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Characteristics of post-exercise responders versus non-responders following aerobic or isometric exercise in physically inactive adults of African and South Asian descent with high-normal blood pressure or grade I hypertension.

OBJECTIVE: To investigate interindividual variability in post-exercise hypotension (PEH) and to characterise cardiovascular and autonomic differences between responders and non-responders following aerobic and isometric exercise in adults of African and South Asian descent with elevated blood pressure (BP). METHODS: Physically inactive adults of African and South Asian descent living in Suriname (18-65 years) with high-normal BP or grade I hypertension participated in a randomised controlled crossover trial. In this randomised cross-over trial, 47 adults (50.1 ± 10.8 years; 38% male) with high-normal blood pressure or grade I hypertension completed three conditions: aerobic exercise (30 min at 40-60% heart rate reserve), isometric handgrip exercise, and a non-exercise control. Ambulatory BP was assessed over 24 h. PEH was defined as the net effect: (post-exercise - pre-exercise) - (post-control - pre-control). Participants were classified as responders if daytime BP decreased ≥5 mmHg. Arterial stiffness, cardiac, and autonomic parameters were assessed. RESULTS: Following aerobic exercise, 46% of participants were classified as systolic responders compared with 28% after isometric exercise. No baseline differences were observed in demographic or clinical characteristics between responders and non-responders, suggesting that PEH variability may reflect underlying physiological rather than clinical differences. Aerobic responders demonstrated greater reductions in aortic augmentation index (-19.4% vs. -10.9%, p = 0.05), larger increases in stroke volume (+8.1 vs. -5.3 mL, p = 0.05) and cardiac output (+1.54 ± 1.89 vs. +0.58 ± 1.60 L/min, p = 0.009), and more favourable autonomic recovery. Among all variables, only the change in cardiac output was associated with PEH magnitude (r = -0.46, p = 0.006). No consistent physiological differences were observed following isometric exercise. CONCLUSION: PEH following aerobic exercise is characterised by a distinct responder phenotype associated with greater reductions in aortic augmentation index and favourable cardiac adaptations. These findings highlight substantial interindividual variability in BP responses and support the need for individualised exercise strategies in hypertension management.

Adolescent

A User-Friendly Protocol for Microinjection into Teleost Embryos to Study Gene Function.

Zebrafish (Danio rerio) and medaka (Oryzias latipes) are popular teleost models used in developmental biology and functional genomics. To achieve high-quality and reproducible microinjections, it is essential to have robust protocols for breeding, egg collection, and the precise delivery of genetic material. In this protocol, we present a comprehensive and optimized methodology for setting up breeding tanks under controlled photoperiod conditions to maximize egg yield while minimizing contamination. We provide detailed procedures for sex identification, pair selection, the use of grated breeding inserts, and methods to increase egg collection efficiency. We outline procedures for making injection gel beds, pulling needles, and calibration using one-microliter microcapillaries to achieve consistent nanoliter-scale injections. Our protocol outlines settings for the pico-liter injector that are optimized to deliver a precise amount per pulse with minimal variability. Finally, we demonstrate the application of these methods for gene knockdown using morpholino antisense oligonucleotides, gene knockout using CRISPR-Cas9, and gain-of-function mRNA overexpression experiments. Phenotypic assessments conducted at various developmental stages to evaluate gene-specific effects reveal consistent phenotypic outcomes between the morpholino and CRISPR-Cas9 approaches. This easy and comprehensive protocol enables efficient, precise, and scalable genetic manipulation of zebrafish and medaka embryos, thereby supporting advanced functional studies in developmental biology and disease modeling. To our knowledge, this is the first unified protocol for both zebrafish and medaka microinjection systems achieving 97.7% phenotype penetrance in CRISPR-Cas9 knockouts with precision together with a triple validation approach that confirms gene function across multiple techniques.

Animals

Extended Venous Thromboembolism Prophylaxis After One-Anastomosis Gastric Bypass: A Three-Arm Randomized Trial of Enoxaparin Duration and Rivaroxaban.

BACKGROUND: Venous thromboembolism (VTE) is a serious but preventable complication after bariatric surgery, most of them after hospital discharge. The optimal regimen and duration of post-discharge prophylaxis, particularly the role of direct oral anticoagulants, remain uncertain. OBJECTIVES: To estimate 30-day VTE and bleeding event rates in high-risk patients undergoing one-anastomosis gastric bypass who received 15-day enoxaparin, 30-day enoxaparin, or 30-day rivaroxaban prophylaxis, and to perform exploratory comparisons among the regimens. METHODS: In this randomized, open-label, three-arm clinical trial, high-risk adults undergoing laparoscopic OAGB were randomized before discharge (1:1:1) to enoxaparin 40 mg subcutaneously twice daily for 15 days, enoxaparin 40 mg twice daily for 30 days, or rivaroxaban 10 mg orally once daily for 30 days, after standardized in-hospital enoxaparin and early ambulation. Participants underwent clinical assessment and duplex ultrasonography of the lower-limb and porto-mesenteric veins on postoperative days 15 and 30. The primary outcome was objectively confirmed VTE within 30 days. Bleeding was classified as International Society on Thrombosis and Haemostasis (ISTH) major bleeding or clinically relevant non-major bleeding (CRNMB). Because the expected event rate was low and no non-inferiority or equivalence margin was prespecified, comparisons were interpreted as exploratory. RESULTS: A total of 288 patients were randomized to 15-day enoxaparin (n = 97), 30-day enoxaparin (n = 97), or 30-day rivaroxaban (n = 94). One symptomatic lower-limb deep vein thrombosis occurred in the 15-day enoxaparin group (1.0%; 95% CI, 0.03%-5.6%); no VTE events occurred in the 30-day enoxaparin group (0%; 95% CI, 0%-3.7%) or the rivaroxaban group (0%; 95% CI, 0%-3.8%). Total bleeding occurred in 4/97 patients (4.1%) in each enoxaparin group and 8/94 patients (8.5%) in the rivaroxaban group. The absolute difference in total bleeding between rivaroxaban and 30-day enoxaparin was 4.4% points (95% CI, - 2.9 to 12.2), indicating substantial imprecision. No porto-mesenteric venous thrombosis was detected. CONCLUSION: Only one VTE event occurred, precluding reliable conclusions regarding comparative efficacy or prophylaxis duration. Bleeding estimates were also imprecise and do not establish comparative safety or equivalence between rivaroxaban and enoxaparin. The trial adds descriptive event-rate data from a standardized OAGB pathway, but larger multicenter studies with prespecified comparative hypotheses and assessment of adherence, oral tolerance, and drug exposure are required. The study was approved by the Research Ethics Committee and registered at ClinicalTrials.gov.

Humans

Treating neurogenic detrusor overactivity in order to manage autonomic dysreflexia - A systematic review.

INTRODUCTION: Autonomic dysreflexia (AD) is a severe and potentially life-threatening complication of a spinal cord injury (SCI), particularly in patients with lesions at or above the sixth thoracic level. Neurogenic detrusor overactivity (NDO) is one of the main triggering factors. The impact of NDO treatment on AD remains insufficiently clarified. METHODS: We conducted a systematic review of the literature in PubMed and Cochrane Database between January 1990 and May 2025. Eligible studies included patients with SCI and AD undergoing treatment for NDO, including antimuscarinics, botulinum toxin (BTX) or augmentation cystoplasty. The primary outcome was the assessment of systolic blood pressure (SBP) parameters in patients undergoing cystomanometry. RESULTS: Of the thirteen eligible studies, only five were included. No study evaluated augmentation cystoplasty. One study (12 patients) evaluating fesoterodine and four studies (95 patients) evaluating BTX injection demonstrated improved urodynamic parameters and a decrease in severity of AD during urodynamic studies and in daily life. Improvements in AD-HR-QoL and I-QoL scores were also demonstrated. DISCUSSION: Controlling NDO with fesoterodine or BTX injection reduces the prevalence and severity of AD, likely by limiting abnormal C-fiber recruitment and reducing neurogenic inflammation. BTX additionally modulates TRPV1-expressing afferents, which further reduces AD risk. Although hypertensive peaks improve, submaximal parameters remain unchanged, highlighting the need for additional complementary strategies. CONCLUSION: The use of BTX and fesoterodine for NDO treatment effectively reduces AD episodes in patients with SCI. Further long-term studies are needed to confirm the cardiovascular benefits and inform future therapeutic strategies.

Humans

Risk of mortality and complications in people with depressive disorder and co-occurring diabetes mellitus: a systematic review and meta-analysis.

AIMS: People with depressive disorder have increased premature mortality and higher rates of diabetes mellitus than general population. Evidence shows that diabetes may further increase their risk of premature death from diabetes-related complications, especially cardiovascular diseases (CVDs). Earlier studies examining depression-associated outcomes in diabetes patients have shown mixed results and were hindered by important limitations, especially the use of self-reported questionnaires to ascertain depression, causing misclassification bias by identifying subclinical symptoms or diabetes distress. Associations of depression with specific diabetes complications have not been systematically evaluated. This meta-analysis aimed to investigate the risk of mortality and complications among patients with depression and co-occurring diabetes (depression-diabetes group) relative to patients with diabetes-only (diabetes-only group), on their all-cause mortality rates, and if applicable cause-specific mortality rates, and occurrence of specific diabetes complications. METHODS: We systematically reviewed and quantitatively synthesized diabetes-related outcomes in patients with depression by searching Embase, MEDLINE, PsycInfo and Web-of-Science from inception to 20 December 2024, and included studies that examined mortality and complication outcomes in depression-diabetes group relative to diabetes-only group. Results were synthesized by random-effects meta-analytic models, with stratified-analyses (subgroup analyses and meta-regression) by study-level characteristics, including age, gender, study period, geographic region, follow-up duration and nature of diabetes sample. The study was registered with PROSPERO (CRD42024595145). RESULTS: Twenty-six studies were identified from nine geographic regions. Regarding mortality risk, depression-diabetes group exhibited increased risks of all-cause mortality (RR = 1.30 [95% CI: 1.21-1.39]) and CVD-specific mortality (1.15 [1.02-1.29]) relative to diabetes-only group. Regarding complication risk, depression-diabetes group showed increased risk of complications (1.28 [1.18-1.40]) relative to diabetes-only group, especially in incident-diabetes sample signifying advanced disease stage upon presentation, with stratified-analyses showing higher risk of metabolic complications (1.63 [1.33-1.99]) and cardiovascular complications (1.20 [1.11-1.29]), and lower likelihood of retinopathy (0.84 [0.76-0.94]), albeit comparable rates of cerebrovascular complications (1.36 [0.99-1.87]), nephropathy (1.09 [0.93-1.27]) and peripheral-vascular complications (0.97 [0.79-1.18]). Both overall mortality and complication risks were present in various regions and persisted over time. Heterogeneities were noted and could not be entirely explained by stratified analyses. CONCLUSIONS: Our study demonstrated that patients with depression and co-occurring diabetes were associated with elevated overall mortality risk and complication risk (particularly metabolic and cardiovascular-complications) than non-depressed counterparts, suggesting an overall poorer glycemic control that might eventually drive their earlier death. Comprehensive and multipronged interventions are needed for individualized risk estimation of diabetes-related outcomes, with consequent early interventions to minimize the avoidable physical morbidity and premature mortality in this vulnerable population.

Humans

Efficacy, tolerability, and threshold effect of atropine eye drops for myopia control: A systematic review and dose-response meta-analysis.

Atropine is an emerging therapy for myopia, yet the optimal concentration for prescription remains uncertain. We searched PubMed, Embase, Web of Science, Cochrane Library, World Health Organization International Clinical Trials, and ClinicalTrials.gov registry platforms. We included the randomized clinical trials (RCTs) that compared any dose of atropine against a placebo in myopic children. Among 3566 studies assessed, we identified 33 eligible RCTs involving 6301 children aged 4-18 years, with 10 different concentrations and a mean follow-up time of 19.5&#x202f;&#xb1;&#x202f;12.3 months. A nonlinear relationship was observed between atropine dosage and treatment efficacy (P&#x202f;<&#x202f;0.001). Compared to placebo groups, the mean differences in reducing annual spherical equivalent refraction progression for atropine concentrations of 0.01%, 0.02%, 0.03%, 0.04%, and 0.05% were 0.21 diopters (D) (95% CI, 0.13-0.28), 0.35 D (95% CI, 0.23-0.46), 0.42 D (95% CI, 0.28-0.56), 0.45 D (95% CI, 0.30-0.60), and 0.46 D (95% CI, 0.32-0.61) respectively For higher concentrations, the estimates were 0.49 D (95% CI, 0.34-0.63) for 0.1% and 0.99 D (95% CI, 0.66-1.31) for 1%, although these were based on fewer and smaller trials. Higher doses of atropine were associated with decreased amplitude of accommodation (P&#x202f;=&#x202f;0.02), increased pupil diameters (P&#x202f;=&#x202f;0.01) and a higher frequency of photophobia (P&#x202f;=&#x202f;0.02). Our findings suggest that the increase in treatment efficacy with higher concentrations may plateau beyond a certain range, and that the current practice of increasing atropine concentrations for children who show inadequate responses to lower doses should be confined to a specific concentration range. This analysis is limited by the number, design heterogeneity, and sample sizes of available trials for higher concentrations, and by the frequent lack of pre-intervention refractive history in included studies. Therefore, estimates-particularly for doses exceeding 0.1%-should be interpreted with caution.

Humans

A randomized trial of viral vector and adjuvanted protein HBV therapeutic vaccine in people with chronic hepatitis B on nucleos(t)ide analogs.

BACKGROUND: This study assessed the safety, efficacy, and immunogenicity of a therapeutic immunization strategy aimed at reaching a functional cure for chronic hepatitis B (CHB), relying on a heterologous prime-boost with viral vectors ChAd155-hIi-HBV and MVA-HBV, combined with sequential or concomitant administration of adjuvanted recombinant HBV proteins (HBc-HBs/AS01B). METHODS: This single-blind, randomized, controlled, first-in-human, phase 1/2 trial enrolled adults aged 18-65 years with HBeAg-negative CHB, virally suppressed on nucleos(t)ide analogs (NAs), with HBsAg >50&#xa0;IU/mL. Participants received NAs and the following regimens of 4 doses (8-week intervals): sequential administration of ChAd155-hIi-HBV, MVA-HBV, and 2 HBc-HBs/AS01B doses; co-administration of ChAd155-hIi-HBV+HBc-HBs/AS01B, followed by 3 co-administered MVA-HBV+HBc-HBs/AS01B doses; 4 HBc-HBs/AS01B doses; 2 placebo doses followed by ChAd155-hIi-HBV and MVA-HBV administered alone or with HBc-HBs/AS01B; or 4 placebo doses. Safety, efficacy (&#x2265;1-log decrease in quantitative (q)HBsAg or HBsAg loss 24 weeks post-dose 4 [day (D)337]), antibody, and T-cell responses were evaluated. RESULTS: In all, 134 participants were vaccinated. Grade 3 solicited adverse events (AEs) (median duration: 2-3 days) were more frequent after co-administration (systemic: 59.3%; administration-site: 33.3%) than sequential administration (systemic: 10.3%; administration-site: 12.8%) of high-dose viral vectors and proteins. No vaccine-related or fatal serious AEs were reported. After 4 doses, no participant had HBsAg loss or &#x2265;1-log decrease in qHBsAg (D337 vs. D1). Co-administration induced the strongest anti-HBs response (73.7% achieved anti-HBs &#x2265;10&#xa0;mIU/mL 2 weeks post-dose 4 vs. 40.0% after sequential administration). Both sequential and co-administration induced HBc-specific CD4+ and CD8+ T-cell responses, with a prime-boost effect of the viral vectors. CONCLUSIONS: Heterologous prime-boost with ChAd155-hIi-HBV and MVA-HBV, combined with sequential or co-administration of HBc-HBs/AS01B, had an acceptable safety profile, were moderately immunogenic, but no participants showed the expected efficacy outcome.

Humans

Outcomes of Experiencing Interpersonal Violence in Autism: A Mixed Methods Systematic Review and Meta-Analysis.

In this review and meta-analysis, we aimed to examine outcomes of interpersonal violence among autistic people. Intersectionality and minority theories suggest that negative outcomes are heightened among people with multiple marginalized identities. Thus, we also aimed to investigate gender-related outcomes of interpersonal violence among autistic people. We conducted a systematic database search with inclusion criteria including mixed methods, peer-reviewed research examining any harmful interpersonal act (e.g., physical, sexual, and psychological) experienced by autistic people. We undertook a random-effects meta-analysis with pooled data from 9 studies, comprising 3,647 autistic participants aged 1 to 80&#x2009;years. Violence was associated with worsened mental health, with the strongest association for internalizing symptoms (d&#x2009;=&#x2009;0.66, p&#x2009;<&#x2009;.001; 95% CI [0.51, 0.80]) and suicidal thoughts and behavior (d&#x2009;=&#x2009;0.63, p&#x2009;<&#x2009;.001; [0.44, 0.82]). Narrative synthesis of 57 studies comprising 37,418 participants (13,127 autistic, 24,291 non-autistic) found violence was associated with numerous adverse health, development, and functional outcomes, including worsened mental health and behavioral difficulties compared to non-autistic controls from childhood. Females and gender minorities reported greater intra- and interpersonal health and development difficulties related to violence, emerging in early childhood and enduring into adulthood. Findings provide strong evidence of lifelong negative outcomes associated with interpersonal violence experienced by autistic people, providing evidence for the relevance of minority stress and intersectionality theories in understanding risk. Indeed, our results raise concerns that autistic people, and particularly non-male (female, gender diverse) individuals, have higher susceptibility for abuse from a young age, while being conditioned to respond with social desirability, superficial adaptivity, and dissociation.

Humans

Cost-Effectiveness and the Economics of Genomic Testing and Molecularly Matched Therapies.

Cost-effectiveness analysis of precision oncology can help guide value-driven care. Next-generation sequencing is increasingly cost-efficient over single gene testing because diagnostic algorithms require multiple individual gene tests to determine biomarker status. Matched targeted therapy is often not cost-effective due to the high cost associated with drug treatment. However, genomic profiling can promote cost-effective care by identifying patients who are unlikely to benefit from therapy. Additional applications of genomic profiling such as universal testing for hereditary cancer syndromes and germline testing in patients with cancer may represent cost-effective approaches compared with traditional history-based diagnostic methods.

Humans

Systemic biomarkers of treatment response to methotrexate in people with painful knee osteoarthritis: A biological substudy of the PROMOTE randomised controlled clinical trial.

OBJECTIVE: Stratification of therapeutic responses may help identify efficacious therapies for osteoarthritis (OA). In the PROMOTE randomised trial, participants with elevated baseline high-sensitivity C-reactive protein (hs-CRP) showed greater pain reduction after methotrexate treatment. We set out to interrogate a broader panel of serum/plasma inflammatory response markers relevant to methotrexate actions as potential biomarkers of therapeutic effect. Our objectives were to: (i) characterize changes in these systemic markers during methotrexate treatment; determine whether (ii) baseline levels or (iii) changes in any marker during treatment were associated with treatment response; and (iv) compare these findings with the more established clinical inflammatory marker, hs-CRP. DESIGN: Plasma/serum samples from participants in PROMOTE's biological substudy were analysed for 35 inflammatory markers at baseline (pre-treatment) and at 6-months (post-treatment), by MesoScale V-plex multiplex assay. Those with paired biological and clinical data at both baseline and 6-months were included in the substudy analysis set. Relationships between markers and overall data structure were assessed by Pearson correlation and Principal Component analysis. Associations between markers (baseline levels or change over time) and change in average knee pain severity in past week (numerical rating scale, NRS) were evaluated by univariable linear regression, adjusting for baseline age, sex, and body mass index. Least Absolute Shrinkage and Selection Operator (LASSO) regression with bootstrap resampling enabled marker selection. Benjamini-Hochberg correction adjusted for multiple testing (Padj). RESULTS: 87 participants with paired blood marker and clinical data were eligible for substudy analysis. 18/35 markers were quantifiable and analysed. Systemic IL-8 and TNF-&#x3b1; levels decreased (Padj=0.015, 0.048 respectively) while IL-15 increased (Padj=0.033) with methotrexate treatment over 6-months. Analysing within this active treatment randomised arm, higher baseline IFN-&#x3b3; was associated with greater reduction in NRS pain change (0.66 [0.01, 1.31], P=0.047), as was decreasing TNF-&#x3b1; over 6-months (2.25 [0.00, 4.5], P=0.049). LASSO identified higher IFN-&#x3b3;, lower plasma IL-15 and IL-16, and younger age as the most important baseline predictors of pain improvement. hs-CRP was highly selected by LASSO for treatment response in both arms. In a secondary univariate treatment arm-by-biomarker interaction analysis, of the 19 markers, only hs-CRP showed consistent effects in adjusted models (at baseline, coeffic. 2.34 [0.53, 4.15], P=0.001; change over 6-months, (0.36 [0.06, 0.66], P=0.018). CONCLUSIONS: Blood measurement of IFN-&#x3b3;, TNF-&#x3b1;, IL-15 and IL-16 as well as hs-CRP could act as potential markers to stratify the treatment response by average knee pain to methotrexate in knee osteoarthritis.

Humans

Clinical effectiveness of transversus abdominis plane block versus local anaesthesia wound infiltration for postoperative pain relief after laparoscopic appendicectomy in children: A multicentre, double-blind, randomised, controlled phase III trial.

BACKGROUND: Postoperative pain relief after laparoscopic appendicectomy in children provided by transversus abdominis plane (TAP) block and local anaesthesia wound infiltration (LAWI) of trocar insertion sites has never been compared. OBJECTIVE: To investigate whether TAP block could decrease postoperative opioid requirements after laparoscopic appendicectomy in children compared with LAWI. DESIGN: Multicentre, double-blind, phase III randomised trial. SETTING: Two tertiary paediatric surgery centres. PATIENTS: Children aged 3 to 15&#x200a;years admitted for laparoscopic appendicectomy. MAIN OUTCOME MEASURES: The primary outcome was the total dose of nalbuphine delivered within 24&#x200a;h after surgery. Secondary outcomes were the Face Legs Activity Cry Consolability (FLACC) scale values at 1, 2, 6, 12 and 24&#x200a;h, the time from levobupivacaine injection to the first dose of nalbuphine, and the time from the end of surgery to the first mobilisation. Patients received either ultrasound-guided TAP block (TAP group) or LAWI of trocar insertion sites (infiltration group) with 0.6&#x200a;ml&#x200a;kg -1 of levobupivacaine 2.5&#x200a;mg&#x200a;ml -1 , combined with standardised systemic multimodal analgesia including paracetamol, ketoprofen, phloroglucinol and nalbuphine. RESULTS: Forty-six and 50 patients were analysed in the TAP and infiltration groups, respectively [age: 10 [7 to 12] versus 10 [8 to 12] years; females: 16 (35%) versus 25 (50%); duration of surgery: 71 [64 to 90] versus 69 [56 to 89] min]. The primary outcome (total nalbuphine dose) was 0.2 [0.0 to 0.2] and 0.2 [0.0 to 0.2] mg&#x200a;kg -1 in the TAP and infiltration groups, respectively ( P &#x200a;=&#x200a;0.95). FLACC scale values did not significantly differ between the two groups ( P &#x200a;=&#x200a;0.78). Time to the first dose of nalbuphine or to first mobilisation was not significantly different between groups ( P value for log-rank test&#x200a;=&#x200a;0.095 and 0.18, respectively). CONCLUSION: TAP block does not appear to provide a greater opioid-sparing effect than LAWI of trocar insertion sites after laparoscopic appendicectomy in children, when combined with systemic multimodal analgesia including nonsteroidal anti-inflammatory drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04969133.

Humans

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33&#xb7;5 years (SD 12&#xb7;1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2&#xb7;3 min (SD 2&#xb7;7) for placebo, 24&#xb7;0 min (8&#xb7;7) for alixorexton 4 mg, 25&#xb7;9 min (9&#xb7;4) for 6 mg, and 28&#xb7;2 min (11&#xb7;4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22&#xb7;2 min (95% CI 17&#xb7;2-27&#xb7;2) for alixorexton 4 mg, 24&#xb7;1 min (19&#xb7;0-29&#xb7;1) for 6 mg, and 26&#xb7;0 min (21&#xb7;0-31&#xb7;0) for 8 mg (adjusted p=0&#xb7;0099 for 4 mg, adjusted p<0&#xb7;0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans

Phase IIB, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in COVID-19.

INTRODUCTION: Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS: One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p&#x2009;=&#x2009;0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.

Adult

Gout and allopurinol adherence in newly diagnosed patients and the risk of fractures: a nationwide cohort study.

INTRODUCTION / OBJECTIVES: The association between gout and fractures remains controversial due to the competing effects of uric acid's antioxidant properties and gout-induced chronic inflammation. Our study aimed to evaluate the risk of fractures in newly diagnosed gout patients and to analyze the impact of Allopurinol medication adherence on this risk. METHODS: This nationwide cohort study utilized the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) database (2002-2019). We identified 4,107 patients newly diagnosed with gout who remained on continuous allopurinol therapy during the 24-month medication assessment period and matched them 1:3 with 12,321 non-gout controls using propensity score matching. Allopurinol adherence was assessed via the Medication Possession Ratio (MPR) over a 24-month period and categorized into three groups: MPR&#x2009;<&#x2009;0.3, 0.3&#x2009;&#x2264;&#x2009;MPR&#x2009;<&#x2009;0.8, and MPR&#x2009;&#x2265;&#x2009;0.8. Multivariable Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for fractures (vertebral, hip, and distal radius). RESULTS: Gout patients demonstrated a significantly higher risk of overall fractures compared to the non-gout group (aHR 5.52; 95% CI 4.19-7.26). A significant inverse linear relationship was observed between allopurinol adherence and fracture risk (P for trend&#x2009;<&#x2009;.001). The risk was highest in the low-adherence group (MPR&#x2009;<&#x2009;0.3; aHR 5.91; 95% CI 4.40-7.93) and relatively lower in the high-adherence group (MPR&#x2009;&#x2265;&#x2009;0.8; aHR 4.77; 95% CI 2.94-7.72). Consistent trends were observed for vertebral (aHR 5.68) and hip (aHR 4.22) fractures. These associations remained consistent across all subgroups, including age, sex, and comorbidities. CONCLUSION: Newly diagnosed gout is associated with a substantially increased risk of fractures. Higher adherence to Allopurinol therapy is correlated with a significant reduction in this risk, suggesting that consistent urate-lowering therapy may mitigate gout-related bone fragility. Key Points &#x2022; Newly diagnosed gout patients have a significantly higher risk of major osteoporotic fractures compared to the non-gout population. &#x2022; A significant inverse linear relationship exists between Allopurinol adherence and fracture risk, with the highest adherence group (MPR &#x2265; 0.8) showing a relatively lower risk. &#x2022; Consistent urate-lowering therapy (ULT) may mitigate bone fragility in gout patients by reducing systemic inflammatory burden caused by urate crystal deposition.

Humans

Obstructive sleep apnea and long-term risk of site-specific cancers: A population-based cohort study.

BACKGROUND: Obstructive sleep apnea is common, but its long-term association with site-specific cancers remains unclear. In this study, we examined 15-year risks of site-specific cancers in people with obstructive sleep apnea compared with the general population and to people with overweight or obesity. METHODS: We conducted a nationwide population-based cohort study using Danish registries, 1995-2021. People diagnosed with obstructive sleep apnea were compared with the general population and to people with overweight or obesity. Adjusted (weighted) 15-year risks, risk differences, and risk ratios (RRs) were estimated using the Aalen-Johansen estimator. Confounding was addressed using standardized morbidity ratio weighting. RESULTS: The study included 114,264 people with obstructive sleep apnea, 115,497 members of the general population, and 113,034 with overweight or obesity. After weighting, the distributions of sex (74% male), age (median 53 years), and comorbidities were comparable across the three cohorts. Obstructive sleep apnea was associated with an increased risk of cancers of the brain (adjusted 15-year risk: 5.78 vs. 3.61 per 1,000 persons; aRR 1.60 [95% CI 1.43-1.78]) and spinal cord (1.65 vs. 1.17 per 1,000 persons; aRR 1.41 [95% CI 1.16-1.72]) compared with the general population. Associations persisted when the obstructive sleep apnea cohort was compared with those with overweight or obesity. No associations were observed for other site-specific cancers. CONCLUSION: Obstructive sleep apnea was associated with an increased risk of brain and spinal cord cancers. These findings highlight the importance of effective prevention of obstructive sleep apnea and the need for further research on treatment.

Cohort Study

Relationship between participant-reported outcomes, residual beta cell function and metabolic parameters in youth with newly diagnosed type 1 diabetes.

AIMS/HYPOTHESIS: Clinical trials of interventions to preserve beta cell function in new-onset type 1 diabetes frequently employ participant-reported outcome measures (PROMs). However, the expected changes in PROMs scores immediately following diagnosis and their association with residual beta cell function, metabolic markers and continuous glucose monitoring (CGM) are unclear. METHODS: Repeated PROMs including Paediatric Quality of Life Inventory diabetes module (PedsQL) and hypoglycaemia fear survey (HFS) were recorded from participants aged 10-18 years with newly diagnosed type 1 diabetes and their parents in two clinical trials: CLOuD (N=97, hybrid closed loop [HCL] vs multiple daily injections [MDI]) and USTEKID (N=72, ustekinumab immunotherapy vs placebo). Scores were compared with serial mixed meal-stimulated C-peptide levels (AUC C-peptide), HbA1c and CGM data. RESULTS: PedsQL and HFS scores for children/adolescents and their parents showed wide variation between individuals but did not change substantially within individuals over the first 48 months from diagnosis. Baseline scores were highly predictive of scores at 12-48 months (p<0.001). PedsQL scores were higher (better) in those reported by children/adolescents than by their parents (p<0.01). In contrast, HFS scores were higher in parents than children (p<0.001), indicating more fear. Strong correlations were observed between child and parent scores (p<0.001). No significant improvement in these scores was detected following intervention (ustekinumab or HCL). Meta-analysis revealed modest but statistically significant associations between HbA1c and PedsQL (&#x3b2;(std)=-0.11; 95% CI -0.20, -0.03) and HFS (&#x3b2;(std)=0.11; 95% CI 0.00, 0.21), and between CGM time in range and PedsQL (&#x3b2;(std)=0.14; 95% CI 0.03, 0.26) but not HFS (&#x3b2;(std)=-0.05; 95% CI -0.16, 0.06). Beta cell function (AUC C-peptide) was strongly associated with HbA1c (&#x3b2;(std)=-0.29; 95% CI -0.39, -0.20) and CGM time in range (&#x3b2;(std)=0.41; 95% CI 0.30, 0.52). Higher beta cell function showed a trend towards better PedsQL (&#x3b2;(std)=0.11; 95% CI -0.03, 0.25) and lower HFS (&#x3b2;(std)=-0.05; 95% CI -0.17, 0.07) but this did not reach statistical significance. CONCLUSIONS/INTERPRETATION: PedsQL and HFS scores changed little during the first 48 months after diagnosis of type 1 diabetes. These scores showed modest but statistically significant associations with measures of glucose management (HbA1c and CGM time in range), whereas the relationships with residual beta cell function (C-peptide) were weaker and did not reach significance. The modest size of these effects suggests current PROMs capture only limited aspects of the clinical benefit associated with beta cell preservation. Future research should incorporate psychometric instruments that are specifically adapted for young people using modern diabetes technologies and undergoing disease-modifying therapy, to ensure outcomes are meaningfully represented in early-stage type 1 diabetes trials.

Adolescent

Indigenous body image amid rapid social and economic change: A reflexive thematic analysis of Wayuu narratives.

The Wayuu, Colombia's largest Indigenous group, are experiencing rapid social, economic, and technological change, including expanding internet access, educational opportunities, and increasing exposure to globalised media. Though the harmful effects of appearance-idealised media imagery on body image are well documented, indigenous body image research remains unevenly distributed across global contexts, with Latin American Indigenous communities particularly underrepresented. This study explored how Wayuu people understand and experience appearance ideals and body image in the context of expanding digital media exposure and rapid sociocultural and economic change. Five focus groups of up to 9 participants were conducted with 29 Wayuu participants (18-68 years; 23 women, 6 men). Using reflexive thematic analysis, three overarching themes were identified: (1) Intersecting sources of appearance pressure: encompassing influences from social media, Wayuu family expectations, and discrimination from non-Indigenous peers; (2) Negotiating and resisting appearance ideals: from body dissatisfaction and restrictive eating to affirmation of cultural identity as protection; and (3) The changing role of appearance in today's Wayuu culture: participants linked globalised appearance ideals to expanding educational opportunities, migration, digital connectivity, and broader socioeconomic transformations occurring within Wayuu territories. While exposure to global ideals fostered comparison and dissatisfaction, cultural pride and collective belonging appeared to buffer against internalised colonial values. Culturally grounded media literacy and education initiatives co-developed with Wayuu communities could foster critical reflection while strengthening heritage. These results highlight the need for decolonial, community-based approaches to body image research and intervention in Indigenous contexts.

Adolescent

Photothermal-Activated Platelet-Rich Plasma Versus Conventional Platelet-Rich Plasma for Melasma: A Split-Face, Double-Blind Randomized Controlled Trial.

BACKGROUND: Melasma is a common acquired pigmentary disorder that predominantly affects women with darker skin types and substantially impairs quality of life. Current treatments are limited by variable efficacy, adverse effects, and frequent recurrence. Platelet-rich plasma (PRP) has emerged as a potential regenerative treatment through growth-factor-mediated modulation of melanogenesis. Photothermal activation, which combines photobiomodulation with controlled hypothermic conditioning, has been hypothesized to promote a more sustained growth-factor release than conventional PRP. This study compared the efficacy and safety of photothermal-activated PRP (PT-PRP) and conventional PRP (C-PRP) for melasma treatment. METHODS: This split-face, double-blind, randomized controlled trial included 26 women with epidermal or mixed-type melasma. Each participant received three monthly sessions of intradermal PRP, with PT-PRP and C-PRP injected into opposite facial sides. Outcomes were assessed at weeks 0, 4, 8, and 12 using the modified Melasma Area and Severity Index (mMASI), Mexameter melanin and erythema indices, patient satisfaction, overall improvement, and adverse events. RESULTS: Both treatments significantly reduced mMASI by week 12, with no significant between-group differences at any time point. C-PRP showed significant mMASI improvement from week 4, whereas PT-PRP reached significance from week 8. For the melanin index, PT-PRP produced a significant within-group reduction at week 12, while C-PRP did not. At week 12, PT-PRP showed a significantly lower melanin index than C-PRP. Mild injection-site bruising was the only adverse event. CONCLUSION: PT-PRP and C-PRP produced comparable clinical improvement, but PT-PRP achieved greater objective melanin reduction at week 12. PT-PRP may represent a safe alternative treatment for melasma. TRIAL REGISTRATION: Thai Clinical Trials Registry: TCTR20260318004.

Humans