gov.</p
Reduction of bowel loop motion during radiotherapy for gynaecological cancer assessed by 3D cine-MRI
No full textIntroduction: Gastrointestinal toxicity is a major concern after radiotherapy for gynaecologic cancer. Strong dose–effect relationships for the bowel and individual loops are lacking, which might be explained by challenges in accurate radiation dose estimation due to continuous motion of the bowel loops. The objective of this study was to evaluate whether changes in bowel loop motion occur over the course of radiotherapy, with the use of three-dimensional (3D) cine-MRI. Methods and Materials: This study prospectively enrolled patients with gynaecologic cancer undergoing primary radiotherapy with curative intent. To measure bowel loop motion, three 3D cine-MRI scans were acquired: before external beam radiotherapy (EBRT), in the last week of EBRT, and on the day of brachytherapy. A MR image was acquired every 3.7 s during a 10-minute scan. Deformable image registration was used to generate a motion map and a motion volume histogram. Changes in bowel loop motion over the course of treatment were assessed by the Wilcoxon signed-rank test using the median bowel loop motion in millimetres per 3.7 s of 50% of all voxels. Results: For 15 of the 22 patients, 3D cine-MR scans were available at all three time points. Median bowel loop motion per 3.7 s was 1.8 mm (range 0.6–3.3 mm) before EBRT, 1.0 mm (range 0.6–2.3 mm) in the last week of EBRT, and 0.7 mm (range 0.4–1.1 mm) at brachytherapy. Most patients (14 out of 15) showed reduced bowel loop motion in the last week of EBRT compared to the first MR, with the lowest motion at brachytherapy in 13 patients (87 %). Median bowel loop motion decreased significantly with each subsequent MRI scan (p = 0.005 and p = 0.020, respectively). Conclusions: The results of this study demonstrate a statistically significant decrease in bowel loop motion over the course of primary radiotherapy for gynaecological cancer.</p
Variant selection to maximize variance explained in cis-Mendelian randomization
No full textOptimal selection of instrumental variables (IVs) from a single gene region in cis-Mendelian randomization is challenging as variants are highly correlated due to linkage disequilibrium (LD). Using only the lead variant is convenient but may not achieve full statistical power if multiple signals exist. We compared four selection methods that incorporate correlated non-lead variants, including LD-pruning, conditional and joint analysis (COJO), Sum of Single Effects (SuSiE) regression, and principal component analysis (PCA), and evaluated their ability to increase instrument strength, measured by variance explained in the exposure (R2), relative to the lead-variant-only approach. We applied these methods to circulating haptoglobin (HP), to simulated traits with known variance explained, and to 15 additional gene regions where non-lead cis-pQTLs contributed varying proportions of cis-genetic variance. R2 was estimated from variant-protein association estimates (Fenland study, N=10,708) using LD from the UK Biobank (N=356,557). In the HP region, the four methods produced a median proportional gain in R2 of 145.1% compared with the lead variant alone (range: 69.6% - 169.4%), with a median reduction in the MR standard error of 36.3% (range: -37.9% to -19.3%). In simulations, all methods were able to recover the expected genetic variance. Across the 15 gene regions, methods incorporating non-lead variants consistently outperformed the lead-variant-only approach. Variant selection methods incorporating correlated non-lead variants can reliably improve instrument strength in cis-MR analyses. We recommend using such methods but advise comparing their estimates with the lead-variant-only estimate to safeguard against numerical instability.<br/
Comparing different retrieval practice strategies using virtual patients:A stratified randomized trial
No full textObjectivesThis study evaluated the effectiveness of three retrieval practice strategies: re-solving virtual patient (VP) cases, answering multiple-choice questions (MCQs), and answering short answer questions (SAQs), on long-term memory retention of medical students using a VP simulation platform.MethodsEighty fifth-year medical students participated in a stratified randomized trial conducted in three phases. In the initial learning phase, participants completed a 14-item baseline test (seven MCQs and seven SAQs) to assess prior knowledge and enable stratified randomization. They then engaged with two clinical cases using the Paciente 360 (R) VP platform. One week later, participants were randomly assigned to one of three retrieval practice conditions: re-solving the original VP cases, answering 24 related MCQs, or answering 24 related SAQs. Six weeks after the intervention, participants completed a 40-item retention test (20 MCQs and 20 SAQs), which included both previously encountered and novel questions to assess long-term retention and transfer of learning.ResultsParticipants in the SAQ condition demonstrated a statistically significant improvement in performance over time, while those in the re-solving the virtual case and MCQ conditions maintained their knowledge levels. No significant differences were observed between performance on repeated versus novel questions or between MCQs and SAQs.ConclusionsRetrieval practice using VP simulations supports knowledge retention, with SAQs yielding the greatest improvement from baseline. Comparable performance on repeated and novel questions suggests that retrieval practice may also promote transfer of learning to new clinical scenarios
Osteoarthritis year in review 2025:Rehabilitation and outcomes including sex and gender reporting
No full textThis year in review (1) narratively synthesises the effect of, or patient experience with, non-pharmacological or non-surgical rehabilitation treatments for osteoarthritis at any joint; and (2) describes how sex and/or gender are defined, reported, and analysed. We searched three databases (Medline, Embase, CINAHL) for studies that met predefined criteria and selected those of perceived moderate-to-high quality and importance published between 12th March 2024 and 1st March 2025. Studies were grouped according to predominant treatment topic areas (e.g. core [exercise, diet]; adjunct [electrotherapy, manual therapy]; multimodal [different rehabilitation treatments]). Two authors independently screened records. One author extracted data, and another checked 10% of the accuracy. Full-text screening identified 158 eligible studies, reduced to 39 for synthesis. We identified eight themes: i) Exercise is effective for knee osteoarthritis and comorbidities, but has varied effects for hip osteoarthritis; ii) Diet plus exercise is effective for weight loss, but may not reduce pain; iii) Digital rehabilitation is a viable alternative to in-person care; iv) No added benefit of mind/behavioural treatments; v) Effects of electrotherapy modalities on pain were inconsistent and region-specific; vi) Orthoses may relieve pain, but should be individualised to patient preferences; vii) Acupuncture and blood flow restriction treatment show effectiveness in single clinical trials; viii) Treatment packages for osteoarthritis have varied benefits. Sex and gender were reported in 23 and 11 studies, respectively. For gender, most studies used female/male/woman/man interchangeably. No study defined sex or gender, 5% reported results disaggregated by sex or gender, no study justified why results were not, and 5% summarised key sex or gender findings.</p
Progression of structural lung disease and lung function in adolescents with cystic fibrosis
No full textBackground Cystic fibrosis (CF) lung disease begins early in life and progresses throughout childhood into adolescence. Children completing the Australasian CF Bronchoalveolar Lavage (ACFBAL) trial were followed longitudinally (CF-FAB study) to determine progression of CF lung disease during adolescence using visual and automatic methods and to correlate CT-derived metrics with spirometry outcomes. Methods CTs from start and end visits of CF-FAB (mean 24 [SD 12] months apart) were analysed using visual PRAGMA-CF scoring and automatic bronchus-artery (BA) analysis. PRAGMA-CF assessed %Disease by summing %Bronchiectasis, %Mucus plugging, % Airway wall thickening on inspiratory scans and %Trapped air on expiratory scans. The BA-analysis segments the bronchial tree, identifies segmental bronchi (G0) and distal generations (G1, G2, G3…), measures diameters of bronchial outer wall (Bout), inner wall (Bin), wall thickness (Bwt), and artery (A), and computes BA-ratios (Bout/A, Bin/A, Bwt/A, Bwa/Boa[=bronchial wall area/bronchial outer area]) to evaluate bronchial dilatation and wall thickening. Results 120 children (median age 13 years, IQR 11.4-14) contributed 115 start and 105 end scans. Eleven children were treated with CFTR modulators prior to the start of the study and four received the treatment during the study. Progression was found in PRAGMA-CF %Bronchiectasis (p=0.02) and %Mucus plugging (p=0.02), and Bout/A (p=0.01), Bwt/A (p<0.001), and Bwa/Boa (p<0.001). Spirometry outcomes showed no significant decline. BA-metrics correlated more strongly with spirometry outcomes than PRAGMA-CF scores. Conclusion Heterogeneous progression of structural lung disease in children with CF during adolescence was detected using visual PRAGMA-CF scores and automatic BA-analysis. Spirometry outcomes showed no significant decline.</p