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Mechanisms of impact of mental health peer support in high-, middle- and low-income settings: mediation analysis of the UPSIDES randomised controlled trial.

AIMS: While there is growing evidence for the effectiveness of peer support (PS) in improving psychosocial outcomes among individuals with severe mental health conditions, the mechanisms through which these effects occur remain insufficiently understood. This study examines whether social inclusion, hope and empowerment mediate the relationship between PS, personal recovery and health and social functioning. METHODS: Data were collected from 565 adults with severe mental health conditions who participated in the multicentre UPSIDES randomised controlled trial across six sites in Germany, Uganda, Tanzania, India and Israel. Participants in the intervention group received structured PS from trained peer workers over a 6- to 8-month period. Standardised, self-report measures of social inclusion, hope, empowerment and personal recovery, as well as clinician-rated health and social functioning, were administered at baseline, 4&#xa0;months, end of intervention (8&#xa0;months) and 12-month follow-up. Cross-lagged panel modelling was used to explore longitudinal associations and mediating pathways. RESULTS: The cross-lagged models showed strong autoregressive effects across all variables, indicating high temporal stability. There were no significant direct effects of PS on recovery or health and social functioning. However, mediation analysis identified significant indirect effects of PS on personal recovery via social inclusion (&#x3b2;&#xa0;=&#xa0;0.114, 95% confidence interval [CI] [0.049, 0.194], P&#xa0;<&#xa0;0.05) and hope (&#x3b2;&#xa0;=&#xa0;0.037, 95% CI [0.001, 0.086], P&#xa0;<&#xa0;0.05). Similar indirect effects were observed for health and social functioning (via social inclusion: &#x3b2;&#xa0;=&#xa0;-0.035, 95% CI [-0.064,&#xa0;-0.013]; via hope: &#x3b2;&#xa0;=&#xa0;-0.026, 95% CI [-0.052, -0.006]; both P&#xa0;<&#xa0;0.05). CONCLUSIONS: Findings suggest that PS affects recovery-related outcomes primarily through intermediate mechanisms of enhanced hope and social inclusion. These results support theoretical models positing indirect pathways of change in PS interventions and highlight the value of targeting social and psychological domains when designing and implementing PS in mental health services. Individuals with lower baseline levels of hope and social inclusion may particularly benefit from PS.

Humans

Effects of Lactiplantibacillus plantarum KABP051 Probiotic on Body Composition, Microbiome and Mood in Healthy Overweight Adults.

Obesity and mental health disorders are among the greatest public health challenges of the 21st century. Interestingly, an altered microbiome profile has been associated with both conditions. The aim of this randomized, double-blind, placebo-controlled clinical trial was to evaluate the effects of dietary supplementation with a specific probiotic strain (Lactiplantibacillus plantarum KABP051) on body composition and gut microbiome balance, together with measures of mood state, in a population of healthy overweight subjects. Sixty healthy, moderately stressed, nondepressed and overweight or obese volunteers were supplemented for 12 weeks with probiotic (L. plantarum KABP051; 1 billion colony forming units/day) or placebo (microcrystalline cellulose). The KABP051 group experienced significantly greater improvements compared with placebo on body composition measurements, including a reduction in body weight and waist circumference, which decreased in 1.97 &#xb1; 0.77 (mean &#xb1; SE) kg and 2.15 &#xb1; 0.81 (mean &#xb1; SE) cm versus placebo at the end of the intervention (both P < .05, mixed model for repeated measures [MMRM] and post-hoc analysis). Microbiome composition improved in KABP051 group, with significant increase in the relative abundance of Lactiplantibacillus spp. versus placebo. Body fat percentage, profile of mood states fatigue, and confusion sub-scores showed a global trend toward improvement compared with placebo, with the change at 12 weeks being significant in the three measurements in post-hoc analysis (P = .015, P = .014, and P = .016, respectively). No serious adverse events were registered during the intervention period. These results suggest that a specific strain of probiotic bacteria (L. plantarum KABP051) may have both metabolic and psychobiotic effects and may be beneficial for enhancing weight loss and body composition, improving energy (less fatigue) and mood levels while embarking on a healthy lifestyle regimen. ClinicalTrials.gov identifier: NCT06808061.

Humans

Challenges and future directions in AI-driven biomaterials for microbiome-associated oral infectious diseases: A systematic review.

Oral biofilm-induced antimicrobial resistance is the core pathogenic mechanism of microbiome-associated oral infectious diseases (dental caries, periodontitis, peri-implantitis, and endodontic infection). Traditional therapies and biomaterials are limited by poor biofilm penetration, drug resistance induction, single functionality, and inadequate adaptation to dynamic oral microenvironmental changes (e.g., pH fluctuations, salivary rinsing, masticatory stimulation). Artificial intelligence (AI) has transformed the field by integrating materials science, microbiology, and stomatology data. Via machine learning, deep learning, and multi-physics simulation, AI optimizes biomaterial physicochemical properties, decodes microenvironmental signals, constructs precise sensing-response loops, and supports the full chain of material design, performance prediction, and action simulation, advancing treatment from empirical intervention to precision regulation. This systematic review retrieved literature from PubMed, Embase, and Web of Science (January 2016-January 2026) using keywords across three dimensions: AI, biomaterials, and oral microbiome. Following inclusion/exclusion criteria, 99 articles were included. It elaborates on five core mechanisms of AI-driven oral biomaterials (precise oral microbiome analysis, targeted material design/optimization, performance prediction/simulation, targeted delivery/intervention, effect evaluation/dynamic regulation), analyzes their applications in microbiome-targeted biomaterial research and development (R&D) and clinical practice for the four major oral infectious diseases, addresses technical bottlenecks (insufficient targeting specificity and precision of biomaterials, poor stability and durability in complex oral microenvironments, inadequate biofilm disruption capacity, and clinical translation obstacles), and proposes future directions (multimodal design to enhance targeting specificity, structural and component optimization to improve stability/durability, development of multi-mechanism synergistic biofilm disruption strategies, strengthening translational research for clinical application, and deep integration of AI in the full chain of biomaterial R&D). This work provides comprehensive theoretical and practical support for the R&D, optimization, and clinical translation of AI-driven microbiome-targeted oral biomaterials.

Humans

High-Flow Nasal Oxygen and the Risk of Gastric Insufflation: A Systematic Review and Meta-Analysis Supplemented by Narrative Synthesis.

High-flow nasal oxygen (HFNO) generates positive airway pressure, raising concerns about gastric insufflation and aspiration risk. Although most studies report minimal or no gastric distension, some suggest significant changes. This systematic review and meta-analysis applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to evaluate the effect of HFNO on gastric insufflation and related markers across clinical settings. We searched Medline, Embase, Emcare, and CINAHL through August 2025 for studies reporting qualitative or quantitative markers of gastric insufflation during HFNO use, including comet-tail artifacts, antral cross-sectional area, and gastric volume. Eligible designs included randomized trials, observational and volunteer studies, and case reports. Methodological quality was evaluated using the Mixed Methods Appraisal Tool, and certainty of evidence was rated with GRADE. Meta-analysis was performed for outcomes reported in two or more studies. Six randomized trials, five observational studies, two volunteer studies, one case series, and two case reports were included. Observational studies primarily assessed outcomes before and after HFNO intervention. Pooled analysis of four randomized controlled trials (RCTs; n = 375) showed HFNO significantly reduced gastric insufflation compared with face-mask ventilation during elective peri-intubation (risk ratios [RR] = 0.32; 95% confidence interval [CI], 0.19-0.52; P < .00001; I 2 = 0%), rated moderate-certainty. For antral cross-sectional area, pooled analysis of three RCTs (n = 318) found no significant difference between HFNO and face-mask ventilation (MD -0.33 cm 2 ; 95% CI, -0.72 to 0.05; P = .09; I 2 = 74%), rated moderate-certainty. Observational studies assessing pre- and post-HFNO changes showed no significant increase in antral cross-sectional area (MD 0.08 cm 2 ; 95% CI, -0.29 to 0.45; P = .67; I 2 = 0%) and no significant change in gastric liquid volume (MD -0.01 ml/kg; 95% CI, -0.07 to 0.06; P = .80; I 2 = 0%), both rated low certainty. Nonpooled data suggested possible increases in critically ill patients, but the evidence was of very low certainty. A single study assessing microaspiration found HFNO reduced gastroesophageal reflux and prevented microaspiration compared with face-mask ventilation. No clinically significant aspiration events were reported across studies. Moderate-certainty evidence supports HFNO as safe regarding gastric insufflation and antral cross-sectional area in most elective and procedural contexts. Low-certainty evidence suggests no increase in gastric volume. Caution is warranted due to limited, low-to-very-low-certainty evidence at higher flow rates and among critically ill patients. Larger multicenter trials and robust observational studies are necessary to confirm safety in these settings.

Humans

Acute mild cold exposure with shivering reduces 24 h glucose levels in individuals with type 2 diabetes but not prediabetes.

AIMS/HYPOTHESIS: Repeated cold exposure with shivering has been proposed as a potential strategy to enhance glucose metabolism by increasing energy expenditure and substrate utilisation. However, acute effects/benefits of cold-induced shivering on glucose homeostasis in metabolically compromised individuals are unknown. Here, we aimed to determine whether cold exposure at two different intensities improves 24 h glucose homeostasis in individuals with prediabetes and type 2 diabetes. METHODS: In a randomised crossover trial conducted in the South Limburg/Maastricht region of the Netherlands, men and postmenopausal women with prediabetes (n=12) and stable type 2 diabetes (n=12), aged 40-75 years, body mass index &#x2265;27 and &#x2264;35 kg/m2, non-smoking and sedentary, underwent two whole-body cold exposure sessions using a water-perfused suit. Session order was randomised using an online randomisation tool (randomizer.org); participants were masked to the cold exposure intensity received, but investigators were not. Sessions were designed to elicit ~1.5-fold (mild, 15&#xb0;C) and ~2.5-fold (moderate, 4&#xb0;C) increases in resting metabolic rate (RMR). Continuous glucose monitoring assessed interstitial glucose concentrations over 24 h periods before and after each intervention, with controlled diet and activity. Shivering was confirmed via indirect calorimetry and electromyography. RESULTS: In both study groups and periods, RMR increased significantly vs baseline (p<0.001 for all). In prediabetes, the increase in the final 1 h of cold was 1.53&#xa0;&#xd7;&#xa0;RMR in mild and 1.94&#xa0;&#xd7;&#xa0;RMR in moderate cold. In type 2 diabetes, the increase was 1.57&#xa0;&#xd7;&#xa0;RMR and 2.09&#xa0;&#xd7;&#xa0;RMR in the final 1 h of mild and moderate cold, respectively. In prediabetes, neither mild nor moderate cold exposure altered mean 24 h glucose levels. In contrast, after mild cold exposure the type 2 diabetes group exhibited a significant reduction in mean 24 h glucose levels (-0.6&#xa0;&#xb1;&#xa0;0.5 mmol/l, p=0.003) and fasting glucose (-0.6&#xa0;&#xb1;&#xa0;0.8 mmol/l, p=0.019), as well as an increase in time in normal range (+8.8&#xa0;&#xb1;&#xa0;10.3%, p=0.013) and reduced time in hyperglycaemia (-10.9&#xa0;&#xb1;&#xa0;12.9%, p=0.014). Moderate cold did not significantly affect any of the glucose outcomes in type 2 diabetes. Baseline fasting glucose, age and ALT levels were predictors of the glucose-lowering response, suggesting greater benefits in individuals who have higher baseline glucose levels, are younger and/or have more optimal liver health, i.e. lower ALT. CONCLUSIONS/INTERPRETATION: Acute mild cold exposure with shivering reduced 24 h glucose levels in individuals with type 2 diabetes. No changes were observed in prediabetes. The observed effects appear to depend on baseline metabolic status rather than acute substrate utilisation during cold exposure. These findings support the potential of cold exposure as an adjunct non-pharmacological therapy for type 2 diabetes, although further mechanistic studies and validation in larger cohorts are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT05576025 FUNDING: Dutch Organisation for Knowledge and Innovation in Health, Healthcare and Well-being (ZonMw): 09120012010062.

Humans

Probiotic supplementation improves body composition, lipid profiles, and fatty acid metabolism in combat sports athletes during the weight reduction phase.

PURPOSE: Pre-competition weight control for combat sports athletes may alter body composition and fatty acid metabolism. Probiotics have shown potential to regulate overall metabolism; however, their specific effects on fatty acid metabolism during weight control in athletes remain unclear. METHODS: Thirty-two combat sports athletes participating in the 4-week weight reduction period were assigned to either the probiotic group (Group E) or the placebo group (Group C). Body composition, lipid profiles, and fatty acid metabolism were measured before and after the 4-week weight reduction phase. RESULTS: All the athletes experienced a decrease in body weight, body mass index (BMI), body fat percentage, and muscle mass following the 4-week weight loss intervention. Notably, a more significant reduction in body fat percentage (p&#x2009;<&#x2009;0.05) was observed, along with lower levels of triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), specifically in Group E. Weight loss intervention resulted in increased levels of short-chain fatty acids (SCFAs), specifically acetic acid, propionic acid, and butyric acid. Notably, Group E exhibited higher mean values for SCFAs compared to Group C (p&#x2009;<&#x2009;0.05). Additionally, the serum levels of &#x3b3;-linolenic acid and 8,11,14-eicosatrienoic acid were significantly reduced in Group E (p&#x2009;<&#x2009;0.05). In contrast, the majority of free fatty acids (FFAs) showed significant increases, with greater magnitudes of change observed in Group C (p&#x2009;<&#x2009;0.05). CONCLUSION: Probiotic supplementation can improve body composition, enhance SCFAs levels, and decrease circulating FFAs in combat sports athletes, suggesting that probiotics may have a beneficial impact on pre-competition weight management. TRIAL REGISTRATION NUMBER: chiCTR2400079908 (Reg Date:2024-01-16).

Humans

Novelty seeking and rapid symptom improvement across active and sham accelerated iTBS conditions: A pooled individual-patient data analysis.

INTRODUCTION: Major depressive disorder (MDD) is highly prevalent and often treatment-resistant. Accelerated intermittent theta burst stimulation (aiTBS) is a promising intervention for treatment-resistant depression (TRD), though outcomes vary. Personality traits have been examined in relation to rTMS outcomes, yet their role in aiTBS remains underexplored. This pooled individual-patient-data analysis of two randomized, sham-controlled trials examined associations between baseline Temperament and Character Inventory (TCI) traits and one-week symptom change, and whether they differed by condition. METHODS: The left dorsolateral prefrontal cortex was targeted for 20 sessions over 4&#xa0;days. Personality was assessed with the TCI, depression severity with the 17-item Hamilton Depression Rating Scale (HDRS-17). TCI-symptom-change associations were examined with a robust linear mixed-effects model, adjusting for age, gender, repeated measurements, and study membership. RESULTS: 104 participants were included (M/F 45/59; mean age 40.9&#xa0;&#xb1;&#xa0;12.7; active/sham 50/54). The model yielded a Time &#xd7; Novelty Seeking interaction (&#x3b2;&#xa0;=&#xa0;-1.70, p&#xa0;=&#xa0;0.021): higher baseline Novelty Seeking was associated with faster symptom reduction, without a between-arm difference. However, the interaction did not survive Holm correction across 14 trait-interaction tests (adjusted p&#xa0;=&#xa0;0.294) and is therefore exploratory. No other interaction reached the uncorrected threshold. CONCLUSIONS: Higher baseline Novelty Seeking showed a nominal association with faster symptom reduction, without a difference between active and sham conditions. Because it did not survive multiplicity correction and was not reproduced in within-arm analyses, it is preliminary and may reflect contextual or nonspecific processes. Independent replication is required before temperament assessment can be clinically informative.

Humans

EDucation and eXercise for gluteal tendinopathy in an Irish context (EDX-Ireland): findings from the LEAP-Ireland feasibility randomised controlled trial.

OBJECTIVE: To assess feasibility of a randomised controlled trial (RCT) investigating effectiveness of 6 sessions of an EDucation and eXercise intervention delivered over 8 weeks (EDX-Ireland) for gluteal tendinopathy, against usual care. EDX-Ireland was modified from a 14-session EDucation and eXercise intervention (EDX), delivered over 8 weeks, previously evaluated in an Australian RCT. DESIGN: Feasibility parallel RCT. METHODS: Participants were randomly assigned to physiotherapist-led EDX-Ireland or usual care. EDX-Ireland comprised 6 sessions of education, hip abductor strengthening and functional loading over 8 weeks, supported by a home exercise programme. Primary outcomes included success of different recruitment strategies and recruitment/retention rates. Secondary outcomes measured global rating of change and other clinical outcomes. Descriptive statistics (percentage, mean, standard deviations and 95% confidence intervals (CI)) are presented. RESULTS: Of 323 individuals who expressed interest in study participation, 119 completed physical examination screening, and 65 met criteria and consented to participate (recruitment rate 55%). Sixty-five people (89% women; mean age 53.1&#x202f;&#xb1;&#x202f;9.3 years), were randomised to EDX-Ireland (n&#x202f;=&#x202f;32) or usual care (n&#x202f;=&#x202f;33). Eighty-three percent (n&#x202f;=&#x202f;54) were recruited via social media/community, 3% (n&#x202f;=&#x202f;2) from general practitioners and 14% (n&#x202f;=&#x202f;9) from orthopaedic/rheumatology. Retention was 92% (95% CI 82-97%, n&#x202f;=&#x202f;60) at 8-weeks, and 89% (95% CI 79-96%, n&#x202f;=&#x202f;58) at 3-months. Feasibility thresholds were met. Effect size estimates indicate that 134 participants would be required for a future RCT. CONCLUSION: Pre-defined recruitment and retention thresholds were met, indicating that a RCT evaluating 6 sessions of physiotherapist-delivered education and exercise against usual care for gluteal tendinopathy is feasible. TRIAL REGISTRATION: Clinicaltrials.gov (NCT05516563).

Humans

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56&#xb7;9 years (SD 11&#xb7;5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6&#xb7;73 (95% CI -7&#xb7;48 to -5&#xb7;98) for SAR443820 group (n=169) and -6&#xb7;32 (-7&#xb7;36 to -5&#xb7;27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0&#xb7;41 [95% CI -1&#xb7;71 to 0&#xb7;88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans

Acute and chronic effects of mixed nuts on energy metabolism in women at cardiometabolic risk: a randomized clinical trial.

BACKGROUND AND AIMS: The effect of consuming a mix of Brazilian nuts on energy metabolism has not been explored. Thus, the present study aimed to evaluate the effects of acute and chronic consumption of mixed nuts on markers of energy metabolism in women with overweight/obesity. METHODS AND RESULTS: This is a randomized, controlled, and parallel clinical trial with adult women. In an acute study, participants received a beverage containing mixed nuts (30&#xa0;g of cashew nuts&#xa0;+&#xa0;15&#xa0;g of Brazil nuts) or a control beverage, and energy metabolism markers were assessed for up to 3&#xa0;h postprandially. For the chronic study, participants received 45&#xa0;g of a mix of nuts/day and a -500kcal energy-restricted diet (MNG) or only a -500kcal energy-restricted diet free of nuts (CTG) for 8 weeks, and energy metabolism was assessed before and after the intervention period. In the postprandial period, fat oxidation was higher in the MNG than in the CTG (piAUC: 47.53&#xa0;&#xb1;&#xa0;5.78&#xa0;mg/min vs. 27.93&#xa0;&#xb1;&#xa0;6.98&#xa0;mg/min; p&#xa0;=&#xa0;0.048). After 8 weeks of the intervention, fasting fat oxidation increased in the MNG (+16.0&#xa0;&#xb1;&#xa0;7.0&#xa0;mg/min) and decreased in the CTG (-5.0&#xa0;&#xb1;&#xa0;6.0&#xa0;mg/min), with no significant difference between groups. Other acute and chronic markers also showed no significant changes between groups. CONCLUSION: The acute consumption of mixed nuts increased postprandial fat oxidation, whereas chronic intake within an energy-restricted diet did not affect energy metabolism markers in women at cardiometabolic risk. REGISTRATION NUMBER FOR BRAZILIAN REGISTRY OF CLINICAL TRIALS: RBR-3ntxrm.

Humans

Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.

Theta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes. Sixty male participants with OUD were randomized to receive 20&#x2009;min of active or sham 6&#x2009;Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using time&#x2009;&#xd7;&#x2009;group interaction models to examine (1) modulation of drug cue-related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior. (1) A significant Time&#x2009;&#xd7;&#x2009;Group interaction revealed decreased post-stimulation opioid cue-related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected &#x3b1;&#x2009;=&#x2009;0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement (&#x3b2;&#x2009;=&#x2009;2.63, p=&#x2009;0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum (&#x3b2;&#x2009;=&#x2009;1.99, p=&#x2009;0.037) and left medial amygdala (&#x3b2;&#x2009;=&#x2009;1.97, p=&#x2009;0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r&#x2009;=&#x2009;0.43, p=&#x2009;0.02). Together, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical-subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction.

Humans

Transdermal 17&#x3b2;-Estradiol for the Treatment of COVID-19: Protocol of an Early Terminated Phase 2 Randomized Controlled Trial.

BACKGROUND: Early epidemiological studies suggested that pre- and postmenopausal women receiving estrogen therapy were less likely to develop severe disease or die from COVID-19 infection. Potential mechanisms include estrogen-mediated immunomodulation and 17&#x3b2;-estradiol-induced downregulation of angiotensin-converting enzyme type 2 (ACE2), the cellular receptor for SARS-CoV-2. OBJECTIVE: This study aimed to evaluate the feasibility, safety, and preliminary efficacy of transdermal 17&#x3b2;-estradiol as an adjunctive treatment for COVID-19 in men and postmenopausal women. METHODS: We designed and conducted a randomized controlled trial comparing 17&#x3b2;-estradiol transdermal gel plus standard care with standard care alone in adults with confirmed COVID-19. Initial ethics and funding approvals were obtained in March 2021. Owing to changes in the epidemiology of COVID-19 in Qatar and revisions to national quarantine policies, protocol amendments were required before recruitment commenced in February 2022. The treatment duration was reduced from 10 to 7 days due to changes in national quarantine guidelines. Recruitment and follow-up were conducted between February 2022 and June 2022. RESULTS: Recruitment was substantially lower than anticipated because widespread COVID-19 vaccination, declining disease severity, and revised national quarantine policies markedly reduced the number of eligible hospitalized patients. Consequently, the planned sample size was not achieved, and the study was terminated in June 2022. A total of 29 men with mild COVID-19 were enrolled, with 44.8% (n=13) randomized to standard care and 55.2% (n=16) to transdermal 17&#x3b2;-estradiol plus standard care. The intervention was well tolerated, with no adverse safety signals or thromboembolic events reported. CONCLUSIONS: Although the study was underpowered to assess efficacy because recruitment targets were not achieved, it showed that transdermal 17&#x3b2;-estradiol was well tolerated, with no major safety concerns among enrolled participants. The experience also provided important operational lessons for conducting clinical trials during rapidly evolving pandemics. Adequately powered studies are required to determine whether transdermal estrogen has therapeutic potential against COVID-19, other ACE2-mediated coronavirus infections, or potentially other severe viral illnesses.

Humans

Effects of blood flow restriction training combined with plyometric training on lower limb muscle strength and motor unit recruitment in basketball players: An experimental study.

OBJECTIVE: Previous studies have shown that plyometric training (PT) improves neuromuscular function and explosive power but not maximal strength. Blood flow restriction training (BFR) combined with low-intensity resistance training (RT) increases muscle mass and strength. This study investigated the effects of PT, and BFR combined with PT on lower-limb muscle function. METHODS: Twenty elite basketball players were randomly assigned to two groups: PT-alone group (PT, n&#x202f;=&#x202f;10) and BFR combine with PT group (PT-BFR, n&#x202f;=&#x202f;10). All participants underwent bodyweight-based plyometric training three times per week for eight weeks. Peak torque values for hip and knee flexion and extension, as well as root mean square (RMS) values derived from electromyography, were measured before and after the intervention. RESULTS: After the 8-week intervention, both groups showed significant improvements in knee flexion and extension peak torque at 180&#xb0;/s (all p&#x202f;<&#x202f;0.01). Between-group comparisons revealed greater gains in the PT-BFR group for hip extension and flexion at 60&#xb0;/s (p&#x202f;=&#x202f;0.036-0.002; &#x3b7;p2 = 0.225-0.233). RMS of the rectus femoris increased significantly more in the PT-BFR group than in the PT group (right: p&#x2009;=&#x2009;0.004, &#x3b7;p2 = 0.385; left: p&#x2009;=&#x2009;0.020, &#x3b7;p2 = 0.266), whereas no significant changes were observed in the gastrocnemius, tibialis anterior, or biceps femoris (all p&#x2009;>&#x2009;0.05). CMJ height also improved more in the PT-BFR group, with a significant group &#xd7;&#x2009;time interaction (p&#x2009;=&#x2009;0.042, &#x3b7;p2 = 0.210). CONCLUSION: Both training protocols enhanced bilateral lower-limb strength, with notable gains in the non-dominant leg; however, the magnitude did not differ substantially between groups. In contrast, compared with PT alone, BFR combined with PT produced superior enhancements in lower-limb muscle strength and neuromuscular recruitment. These findings suggest that when PT is employed to improve explosive power, it may be effectively combined with BFR to further augment muscular strength.

Humans

Impact of real-time respiratory function monitoring on neonatal mask ventilation training: a multicentre simulation-based crossover study.

OBJECTIVE: To evaluate whether visibility of respiratory function monitor (RFM) feedback improves mask ventilation performance and influences subsequent ventilation performance during neonatal resuscitation training. DESIGN: multicentre randomised crossover simulation study. PARTICIPANTS: Healthcare professionals involved in neonatal resuscitation training across participating centres. INTERVENTION: Participants performed positive pressure ventilation (PPV) on both term and premature manikins under two conditions: with visible RFM feedback and with the display masked. The order of feedback visibility was randomised. Each participant completed ventilation assessments in both conditions. MAIN OUTCOME MEASURES: Primary outcomes were expired tidal volume (Vte) and mask leak (%). The proportion of breaths within the target Vte range (4-8&#x2009;mL/kg) was calculated as a performance indicator. Secondary outcomes included variability in Vte and mask leak to assess ventilation stability between conditions. RESULTS: Visible RFM feedback was associated with lower mask leak and improved ventilation stability in the preterm manikin and with tidal volumes entering the target range in the term manikin. Participants initially ventilated with visible feedback maintained performance after feedback removal, suggesting a carry-over learning effect. CONCLUSION: In this multicentre crossover simulation study, visible RFM feedback was associated with changes in mask ventilation performance and evidence of a carry-over learning effect following feedback removal. Real-time visibility of respiratory parameters may strengthen neonatal resuscitation training.

Humans

A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

PURPOSE OF REVIEW: Hereditary hearing loss has historically been approached as a diagnostic category rather than a therapeutically modifiable disease. Recent advances in molecular genetics, cochlear gene delivery, and first-in-human clinical trials are changing that. This review summarizes contemporary progress in the genetics of hearing loss, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice. RECENT FINDINGS: Early clinical trials targeting OTOF -related DFNB9 deafness have demonstrated satisfactory safety profiles and meaningful auditory recovery, establishing the first proof-of-concept for cochlear gene therapy in humans, culminating in the April 2026 FDA approval of Otarmeni. Genetic diagnoses are increasingly informing prognosis, cochlear implant counseling, and therapeutic candidacy. Preclinical research continues to expand toward recessive, dominant, and syndromic hearing loss using gene replacement, antisense, RNA interference, and genome-editing strategies. Substantial challenges remain, including heterogeneous outcome measures, uncertain long-term efficacy, regulatory complexity, and inequitable global access. SUMMARY: The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one. Widespread clinical impact will require advances in vector engineering, equitable implementation, multidisciplinary counseling, and integration with established rehabilitation pathways. For otolaryngologists, genetic literacy is becoming essential to contemporary hearing care.

Humans

Holmium laser enucleation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia.

RATIONALE: A range of surgical options is available for the treatment of benign prostatic hyperplasia (BPH), including holmium laser enucleation of the prostate (HoLEP). The evidence is unclear regarding differences in functional, perioperative, and morbidity outcomes between these modalities. OBJECTIVES: To assess the effects of holmium laser enucleation of the prostate compared with other surgical treatments for lower urinary tract symptoms in men with benign prostatic hyperplasia. SEARCH METHODS: We searched multiple databases (including MEDLINE, Embase, CENTRAL, Web of Science, LILACS, and the International HTA database), trial registries, and conference abstracts through April 08, 2026. ELIGIBILITY CRITERIA: We only included randomized trials of men over 40 years of age with a prostate volume of at least 20 mL (assessed by digital rectal examination, ultrasound, or conventional imaging) who exhibited lower urinary tract symptoms (LUTS) defined by an International Prostate Symptom Score (IPSS) of eight or greater undergoing surgical interventions for BPH. OUTCOMES: The critical outcomes measured were the urologic symptoms score, the quality-of-life score, and major adverse events. The important outcomes measured were: re-treatment, erectile function, ejaculatory function, transfusions, acute urinary retention, indwelling urinary catheter duration, and hospital stay duration. RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess for potential sources of bias on a study and outcome level basis. SYNTHESIS METHODS: We pooled outcome data using the random-effects model and performed meta-analyses using the Mantel-Haenszel method. We assessed statistical heterogeneity in the pooled data by visually inspecting forest plots and using the I2 statistic to quantify it. We used the GRADE framework to assess the certainty of evidence. INCLUDED STUDIES: We included 52 trials that included 6242 participants that compared HoLEP to other surgical interventions for benign prostatic hyperplasia. The median age of participants across the studies ranged from 65 to 74 years. The baseline prostate volume ranged from 30 cc to 142 cc. Baseline IPSS scores ranged from 19.6 to 28.6 (range 0-35). SYNTHESIS OF RESULTS: We prioritized comparing HoLEP with transurethral resection of the prostate (TURP) at short-term follow-up (up to 12 months), because TURP is the long-standing reference standard and the predominant comparator in randomized surgical trials. Findings for the four remaining comparisons (laser ablation, alternative energy source enucleation, other minimally invasive therapies, and simple prostatectomy), for long-term follow-up, and for all remaining outcomes are reported in full in the review. Compared to TURP, at short-term follow-up: Critical outcomes - HoLEP may result in little to no difference in short-term urologic symptom scores measured using the IPSS (range 0 to 35; lower values reflect fewer symptoms) (MD -0.67, 95% CI -1.20 to -0.14; I&#xb2; = 93%; 14 studies, 1666 participants, low-certainty evidence). - HoLEP may result in little to no difference in short-term quality of life (range 0 to 6; lower values reflect better quality of life) (MD -0.04, 95% CI -0.23 to 0.15; I&#xb2; = 73%; 6 studies, 876 participants, low-certainty evidence). - HoLEP may result in little to no difference in short-term major adverse events (RR 0.75, 95% CI 0.35 to 1.58; I&#xb2; = 0%; 10 studies, 1147 participants, low-certainty evidence). Important outcomes - HoLEP likely results in little to no difference in re-treatment (RR 0.45, 95% CI 0.14 to 1.50; I&#xb2; = 0%; 8 studies, 813 participants, moderate-certainty evidence). - HoLEP likely results in little to no difference in erectile function (MD -0.03, 95% CI -0.47 to 0.42; I&#xb2; = 0%; 3 studies, 518 participants, moderate-certainty evidence). - Ejaculatory function: we did not find any data for this outcome. - HoLEP likely reduces the need for blood transfusion (RR 0.19, 95% CI 0.09 to 0.42; I&#xb2; = 0%; 15 studies, 1755 participants, moderate-certainty evidence). AUTHORS' CONCLUSIONS: Compared with TURP, HoLEP may achieve similar relief of urologic symptoms, similar quality of life, and similar rates of major adverse events in the first 12 months after surgery, and probably similar re-treatment rates and erectile function. HoLEP likely reduces the need for blood transfusion; this is the only advantage of HoLEP that the randomized evidence, as summarized here, supports as clinically important. There was insufficient evidence to assess outcomes in the subset of individuals with larger prostates or on anticoagulation. Future research should prioritize long-term trials reporting sexual function and urinary incontinence outcomes, recruit men with very large prostates (&#x2265; 150 cc) or on anticoagulation therapy, and evaluate cost-effectiveness and training requirements. FUNDING: No external funding was received for this review. REGISTRATION: The protocol for this review was published in the Cochrane Database 2019 (https://doi.org/10.1002/14651858.CD013291).

Humans

Impacts of Climate Change and Related Weather Events on the&#xa0;Health and Wellbeing of Culturally and Linguistically Diverse Communities: A Systematic Review.

BACKGROUND: Vulnerable populations such as culturally and linguistically diverse communities (CALD), ethnic minorities and racial groups face a disproportionate burden of climate change-related health impacts due to a combination of socio-cultural and economic factors, geographic vulnerabilities and health disparities. This review synthesised the existing evidence on the health and wellbeing impacts of climate change and related weather events among CALD communities. METHODS: A narrative synthesis approach was utilised to conduct a systematic review. Three electronic databases (PubMed, Scopus and Web of Science) were searched, identifying 25 studies for appraisal and synthesis. Studies published in the English language from January 2010 to March 2024 were included in the review. RESULTS: The reviewed studies, mostly carried out in the USA, employed varied study designs, and focused on diverse CALD groups such as migrants, farmworkers and racial and ethnic minorities. The included studies addressed broader and specific climate change-related events, ranging from heat-related impacts and hurricanes to occupational heat exposure. CALD communities were found to be more vulnerable to climate change-related negative physical and mental health issues, further exacerbated by poor living conditions, limited access to healthcare, and cultural and language barriers. CONCLUSION: Future efforts by governments, healthcare agencies, employers and research institutions should prioritise multilingual risk communication strategies, providing culturally appropriate health education and healthcare access, housing improvements and the investigation of long-term health impacts of climate change and coping mechanisms adopted among CALD populations.

Climate Change

Impact of climate change on pediatric health outcomes.

Climate change has become one of the most critical health issues globally in the twenty-first century with children bearing the disproportionate burden of the burden since they are more vulnerable than adults because of their physiological, behavioral, and developmental capacities. It is a systematic review that rates the evidence of the relationship between climatic exposures such as heat, air-pollution, and extreme weather events and pediatric health outcomes. The number of peer-reviewed studies involved was 23 published in 2000-2025, which represented different geographic areas and study designs and assessed acute and chronic health outcomes. The Newcastle-Ottawa Scale and the ROBINS-I tool were used to evaluate the methodological quality, and the majority of the studies had low to moderate risks of bias. The narrative synthesis shows that there are always links between air pollutants especially PM2.5, NO2 and O3 and respiratory morbidity, prevalence of asthma and hospitalization of children. Amplified temperatures as well as heat waves were associated with increased cases of heat illness, dehydration, and febrile state in infants and young children. There were elevated cases of diarrheal and vector-related infections, especially in low-resource settings, which were linked to extreme weather events especially floods. Although the overall results were similar, significant differences in the regions and methods were found, and low-income countries show little evidence. In addition, exposures as analyzed in most studies were usually considered individually, which may have underestimated the cumulative or compound climate risks.

Humans