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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

A systematic review of human avoidance learning: Cognition, computation, and methods.

Avoidance behaviour is fundamental for survival but can become maladaptive in clinical conditions. A large body of literature has accumulated on the dynamics of human avoidance learning. However, current theories and overviews do not provide an exhaustive account of this evidence. In this systematic review, we identify N = 116 studies on human avoidance learning. We analyse these studies with the goal of distilling robust empirical phenomena as a basis for theory-building, and examine their diagnostic value in differentiating between competing theories. We find that the evidence is difficult to reconcile with foundational two-factor and classical safety-signal accounts, and most strongly supports expectancy- and inference-based views, in which avoidance responses are selected with respect to represented consequences. At the same time, no current framework provides a complete account of the evidence: several findings point to an additional role for operant valuation, Pavlovian influences, and contextual or latent-state control over the expression of avoidance. Methodologically, we observe that the problem setting in the most common experimental paradigms is radically simpler than real-world avoidance and therefore unlikely to expose the limits of inferential or reflective mechanisms. Consequently, we argue that paradigms with greater computational demands and more realistic action affordances are required to identify the mechanisms underlying avoidance learning. Collectively, these insights provide a foundation for theoretical refinement, computational modelling, and methodological innovation, with implications for advancing interventions targeting maladaptive avoidance.

Humans

First evaluation of a novel recombinant eCG molecule in ewes reveals a discrepancy between ovulatory response and pregnancy outcome.

This study evaluated the reproductive performance and clinical safety of a novel recombinant eCG (r-eCG) in ewes. Two weeks prior to study onset (Day 0: intravaginal progesterone device insertion), 45 ewes were randomly assigned to negative control (NC; no eCG; n&#x202f;=&#x202f;10), positive control (PC; 400IU commercial non-recombinant eCG; n&#x202f;=&#x202f;20), or treatment group (T; 400IU r-eCG; n&#x202f;=&#x202f;15). Ewes were inseminated with fresh-diluted semen (200&#x202f;&#xd7;&#x202f;106 sperm). Ultrasonography assessed follicle count/diameter (days 11, 13), ovulation (day 13), corpus luteum (CL) number/characteristics (day 20), and pregnancy (day 44). Serum progesterone was measured on day 20; Group T underwent clinical/hematological evaluations (days 0, 20, and 44). Estrus signs were more frequent (P&#x202f;<&#x202f;0.01) in T (100%) than NC (50%), while PC (85%) did not differ. Ovulation rates were similar between T (93%) and PC (95%), but higher than NC (50%; P&#x202f;<&#x202f;0.05). On day 13, largest follicle diameter did not differ (P&#x202f;>&#x202f;0.05) among groups; however, fewer follicles > 2&#x202f;mm occurred in PC than NC and T (P&#x202f;<&#x202f;0.05). CL number was higher in T than PC (2.0&#x202f;&#xb1;&#x202f;0.3 vs. 1.0&#x202f;&#xb1;&#x202f;0.0, P&#x202f;<&#x202f;0.01), while NC did not differ (1.0&#x202f;&#xb1;&#x202f;0.25). Conversely, pregnancy rate was higher (P&#x202f;<&#x202f;0.05) in PC (70%) than T (28.6%) and NC (20%). Among ovulated ewes, progesterone concentration and progesterone/CL ratio did not differ among groups (P&#x202f;=&#x202f;0.92 and P&#x202f;=&#x202f;0.08, respectively). No relevant r-eCG-related clinical or hematological alterations occurred. In conclusion, 400IU r-eCG effectively induces estrus and ovulation without adverse effects; however, the discrepancy between ovulatory response and pregnancy rate underscores the need for further study refinement to improve fertility.

Animals

BIOCARD framework: integrating fecal bile acids, lipids, and metabolites to assess response to a cardiovascular health intervention.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, particularly in under-resourced populations. Although nutritional interventions are important for CVD prevention, their outcomes are commonly evaluated using conventional clinical and behavioral indicators, which may not fully capture early molecular responses. In this study, we developed the BIOCARD framework, an exploratory fecal multi-omics platform integrating bile acids, lipids, and metabolites to evaluate intervention outcomes related to cardiovascular health. Fecal samples were collected from caregiver-child participants enrolled in a 10-week randomized controlled trial comparing a multicomponent garden-based intervention (SHA) with an education-only control group (MSP). Fecal polar metabolites, lipids, and bile acids were analyzed by UHPLC-HRMS-based approaches and integrated with conventional health indicators. Traditional clinical indicators in the present study showed limited sensitivity for detecting intervention-related differences. In contrast, fecal multi-omics analyzes revealed intervention-associated differences in metabolites, lipids, and bile acids, with children showing more apparent molecular variation than parents. Network analysis further revealed associations between selected molecular features and cardiovascular-related indicators, including blood pressure, body fat, skin carotenoids, and Healthy Eating Index scores. Together, these findings suggest that the BIOCARD framework may serve as an exploratory molecular approach to complement traditional outcome measures and improve the evaluation of nutritional interventions for cardiovascular health.

Humans

Glymphatic dysfunction mediates inflammation-driven vascular burden and cognitive decline in cerebral small vessel disease.

BACKGROUND: Cerebral small vessel disease (CSVD) is increasingly recognized as a disorder involving microvascular dysfunction, impaired perivascular clearance, and inflammatory processes. However, how systemic inflammatory burden, neurovascular coupling (NVC), glymphatic MRI markers, vascular lesion burden, and cognition are interrelated remains unclear. MATERIALS AND METHODS: In this prospective study, 155 patients with CSVD and 70 healthy controls (HCs) underwent multimodal MRI. NVC was quantified using the cerebral blood flow/fractional amplitude of low-frequency fluctuations ratio. Glymphatic function was assessed via the diffusion tensor image analysis along the perivascular space (ALPS) index, choroid plexus volume (CPV), and perivascular space (PVS) fractions. Structural equation modeling (SEM) was employed to evaluate the direct and indirect effects of inflammatory markers on vascular burden and cognitive performance. RESULTS: Patients with CSVD exhibited significantly diminished NVC (specifically in the right median cingulate and left frontal gyri) and impaired glymphatic function (lower ALPS-index; higher CPV and PVS fractions) compared to HCs. SEM revealed that inflammatory biomarkers exerted both a direct effect on vascular burden and a substantial indirect effect (accounting for 66.3% of the total effect) mediated through two pathways: a single-mediation path via glymphatic function (42.8%) and a serial-mediation path via NVC and glymphatic function (23.5%). Increased vascular burden was significantly associated with poorer cognitive performance. CONCLUSION: Inflammation drives CSVD progression and cognitive decline primarily through the disruption of NVC and glymphatic clearance mechanisms. These findings highlight glymphatic dysfunction as a critical mediator of inflammation-related structural brain damage.

Humans

Plasticity of hepatic metabolism in Arctic char (Salvelinus alpinus) in response to cyclic hypoxia.

The emergence of cyclic hypoxia puts aquatic organisms' homeostasis under significant strain. Energetic metabolism as well as protein synthesis and folding are particularly altered during hypoxia, while reoxygenation imposes an oxidative challenge. Currently, little is known about how hypoxia-sensitive organisms respond to large oxygen fluctuations. Our previous work on Arctic char revealed that this salmonid, despite being strongly affected by acute hypoxia and reoxygenation (H/R), can successfully reestablish homeostasis, notably through adjustments to hepatic mitochondrial metabolism. However, the mechanisms underlying this acclimation remain poorly understood. We hypothesized that Arctic char remodel their hepatic proteome to optimize energy metabolism, reorganize oxygen-demanding pathways, and maintain cellular homeostasis during repeated H/R cycles. By exposing Arctic char to two or fifteen days of diel cyclic hypoxia, we confirmed this species' limited capacity to respond to acute H/R. Nevertheless, after fifteen cycles, fish adjusted their energetic metabolism through coordinated regulation of carbohydrate and lipid pathways and upregulation of amino acid metabolism. Mitochondrial metabolism was strongly reorganized, particularly at the ubiquinone-Complex III interaction level, alongside adjustments in proline utilization and protein processing. Moreover, protein processing and folding pathways were stimulated in both mitochondria and the endoplasmic reticulum. However, chronic cyclic hypoxia may still promote non-mitochondrial ROS production, DNA replication stress, and impaired immune function. This study highlights how a hypoxia-sensitive fish progressively reorganizes its metabolism and oxygen-demanding pathways to establish a phenotype adapted to chronic cyclic hypoxia, while also revealing the physiological costs associated with this acclimation.

Animals

Peripheral inflammation and executive function among community samples across the lifespan: A systematic review and meta-analysis.

Higher levels of peripheral inflammatory markers are proposed to disrupt cognitive processes; however, the extent to which this relationship applies to executive functions, specifically, has yet to be systematically evaluated. The current meta-analysis synthesizes all available literature measuring the association between peripheral inflammation and executive functions among community individuals across the lifespan. This systematic review searched Web of Science, PubMed, and PsycINFO for published and unpublished studies, in the English language, that assessed the association between markers of peripheral inflammation and self-report and behavioral measures of executive function. In addition to methodological and demographic information, correlation/beta coefficients were extracted from included studies to quantify the association between inflammation and executive functions. This review included 58 studies, 41 of which were included in the random-effects meta-analysis (N&#x202f;=&#x202f;255,539). Among community individuals, higher levels of CRP and IL-6 were associated with poorer executive functioning. These results did not differ when models accounted for potential confounding variables. Meta-regressions revealed that the relationship between inflammatory biomarkers and executive function did not differ as a function of age, adiposity, or percentage of the sample who identified as female. Results of the present review indicate that higher levels of specific inflammatory markers are associated with lower performance on executive function measures; however, we observed significant heterogeneity in the study design and measurement of both inflammation and executive functioning, suggesting important considerations for future research.

Humans

Comparison of clinical outcomes of robotic versus open pyeloplasty in infants under 6 months.

INTRODUCTION: Robotic pyeloplasties have become the popular approach for surgical repair of ureteropelvic junction obstruction (UPJO) in the pediatric population. In infants less than 6 months old, there is concern for lack of intra-abdominal working space and lack of benefit compared to an open approach. Our aim was to compare the peri-operative and post-operative outcomes of patients undergoing open versus robotic pyeloplasty under six months of age. METHODS: A retrospective review was performed of patients less than six months of age undergoing robotic or open pyeloplasty between 2020 and 2024 at a single institution. Patient demographics and clinical outcomes were collected and compared. Surgical success was defined as a >50% reduction in the antero-pelvic diameter (APD) of the affected kidney at one year post pyeloplasty. RESULTS: A total of 32 patients were identified (16 robotic and 16 open), median age at surgery was 4 months old. There was no significant difference in length of hospital stay or narcotic usage between the two groups. The robotic cohort had a significantly longer operative time (209.5 min vs 142.5 min, p < 0.001) compared to the open cohort. There was no significant difference between post-operative complication or surgical success rates between the two groups. CONCLUSION: In this small series, robotic and open pyeloplasty both remain viable options for infants less than 6 months of age with equivalent surgical outcomes and lengths of hospital stay.

Humans

Association between prenatal exposure to tetrachloroethylene and adverse birth outcomes: Systematic review and meta-analysis.

BACKGROUND: Tetrachloroethylene (PCE) is a ubiquitous chlorinated solvent with documented placental transfer. Despite widespread environmental and occupational exposure, no prior systematic review has synthesized evidence on prenatal PCE exposure and adverse birth outcomes. METHODS: We conducted a systematic review and meta-analysis of observational studies. PubMed, Web of Science, PsycINFO, EMBASE, and CINAHL were searched from inception to July 13, 2026. Eligible studies reported associations between prenatal PCE exposure (drinking water or inhalation) and adverse birth outcomes. Study quality was assessed using the Newcastle-Ottawa Scale (NOS) and Agency for Healthcare Research and Quality (AHRQ) criteria. Random-effects meta-analyses were performed using risk ratios (RRs) with 95% confidence intervals (CIs), with Knapp-Hartung adjustments and Paule-Mandel &#x3c4;2 estimation. RESULTS: Twenty one studies (1987-2023) met inclusion criteria. Prenatal PCE exposure was associated with spontaneous abortion (8 studies; RR&#x202f;=&#x202f;1.28, 95% CI 1.00-1.63; I2&#x202f;=&#x202f;64.2%). Analyses of stillbirth, central nervous system defects, oral clefts, neural tube defects, preterm birth, low birthweight, and small-for-gestational-age (SGA) yielded positive but statistically non-significant pooled estimates. The certainty of evidence ranged from very low to low across outcomes (GRADE). CONCLUSIONS: Prenatal PCE exposure may be associated with spontaneous abortion, particularly at higher exposure levels, and with SGA. Findings support ongoing regulatory efforts to limit PCE in occupational and environmental settings, particularly for pregnant individuals. Future prospective studies with biological monitoring and confounder-adjusted designs are needed.

Tetrachloroethylene

Non-parametric differential methylation analysis characterizes histotype-specific promoter regions in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a heterogenous disease with frequent late-stage diagnosis and high mortality rates, for which no reliable screening tests exist. In recent years, epigenetic biomarkers in the form of DNA methylation in CpG-rich regions have gained increased attention in the scientific community due to their robust nature and accessibility, allowing for diagnosis without the need for invasive surgery. In this study, we investigated the aberrant methylation of promoter regions in early stage EOC through non-parametric methods, with the purpose of characterizing candidate epigenetic biomarkers. The approach was used on a cohort of early stage EOC samples, and results were compared to existing programs for differential methylation. Significant regions were then used to construct a CpG panel for stratifying EOC histotypes through predictive classification in external data. Identified promoter regions were highly reproducible across cohorts, and the constructed CpG model stratified histotypes in external cohorts through predictive classification. Comparisons against other DMP and DMR callers showed a degree of homogeneity between results but also revealed promoter regions that were overlooked despite clear signs of aberrant methylation. Finally, EOC histotypes were found to differ in their methylation distribution types, and results indicate that methods sensitive to non-normally distributed data may be poorly suited to compare groups with different distribution types. The non-parametric approach identified aberrantly methylated promoter regions that were highly reproducible across cohorts. Results from predictive classification indicate that these regions may be useful for the purpose of EOC histotype stratification.

Humans

Analyzing the impact of subcutaneous injection needle, device, and administration characteristics on patient pain, anxiety, and safety: a systematic literature review.

The subcutaneous (SC) injection route is a commonly used and important method for therapeutic delivery of a wide range of compounds, and needle characteristics have a significant influence on patient pain, anxiety, safety, and other outcomes. This systematic review evaluates the evidence on how needle-specific characteristics (e.g. gauge, length, tip design, wall thickness, concealment) and administration- or device-related factors can affect patient-reported outcomes and clinical safety indicators during and following SC injections. A comprehensive search was conducted in MEDLINE, PubMed, Embase, and ClinicalTrials.gov in June 2024. Studies were included if they assessed the relationship between needle characteristics and pain, anxiety, safety, or related outcomes in individuals receiving SC injections. A dual-reviewer process was used for study selection, data extraction, and quality assessment. Sixty-two studies met inclusion criteria. Evidence consistently indicated that thinner and shorter needles reduced patient-reported pain and adverse events such as bruising and bleeding. Tapered and lubricated needles, hidden or retractable needle designs, and use of autoinjectors or prefilled syringes also contributed to reduced anxiety and improved user satisfaction. However, results were heterogeneous, and many studies lacked sufficient power or single-variable evaluation of individual needle parameters, limiting definitive conclusions. Needle characteristics significantly influence patient experience and safety with SC delivery. While both clinical evidence and practical experience clearly favor thinner, shorter, and concealed needles, further standardized, high-quality research is needed to isolate and quantify the specific contributions of individual needle characteristics to optimize injection practices and support patient-centered device design.

Humans

Positive Margin Rate Following Transoral Surgery in T2-T3 Laryngeal Carcinoma - a Systematic Review and Meta-Analysis.

BACKGROUND: Transoral endoscopic surgery, using either conventional laser techniques or supported by robotic assistance, represents an established treatment modality for selected patients with T2-T3 laryngeal carcinoma. The goal is complete tumor removal, as positive resection margins have been associated with worse oncological outcomes. This systematic review and meta-analysis aimed to determine the positive margin rate following transoral endoscopic surgery for T2-T3 laryngeal carcinoma and to evaluate its impact on oncologic outcomes. METHODS: A systematic search of Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar was performed from inception through March 2025, identifying studies reporting on surgical margin status after transoral resection of T2 and/or T3 laryngeal carcinoma. A random-effects meta-analysis of proportions was used to estimate a pooled positive margin rate. The oncologic impact of margin status is presented descriptively owing to data heterogeneity. RESULTS: Thirty-nine studies comprising 3,281 patients with T2-T3 laryngeal carcinoma met the inclusion criteria. The positive margin rate was 22.0% (95% CI 17.6 - 27.3, I2 = 83.8%) for the total T2-T3 cohort, with stratified rates of 22.4% for T2 and 30.8% for T3 tumors. Among the eight studies assessing the impact of positive margins in T2-T3 stages, three found a significant association with worse oncological outcomes. Conclusion A 22% positive margin rate was identified in T2-T3 laryngeal cancer treated with transoral endoscopic resection. However, the impact of margin status on oncological outcomes remains uncertain, largely due to challenges in sampling and histopathological assessment.

Humans

Prevalence of unruptured intracranial aneurysms according to comorbidities, risk factors, country, and time period: a systematic review and meta-analysis.

BACKGROUND: The incidence of aneurysmal subarachnoid haemorrhage declined between 1980 and 2010, which coincided with a decline in smoking and prevalence of hypertension. We aimed to investigate whether the decrease in subarachnoid haemorrhage incidence is paralleled by declines in unruptured intracranial aneurysm (UIA) prevalence. METHODS: For this systematic review and meta-analysis, we searched Embase, PubMed, and Web of Science for articles published in any language from Jan 1, 2011 to Dec 31, 2025, and reassessed 68 articles published before March 1, 2011 from a 2011 systematic review and meta-analysis. Articles were eligible for inclusion if they used a cross-sectional or case-control design and provided the crude number of participants and those with UIA. We only included studies reporting numbers of UIA separately from ruptured aneurysms and with ten or more patients. Summary data were independently extracted by JD with AZ or CB and conflicts were resolved by GJER. The primary outcome was proportion of participants with UIA. Relative to a hypothetical reference population (mean age 50 years, 50% women, and no comorbidities), age and/or sex-adjusted prevalence ratios (PRs) for regions, comorbidities, and risk ratios (RRs) for female sex, smoking, and hypertension were estimated using generalised linear mixed models. A time trend analysis was done by binomial meta regression using the mid-year of data acquisition. We assessed the certainty of evidence using GRADE. The study was registered with PROSPERO, number CRD420261296728. FINDINGS: Our search screened 4708 studies. 67 reassessed and 95 newly identified articles, reporting on 316&#x2008;131 participants and 11&#x2008;822 people with UIAs, were included in our meta-analysis. In the reference population, the estimated prevalence of UIAs was 3&#xb7;9% (95% CI 3&#xb7;0-5&#xb7;1). The prevalence of UIAs in individuals with atherosclerosis was 5&#xb7;5% (4&#xb7;7-6&#xb7;4; 2229 of 40970 participants) and the adjusted PR was 1&#xb7;3 (95% CI 0&#xb7;8-2&#xb7;0) compared with the reference population. For positive family history of aneurysmal subarachnoid haemorrhage (aSAH) or UIA, the UIA prevalence was 7&#xb7;9% (5&#xb7;6-11&#xb7;1; 412 of 4252 participants) and the adjusted PR was 2&#xb7;4 (0&#xb7;5-11&#xb7;2). For connective-tissue disorder, the UIA prevalence was 10&#xb7;3% (6&#xb7;5-16&#xb7;0; 94 of 879 participants) and the adjusted PR was 3&#xb7;9 (2&#xb7;0-7&#xb7;6). For autosomal dominant polycystic kidney disease (ADPKD), the UIA prevalence was 12&#xb7;8% (9&#xb7;2-17&#xb7;6; 293 of 1990 participants) and the adjusted PR was 4&#xb7;4 (1&#xb7;5-12&#xb7;6). RRs were for current smoking 1&#xb7;4 (1&#xb7;2-1&#xb7;6; 798 of 27911 participants), for having hypertension 1&#xb7;6 (1&#xb7;5-1&#xb7;7, 4043 of 83053 participants), and for female sex 1&#xb7;9 (1&#xb7;8-2&#xb7;0; 3415 of 65020 women and 2122 of 76130 men). In studies on healthy individuals with MR angiography or CT angiography as imaging modality, the prevalence in 2016-2022 was 6&#xb7;6% (6&#xb7;3-6&#xb7;8; 2904 of 41191 participants). The adjusted PR was 1&#xb7;8 (1&#xb7;1-2&#xb7;8) for 2016-2022 versus 2002-2015. Prevalence of UIAs of 5 mm or larger was 0&#xb7;7% (0&#xb7;6-0&#xb7;8) in 2002-2015 and 1&#xb7;4% (1&#xb7;0-1&#xb7;9) in 2016-2022. The UIA prevalence did not differ between countries. &#x3c4;2 showed significant heterogeneity between studies. The certainty of the evidence ranged from very low to moderate. INTERPRETATION: Prevalence of UIA is increasing, particularly over the past two decades. This increase is only in part explained by improved detection of small UIAs and an ageing population, and other factors-such as environmental-are likely involved. Alongside patients with ADPKD and a positive family history of aSAH, patients with connective-tissue disorders had a higher prevalence of UIA than the reference population. Our findings warrant further investigation into the potential benefit of personalised screening and management strategies in groups at high risk for having UIAs. FUNDING: None.

Humans

Microplastic contamination in South Asian commercially important seafood: A comprehensive assessment of occurrence, source, and human health risk.

Seafood is a cornerstone of global food security and human nutrition, serving as the primary source of animal protein for more than one-fourth of the global population, with South Asia representing one of the world's fastest-growing seafood-consuming regions. However, escalating microplastic (MP) pollution in marine ecosystems poses an emerging threat to seafood safety and human health, yet a comprehensive regional assessment of MP contamination in South Asian seafood remains lacking. This study presents the first region-wide systematic synthesis of the literature on MP contamination in commercially important seafood across South Asia, integrating occurrence patterns, human exposure assessment, polymer-specific hazard evaluation, and bibliometric analysis to address this critical knowledge gap. The meta-analysis estimated an average microplastic exposure of 145&#xa0;particles/person/day through seafood consumption in South Asia, with fish contributing the highest intake (121 particles/person/day). The detected polymers were classified into PHI hazard levels I-IV, with polyvinyl chloride (PVC), polyurethane (PU), and polyacrylamide (PAM) representing the highest hazard categories. The mean pollution load index (PLI) was 7.71 (Category I), with crustaceans exhibiting the highest contamination (PLI&#xa0;=&#xa0;10.07). Polypropylene was the predominant polymer, whereas fragments and blue particles were the most frequently reported microplastic characteristics. These findings provide the first regional baseline for assessing microplastic contamination, polymer-associated hazards, and human exposure through seafood consumption in South Asia, underscoring the need for standardized monitoring and targeted mitigation strategies to safeguard seafood safety and public health.

Animals

Criteria for Safe Hospital Discharge in Bronchiolitis: A Systematic Review.

Bronchiolitis is the leading cause of hospital presentation and admission for infants in Australasia. We aimed to synthesise current evidence on the effect of discharge criteria for infants (aged <&#x2009;12&#x2009;months) who are presenting to or are admitted to hospital with bronchiolitis, to inform a binational guideline recommendation update. Systematic searches were conducted on MEDLINE, EMBASE, PubMed, Cochrane Library and CINAHL (last search 19 February 2025) for non-randomised studies evaluating hospital discharge criteria in bronchiolitis. The primary outcomes were length of stay (LOS) and readmission rates. The risk of bias (ROBINS-I) and certainty of the evidence (GRADE) were appraised, and findings were narratively synthesised. GRADE evidence-to-decision methodology, expert consensus voting and interest-holder consultation were used to finalise the recommendation update. Two retrospective observational studies were included (N&#x2009;=&#x2009;2697) (low to very low quality), reporting on unique discharge criteria. In both studies, use of the discharge criteria was associated with a significant reduction in LOS relative to alternative protocols. There was no significant difference in readmission rates observed in either study. There was low to very low certainty evidence across outcomes due to risk of bias, indirectness and imprecision. The review findings informed a recommendation update for safe discharge criteria in the 2025 Australasian Bronchiolitis Guideline update. Updated, prescriptive discharge criteria and flow chart were developed, covering clinical stability, oxygen saturation/support, feeding difficulties, caregiver confidence and education on deterioration, social factors and follow-up. The revised criteria provide clinicians with increased certainty in decision-making in bronchiolitis, albeit with further research needed.

Humans

Safety of early discharge and abbreviated nimodipine course in patients with good-grade aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating cerebrovascular emergency associated with substantial morbidity and mortality. Current guidelines recommend 14-21&#xa0;days of inpatient monitoring and a 21-day course of nimodipine following aSAH. This retrospective study evaluates early outcomes early discharge (&#x2264;14&#xa0;days post-ictus) and an abbreviated nimodipine course in highly selected patients with good-grade aSAH managed under a standardized institutional protocol. Consecutive patients enrolled in the Vancouver Ruptured Aneurysm Database (VRAD) at Vancouver General Hospital between 2022 and 2025 were included. Inclusion criteria were good-grade aSAH (WFNS Grade I-III) and discharge home within 14&#xa0;days of ictus. The primary outcome was re-presentation to emergency care within 30&#xa0;days of discharge; secondary outcomes included hospital readmission and need for additional treatment. Of 333 total patients in VRAD, 49 patients met inclusion criteria. All patients received&#xa0;&#x2264;&#xa0;14&#xa0;days of nimodipine therapy. Forty-two patients (85.7%) were WFNS Grade I on presentation, 3 (6.1%) were WFNS Grade II, and 4 (8.2%) were WFNS Grade III. Radiographic vasospasm was reported in 18 cases (36.7%). No patients developed DCI or clinical vasospasm. Four patients (8.2%) re-presented to emergency care within 30&#xa0;days of discharge, and only one patient (2%) required hospital re-admission within 30&#xa0;days. While radiographic vasospasm was seen in over one third of patients, none developed clinical sequelae, supporting the premise that radiographic vasospasm alone may be insufficient to preclude early discharge in select good-grade patients.

Humans

Psychotherapy training in psychiatry: a systematic review and narrative synthesis on the supervision experiences of early-career psychiatrists.

BACKGROUND: Supervision is a fundamental component of psychotherapy training, transforming theoretical knowledge into clinical skills through real-world practice. Psychotherapy training practices vary widely between countries, training programs, and over time, including supervision. Our systematic review aimed to investigate and describe the experiences of psychotherapy supervision through early-career psychiatrists' (ECPs) views. METHODS: We systematically searched PubMed/MEDLINE, Scopus, and PubPsych for survey-based studies on ECPs' experiences of psychotherapy supervision during or after their psychiatry training and reported our findings according to the PRISMA guidelines. Of 32,877 articles screened, 29 articles were included. Each article underwent quality assessment, and results were synthesized narratively. RESULTS: Included articles published between 2000 and 2025, were from Europe (N = 16, 55.1%), the Americas (N = 5, 17.2%), Western Pacific (N = 4, 13.7%), South-East Asia (N = 2, 7%), Eastern Mediterranean (N = 1, 3.5%), and Africa (N = 1, 3.5%), with a total of 4691 participants. Supervision access rates ranged from 26.2% in Nigeria to 85.5% in Russia, with significant variation across countries and psychotherapy modalities. Most ECPs received 50-100 total hours of supervision, frequently delivered in weekly sessions. While formats, individual, group, or mixed, varied by country and training scheme, supervision was generally provided by a psychiatrist-psychotherapist. Common learning techniques included oral consultations and case discussions, followed by audio recordings or transcripts. The need to self-fund psychotherapy supervision costs was identified as a prominent barrier. CONCLUSIONS: Psychotherapy supervision is inconsistent globally, with barriers including supervisor availability and cost. There is a large implementation gap between recommendations and evaluated practice. Digital tools and competency-based frameworks may improve access and quality.

Humans

Littoral and wetland vegetation decrease carbon emissions from dry inland waters.

Lakes are recognized as active components of the inland water carbon (C) cycle, as organic matter is processed by microbial respiration, inducing large carbon dioxide (CO2) and methane (CH4) emissions. In the context of long-lasting drought periods, large uncertainties remain about: (1) the influence of wet-dry cycle on CO2 and CH4 fluxes in littoral zones and lacustrine wetlands; and (2) the contribution of emergent vegetation to C fluxes in dry inland waters. At the water-land interface of two shallow lakes, this study focuses on CO2 and CH4 fluxes from vegetated and bare dry inland waters in relation to hydrological fluctuations. Three seasonal campaigns were conducted to measure daytime CO2 and CH4 fluxes in pelagic, littoral and wetland surface waters, as well as in temporarily air-exposed sediments, using floating and static chambers, respectively. Our results reveal that wet-dry cycle in the littoral zone and wetlands strongly influence gaseous C fluxes through contrasting patterns, especially in late summer, when the biological processes are most active (primary production and respiration). In air-exposed littoral zones, organic-poor sandy sediments presented the lowest CO2 and CH4 emissions, whereas in air-exposed lacustrine wetlands, water-saturated sediments accumulated high amounts of plant-derived organic matter, promoting intense microbial activity and the highest C emissions. However, amphiphytes and helophytes vegetation in exposed littoral zones and wetlands reversed the direction of C fluxes, inducing the highest CO2 uptake due to high photosynthesis rates. This study underlines the relevance of considering vegetation in dry inland waters, particularly in lacustrine littoral zones and wetlands, to obtain comprehensive lake C budgets, especially under climate change scenarios.

Wetlands