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Imaging‑based models for predicting cerebrovascular complications of carotid stenosis.

This is a protocol for a Cochrane review (prognosis). The objectives are as follows: Primary objective To systematically review and critically appraise multivariable prognostic models developed for adults (≥ 18 years) with carotid stenosis in which imaging biomarkers (e.g. plaque characteristics derived from magnetic resonance imaging (MRI), computed tomography (CT), or ultrasound) constitute the core predictors. The primary focus is to evaluate the predictive performance of these models for cerebrovascular complications - specifically ipsilateral ischaemic stroke and transient ischaemic attack (TIA) - which are the clinical outcomes to be predicted. Where feasible, we will summarise and compare the models' discrimination (C‑statistic/area under the curve (AUC)) and calibration (calibration‑in‑the‑large, calibration slope, observed‑to‑expected ratio) across studies, and assess their potential for clinical application and external validation. For the purpose of defining symptomatic carotid stenosis as an eligibility criterion and subgroup variable, we will include studies that also considered retinal ischaemia (e.g. retinal embolism, amaurosis fugax) as a qualifying event. Secondary objectives To describe the combinations of imaging markers, modelling techniques, sample sizes, and variable‑selection strategies used in the development of the included models To evaluate the performance of these models for additional secondary clinical outcomes: plaque progression or regression, incident high‑risk imaging features, and the transition from asymptomatic to symptomatic disease To explore whether predictive performance differs according to imaging modality (MRI versus CT versus contrast‑enhanced ultrasound (CEUS)) or technical protocol (e.g. 3 T versus 1.5 T, spectral CT versus conventional CT) For studies that report both cerebrovascular and broader cardiovascular outcomes (major adverse cardiovascular events, myocardial infarction, etc.), we will only extract the performance metrics relating to cerebrovascular events for the primary analysis. Performance metrics for cardiovascular outcomes will be considered exploratory and will not form part of the main synthesis.

Humans

In Vivo Genome Editing Approach to Disrupt Hydroxyacid Oxidase 1 for the Treatment of Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder that leads to kidney and liver failure. PH1 is caused by a mutation in the alanine glyoxylate aminotransferase (AGXT) gene, which encodes a key metabolic enzyme that converts glyoxylate to glycine in the liver. Inability to metabolize glyoxylate leads to oxalate overproduction, yielding insoluble calcium oxalate crystals; accumulation of these crystals leads to progressive organ failure. Here, we used a novel, minimally disruptive genome-editing approach to disrupt the mechanism of action of hydroxyacid oxidase 1 (HAO1), an upstream enzyme in the glyoxylate metabolic pathway. Successful gene editing and disruption of the HAO1 gene is expected to increase levels of glycolate, a harmless intermediate of the glycine metabolic pathway, thereby preventing the formation of calcium oxalate crystals. We intravenously administered an adeno-associated virus (AAV) vector expressing the M1HAO1 meganuclease to both wild-type and Agxt-/- mice, a mouse model of PH1. We observed >30% editing of HAO1 in Agxt-/- mice, correlating with a dose-dependent increase in serum glycolate levels. At the highest dose tested, urine glycolate levels increased by 79%, with a concomitant 75% decrease in urine oxalate levels. We also evaluated in vivo targeting in rhesus macaques injected with AAV expressing two different versions of the HAO1 meganuclease. Dose-dependent editing of hepatic DNA and RNA was achieved, and serum glycolate levels changed in a manner consistent with successful liver editing; additionally, the treatment was well tolerated. Our results indicate that AAV-delivered meganucleases can effectively target HAO1 in mice and nonhuman primates to achieve high levels of HAO1 gene editing. Moreover, increased glycolate levels in serum indicate that this intervention significantly impacts the HAO1-mediated glycolate-to-glyoxylate pathway. These data suggest that this approach may represent an effective treatment for PH1.

Hyperoxaluria, Primary

Copper-Containing Surface Engineering for Soft-Tissue Biomedical Devices: Structure-Function Relationships and Ion Release-Driven Biological Performance, A Systematic Review.

Copper and copper-based materials have gained increasing attention for the functional modification of implantable medical devices intended for prolonged soft-tissue contact, including vascular stents, catheters, and intrauterine devices. Owing to their broad-spectrum antimicrobial activity, redox reactivity, and involvement in angiogenesis and cellular signaling, copper-based systems offer significant potential for multifunctional surface engineering. However, achieving a balance between antibacterial efficacy, corrosion behavior, controlled ion release, and cytocompatibility remains a critical challenge. This PRISMA-compliant systematic review analyzes copper-containing materials and surface modification strategies for soft-tissue biomedical applications. A structured search of Scopus, Web of Science, and PubMed (2015-2025) identified 65 eligible studies. The review encompasses bulk copper-containing alloys, electrochemical and chemical surface modification techniques, physical vapor deposition approaches, and advanced hybrid systems integrating copper with polymers, hydrogels, or metal-phenolic networks. Across the reviewed literature, antibacterial performance was strongly dependent on copper concentration, microstructural distribution, and spatiotemporal ion release profiles. Moderate, well-controlled copper incorporation frequently improved antibacterial efficacy while maintaining acceptable hemocompatibility and cytocompatibility, particularly in vascular and blood-contacting devices. In contrast, excessive copper loading often accelerated corrosion and induced adverse cellular responses. Emerging multifunctional architectures demonstrated improved regulation of biological interactions, enabling simultaneous antibacterial, antithrombotic, and proendothelial effects. Overall, copper-based surface technologies represent a versatile platform for soft-tissue implant modification. Future translational progress will require precise control of copper release kinetics and comprehensive long-term in vivo validation to ensure safety and sustained therapeutic performance. From the authors' perspective, the most promising future direction involves multifunctional copper-based hybrid coatings capable of dynamically regulating ion release, host tissue integration, and antibacterial performance simultaneously. Strategies integrating hierarchical architectures, stimulus-responsive release systems, and clinically scalable fabrication methods are expected to play a key role in translating copper-containing surfaces from experimental concepts toward commercially viable soft-tissue biomedical devices.

Copper

Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.

BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.

Journal Article

High-flow nasal cannula oxygenation in sedated endoscopy for high-risk obstructive sleep apnea patients: study protocol for a multicentre randomised controlled trial.

BACKGROUND: Hypoxemia is the most common adverse event during sedated gastrointestinal endoscopy. Patients with high obstructive sleep apnea (OSA) risk (STOP-Bang &#x2265;5) are susceptible due to sedation-induced loss of upper airway tone exacerbating airway collapsibility. Although high-flow nasal cannula (HFNC) benefits general at-risk populations, its efficacy in this specific cohort remains uncertain, as its mild positive pressure falls far below therapeutic continuous positive airway pressure levels for moderate-to-severe OSA, questioning its ability to stent the collapsible airway. Our prior proof-of-concept study in this cohort observed a 5% incidence of hypoxemia with HFNC, confirming feasibility and safety and justifying this confirmatory trial. METHODS: This prospective, multicenter, randomized controlled single-blind trial will enroll 600 adults (STOP-Bang score &#x2265;5) undergoing elective sedated gastroenteroscopy across three centers. Participants will be 1:1 randomized (stratified by center) to HFNC (30&#x2009;L/min pre-oxygenation, 60&#x2009;L/min post-induction) or conventional nasal cannula (6&#x2009;L/min). Both groups receive standardized propofol-alfentanil sedation. The primary outcome is the proportion of patients with at least one episode of hypoxemia (SpO2 75%-90% <60&#x2009;s). Secondary outcomes include the proportion of patients with at least one episode of severe hypoxemia (SpO2 <75% or 75%&#x2264;SpO2<90% &#x2265;60&#x2009;s), the proportion with subclinical respiratory depression (90%&#x2264;SpO2<95%), and the frequency of other adverse events. DISCUSSION: This trial will provide definitive evidence on HFNC's efficacy in high-risk OSA patients, addressing whether it can overcome pressure limitations to prevent hypoxemia. Results are expected to inform sedation management guidelines, establish a new standard of care for this subgroup, and enhance procedural safety. TRIAL REGISTRATION: The trial was registered at the ClinicalTrials.gov on 14 December 2025 (NCT07307560).

Humans

Finerenone and quality of life in heart failure: component-level analyses and clinical relevance of the Kansas City cardiomyopathy questionnaire.

AIMS: Finerenone was shown to improve overall health status, as measured by the aggregate 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) score, in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). This study aimed to contextualize KCCQ changes in a manner that is relevant to patients and clinicians, thereby improving understanding of this metric in HFmrEF/HFpEF. METHODS AND RESULTS: In this prespecified analysis of FINEARTS-HF, a double-blind, randomized, placebo-controlled trial of finerenone in HFmrEF/HFpEF, we performed exploratory assessments of treatment effects on mean score changes from baseline to 12 months for each of the 23 KCCQ components (scaled from 0 [worst] to 100 [best]) using multivariable linear regression. We further compared the impact of finerenone on the KCCQ-overall summary score (KCCQ-OSS) at 12 months with the expected decline per year. Of 6001 participants in FINEARTS-HF, 5006 completed the KCCQ both at baseline and 12 months (age: 72 &#xb1; 10 years, women: 45%, baseline KCCQ-OSS: 63.9 &#xb1; 22.0). Finerenone, compared with placebo, numerically improved all but one KCCQ component, with the greatest nominal improvement observed in lower limb oedema frequency (+2.5, 95% CI: 0.9-4.1), fatigue burden (+2.2, 95% CI: 0.9-3.5), fatigue frequency (+2.1, 95% CI: 0.7-3.6), and lower limb oedema burden (+1.8, 95% CI: 0.6-2.9). KCCQ-OSS at 12 months was inversely related to age, with finerenone shifting the age-KCCQ-OSS relationship by 4.7 (95% CI: 0.4-9.1) years. CONCLUSIONS: In FINEARTS-HF, finerenone was associated with modest improvements in health status-most notably lower limb oedema and fatigue-in patients with HFmrEF/HFpEF.

Humans

Psychological Capital and Perceived Stress in Nurses: The Mediating Role of Need for Recovery and Recovery Experiences.

AIM: To examine whether recovery experiences and need for recovery mediate the association between psychological capital and perceived stress in nurses. DESIGN: Cross-sectional online survey. METHODS: A total of 184 nurses currently practicing in France completed an anonymous online questionnaire administered in January 2023. Participants completed the French versions of the Psychological Capital Questionnaire, the Recovery Experience Scale, the Need for Recovery Scale, and the Perceived Stress Scale. Two mediation models were estimated using ordinary least squares regression with percentile bootstrap inference for the indirect effects. RESULTS: Psychological capital was positively associated with recovery experiences and negatively associated with need for recovery. Need for recovery was strongly and positively associated with perceived stress, while psychological capital showed no direct association with perceived stress. The indirect effect of psychological capital on perceived stress through need for recovery was statistically detectable, whereas a complementary indirect effect through recovery experiences was in the expected direction but did not meet the bootstrap criterion for statistical significance. CONCLUSION: In this cross-sectional sample, psychological capital was associated with lower perceived stress primarily through its association with reduced need for recovery rather than through a direct association with stress. Interventions intended to protect nurse well-being should therefore be conceived as combining individual resource-building with organizational architectures that enable effective recovery. IMPLICATION FOR NURSING PRACTICE: Psychological capital should be seen as one element in integrated interventions rather than a stand-alone solution to nursing stress. Brief recovery-focused interventions for nurses need to be combined with scheduling practices and organizational policies that protect rest and make recovery feasible, a configuration that appears more promising than psychological capital training alone. REPORTING METHOD: The study followed the STROBE Statement for the reporting of cross-sectional studies. NO PATIENT OR PUBLIC CONTRIBUTION: This study focused on nurses as study participants. No patient or public stakeholder was involved in the design, conduct, or interpretation of the research, since the research question concerns occupational psychological resources rather than clinical practice or care delivery.

Humans

Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin: A Randomized Controlled Trial.

BACKGROUND: Fear of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of community-acquired pneumonia (CAP) frequently leads to empiric vancomycin coverage. Data evaluating the use of MRSA polymerase chain reaction (PCR) nasal swab testing to guide vancomycin de-escalation is limited for patients in the intensive care unit (ICU). METHODS: Swab Testing to Optimize Pneumonia Treatment With Empiric Vancomycin (STOP-Vanc) is a pragmatic, prospective, single-center, non-blinded randomized trial in which adult ICU patients with suspicion of CAP were randomized 1:1 to receive usual care either with (intervention) or without (control) the addition of MRSA nares PCR testing following ICU admission. The primary outcome was vancomycin-free hours alive, defined as the expected number of hours alive and free of vancomycin use within the first 7 days of trial enrollment as estimated using a longitudinal proportional odds state transition model adjusted for baseline covariates. RESULTS: A total of 277 adult ICU patients were randomized. Methicillin-resistant Staphylococcus aureus PCR nasal swab testing had a negative predictive value (NPV) of 98.9% in the intervention arm. The primary endpoint, vancomycin-free hours alive, was 105.7 in the control arm and 109.7 in the intervention arm (adjusted difference, 4 hours; 95% CI, -9.5-18.2; P = .458). CONCLUSIONS: Despite MRSA PCR nasal swab testing demonstrating a high NPV in this critically ill population, MRSA PCR nasal swab testing did not decrease the duration of vancomycin use or 30-day mortality among ICU patients with suspected CAP. Additional clinician education and antimicrobial stewardship interventions might be needed to reduce vancomycin use in this patient population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT06272994 (STOP-Vanc).

Humans

Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.

BACKGROUND: Patients with chronic neurological diseases (CND) are at increased risk of pulmonary complications that often require ICU admission. This study aimed to identify clinical factors associated with ICU mortality and long-term survival in patients with CND who developed acute respiratory failure (ARF). METHODS: This retrospective cohort study was conducted in a level III respiratory ICU. Patients with pre-existing CND admitted to the ICU with ARF were included. ICU mortality was analyzed using multivariable logistic regression. Long-term survival after ICU discharge was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. Mortality timing was further characterized using hazard function analysis. RESULTS: A total of 220 patients were included; the most common neurological diagnoses were dementia (37.3%), stroke (22.7%), and amyotrophic lateral sclerosis (14.1%). ICU mortality was 33.6%. Higher APACHE II scores were independently associated with increased ICU mortality (OR 1.076 per point increase; 95% CI 1.029-1.126; p&#xa0;<&#xa0;0.001). Long-term survival differed significantly by post-discharge respiratory support strategy, with Kaplan-Meier analysis demonstrating more favorable survival patterns among patients receiving home non-invasive mechanical ventilation (NIMV) (p&#xa0;=&#xa0;0.003). In Cox regression analysis, age, home NIMV, and feeding modality at discharge were independently associated with long-term outcomes. Survival analyses revealed an early clustering of deaths within the first months after ICU discharge, particularly among patients with dementia. CONCLUSIONS: In patients with CND, acute physiological severity was the main determinant of ICU mortality, whereas long-term survival after ICU discharge was poor, with deaths clustering within the first months thereafter. Post-discharge respiratory support and nutritional management should be individualized according to the expected clinical trajectory and patient values.

Humans

RENOIR phase 3 rituximab-lenalidomide vs rituximab as maintenance treatment in relapsed/refractory follicular lymphoma.

Maintenance treatment in older patients with relapsed or refractory (R/R) follicular lymphoma (FL) remains an area of investigation. RENOIR was a multicenter, phase 3, open-label randomized trial conducted by the Fondazione Italiana Linfomi (FIL) in older patients with R/R FL after 1 or 2 previous therapies. Patients achieving partial response or complete response (CR) after 4 to 6 cycles of standard rituximab (R)-based chemotherapy were randomized 1:1 to maintenance with R alone (standard arm) or R plus lenalidomide (R2; experimental arm). The primary end point was 2-year progression-free survival (PFS) from randomization, with an expected hazard ratio (HR) of 0.5. A total of 152 patients (median age, 71 years) were enrolled. After induction, 129 (85%) achieved an overall response (CR, 58%) and were randomized to R (n = 65) or R2 (n = 64). At a median follow-up of 68 months, the 2-year PFS was 73% in the R2 arm and 64% in the R arm. An unplanned hypothesis-generating subgroup analysis showed a greater 2-year PFS benefit with R2 in patients aged <70 years: R2, 96% vs R, 69%. Two-year overall survival rates were similar (R2, 80% vs R, 89%). Grade 3/4 adverse events were more frequent in R2, mainly neutropenia and gastrointestinal disorders. In conclusion, the primary end point of the study was not met, and R2 maintenance did not significantly improve 2-year PFS in older patients with R/R FL, although a numerical benefit was observed. R2 showed a more favorable benefit-risk profile in patients aged <70 years, whereas in older patients careful consideration of individual tolerability is warranted. This trial was registered at www.clinicaltrials.gov as NCT02390869.

Humans

Exploring the perceptions, experiences, and behaviours that nurses and midwives face in relation to sleep: A systematic review of qualitative evidence.

BACKGROUND: The importance of sleep for nurses and midwives is increasingly being recognised. Poor sleep is known to have negative impacts on physical health, mental wellbeing, and work performance. This has prompted efforts to promote and support staff sleep. However, further efforts are needed to understand how nurses and midwives consider and manage sleep to ensure that meaningful and effective interventions are adopted and sustained. AIMS: This review of qualitative evidence aims to examine nurses' and midwives' perceptions, experiences, and behaviours around sleep. METHODS: This review followed JBI's systematic meta-aggregative approach including development of an a priori protocol. A systematic search of six electronic databases (MEDLINE, Embase, Emcare, PsycINFO, CINAHL, and Scopus) was undertaken to identify qualitative studies that examine nurses' and midwives' perceptions, experiences, and behaviours related to sleep. The search was conducted on the 10th of October 2024. Study selection, quality appraisal, data extraction, and synthesis followed JBI approaches and the ConQual approach was used to report assessment of synthesised findings. RESULTS: Thirty-three studies were included for review, and 245 findings were aggregated into 24 categories and nine synthesised findings related to the perceptions, behaviours, and experiences. While sleep was perceived as important, poor sleep was often understood as an expected and inevitable part of the job and that there was a need to always be awake to provide continual care. Experiences influencing sleep related to personal circumstances and work-related factors, as well as professional training and institutional practices. A range of behaviours, including planning time to sleep, using sleep aids, modifying the sleep environment, and altering daytime behaviours were also described. CONCLUSION: This review identified a range of perceptions, behaviours, and experiences that may influence the sleep of nurses and midwives which are vital to supporting individual and workforce wellbeing and safe, effective clinical practice. Insights from this review can be used to better understand nurses' and midwives' relationship with sleep and to develop and enhance targeted sleep interventions and programs that aim to promote and support healthy sleep among nurses and midwives. Open Science Framework Registration: 10.17605/OSF.IO/F32UM.

Humans

Volumetric bone marrow cellularity (VBMC) assessment from routinely processed trephines using three-dimensional x-ray histology and gaussian peak modelling.

Objective.Bone marrow cellularity is routinely estimated from a small number of two-dimensional histology sections, making assessment sensitive to section representativeness, processing artefacts and observer interpretation. Three-dimensional (3D) x-ray histology (XRH), using x-ray computed microtomography (&#xb5;CT), enables non-destructive whole-block imaging of trephine biopsies. This study evaluated whether XRH combined with Gaussian peak modelling could provide a pragmatic whole-block volumetric bone marrow cellularity (VBMC) estimate from formalin-fixed paraffin-embedded (FFPE) trephine biopsy blocks.Approach.Six routinely processed FFPE bone marrow trephine blocks were imaged using &#xb5;CT-based XRH at &#x223c;15 &#xb5;m spatial resolution. VBMC was defined as the red-marrow (RM) fraction of the marrow soft-tissue compartment, RM/(RM + intra-biopsy wax), with wax serving as the volumetric proxy for adipocyte/yellow marrow space. Whole-volume greyscale histograms were modelled using a three-peak Gaussian approach representing intra-biopsy wax, RM and demineralised trabecular matrix. Peak-height and area-under-the-curve metrics were compared with whole-volume 3D segmentation and clinical two-dimensional (2D) cellularity estimates.Main Results.Gaussian peak modelling successfully approximated the segmented tissue-phase distributions. The peak-height-derived VBMC metric showed the closest agreement with whole-volume 3D segmentation, with an average absolute percentage difference of 9.3%, compared with 18.6% for clinical expert 2D cellularity estimates. The area-under-the-curve metric followed similar trends but consistently overestimated VBMC. Clinical 2D cellularity broadly followed whole-biopsy trends but showed one discordant case not explained by slice-position sampling alone. XRH also enabled unrestricted virtual reslicing and visualisation of sectioning-associated artefacts prior to further microtomy.Significance.Pre-sectioning XRH combined with Gaussian peak modelling provides a rapid, segmentation-free route to volumetric cellularity estimation from intact clinical FFPE trephine blocks. The approach supports objective whole-biopsy assessment while remaining compatible with routine histopathology workflows, reflecting the expected limitations of section-based visual estimation despite its role as the current clinical standard. In the near term, it could provide a non-disruptive adjunct to conventional 2D cellularity reporting, pending larger validation studies.

Imaging, Three-Dimensional

Sex modifies the association of high-altitude hypoxia with poor sleep quality and depression in school-age children and adolescents.

BACKGROUND: While chronic exposure to high-altitude hypoxia is known to impair sleep and mental health, whether these effects are sex-dependent remains unclear. This study addresses a critical gap by investigating how sex modifies the association between high-altitude hypoxia and risks of poor sleep quality, depressive symptoms, and their co-occurrence in children and adolescents. METHODS: In this cross-sectional study (March-May 2024), we enrolled 1,345 long-term residents of the Shannan Tibet Autonomous Prefecture (altitude: 3,650-4,800&#xa0;m) and 2,909 age-matched controls from low-altitude plains (Anhui Province, China). Sleep quality and depression were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Montgomery-Asberg Depression Rating Scale (MADRS), respectively. Sex-stratified analyses and interaction metrics (RERI/AP/SI) were employed to evaluate additive and multiplicative effects. RESULTS: High-altitude residents exhibited significantly higher prevalence of poor sleep (24.2% vs. 18.7%, P&#x2009;<&#x2009;0.001), depression (23.6% vs. 15.3%, P&#x2009;<&#x2009;0.001), and their co-occurrence (12.6% vs. 8.6%, P&#x2009;<&#x2009;0.001) compared to low-altitude controls. A significant negative additive interaction (RERI&#x2009;=&#x2009;-&#x2009;0.78, 95% CI: -1.35 to -&#x2009;0.3; P&#x2009;<&#x2009;0.001) indicated that sex modifies the altitude-outcome association. Specifically: (1) high-altitude residence significantly increased poor sleep risk in males (OR&#x2009;=&#x2009;1.60, 95% CI: 1.26-2.03) but not in females (OR&#x2009;=&#x2009;1.39, 95% CI: 1.07-1.79); and (2) the expected female predominance in poor sleep observed in the plain region (OR&#x2009;=&#x2009;1.452, 95% CI: 1.191-1.769) disappeared in the plateau region (OR&#x2009;=&#x2009;0.865, 95% CI: 0.667-1.121). Similar patterns were independently replicated for depressive symptoms. These findings confirm that high-altitude exposure differentially increases risk in males rather than protecting females. CONCLUSION: Males show marked vulnerability to high-altitude-associated sleep and mood impairments, while females demonstrate resilience. Sex-tailored interventions for high-altitude populations, particularly targeting male adolescents, are urgently needed.

Humans

Toward personalized interventions for preventing depression in primary care: Qualitative and quantitative findings from the e-predictD pilot study.

BACKGROUND: The predictD intervention, delivered by family physicians (FPs), has demonstrated effectiveness and cost-efficiency in preventing depression and anxiety. The e-predictD study aims to design, develop, and evaluate a novel personalized intervention for depression prevention by integrating information and communication technologies (ICTs), risk prediction algorithms, and decision support systems (DSS) for both patients and FPs. OBJECTIVE: To evaluate the satisfaction, usability, and acceptability, of a beta version of the e-predictD intervention in primary care settings. METHODS: The e-predictD intervention follows a biopsychosocial approach, including an initial patient-FP interview, specific FP training, and an app. A &#x3b2;-version was tested in a pilot study without a control group over three months. The app integrates a validated depression risk prediction algorithm, decision algorithms, and a monitoring system supporting the DSS. The DSS generates a personalized prevention plan (PPP) from eight intervention modules: physical exercise, social relationships, problem-solving, communication skills, decision-making, assertiveness, sleep improvement, and cognitive restructuring. Patients and FPs discussed the PPP in a 15-minute baseline interview, selecting modules for implementation over three months. Semi-structured interviews gathered feedback. Assessments included depression (PHQ-9), anxiety (GAD-7), quality of life (SF-12), and major depression risk (predictD algorithm). RESULTS: Six FPs from six Spanish cities enrolled 56 non-depressed patients at moderate-to-high risk of depression; 47 (84%) completed follow-up. The app was used for a median of six days (interquartile range: 1-30). Both FPs and patients expressed satisfaction, leading to incorporated improvements. After three months, significant reductions in major depression risk and anxiety symptoms were observed, alongside improved mental quality of life. However, no significant changes were found in depressive symptoms or physical quality of life. CONCLUSION: This pilot study supports the feasibility and acceptability of the e-predictD &#x3b2;-version, despite lower-than-expected app usability. Health improvements were observed, warranting confirmation in a randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03990792.

Adult

Impact of PerioperAtive LidocAine Infusions on Enhanced Recovery After Noncardiac Surgery (IMPALA-ERAS) in an inpatient setting: rationale, design and protocol for a sequential, repeated crossover trial.

INTRODUCTION: Multimodal analgesic strategies designed to minimise perioperative opioid exposure are fundamental components of enhanced recovery after surgery (ERAS) pathways. Despite widespread implementation of ERAS protocols, the optimal analgesic regimen remains undefined, as the individual contributions of specific agents to overall analgesic efficacy and opioid-sparing effects are not fully elucidated. Intravenous lidocaine, a widely utilised local anaesthetic, possesses both analgesic and anti-inflammatory properties and has been associated with improved gastrointestinal recovery. This study seeks to pragmatically evaluate the impact of incorporating perioperative intravenous lidocaine infusion into established ERAS pathways on postoperative functional recovery. METHODS AND ANALYSIS: The Impact of PerioperAtive LidocAine Infusions (IMPALA) on ERAS trial is a single-centre, pragmatic, cluster-randomised, double-blinded, placebo-controlled study. A total of 2290 patients undergoing elective colorectal surgery, emergency general surgery, urology, ventral hernia repair, surgical oncology or spine surgery will be randomly assigned to receive either intraoperative and postoperative intravenous lidocaine infusions (administered for up to 48 hours) or placebo as part of a standardised multimodal analgesic regimen integrated into established ERAS pathways. The primary outcome is case mix index-adjusted resource length of stay, defined as the time interval from surgical initiation to hospital discharge adjusted for case mix index. The primary outcome is total inpatient opioid consumption within the first 72 hours, reported in oral morphine milligram equivalents. Secondary outcomes include various in-hospital clinical endpoints derived from the electronic health record. ETHICS AND DISSEMINATION: This protocol and accompanying statistical analysis plan outline the study design, primary and secondary endpoints and analytic methodology. The IMPALA-ERAS trial has received ethical approval from the Vanderbilt University Institutional Review Board (IRB: 250617). The findings will be disseminated via peer-reviewed publications and presentations at national conferences. Results from this trial are expected to inform evidence-based practices regarding perioperative lidocaine infusion and its potential contributions to enhanced postoperative recovery in surgical patients. TRIAL REGISTRATION NUMBER: NCT07224711.

Humans

Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis-version 1.

OBJECTIVE: To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs). METHODS: Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis. INFORMATION SOURCES: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95%&#x2009;CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available. RESULTS: We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as 'Norway 1' and 'Norway 2' for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%). CONCLUSIONS: In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.

Humans

Exploring the role of successful exercise-induced body weight loss on cardiometabolic health in individuals with metabolic syndrome.

BACKGROUND AND AIM: High-intensity interval training (HIIT) is known to improve cardiorespiratory fitness (i.e., VO2MAX), a key marker of cardiometabolic health in individuals with metabolic syndrome (MetS). Nonetheless, body weight loss is widely recognized as a crucial factor in reducing insulin resistance and improving metabolic risk factors. Thus, we aimed to determine the importance of body weight loss following exercise training on improving MetS. METHODS AND RESULTS: Two hundred and twenty-eight adults (55.3&#xa0;&#xb1;&#xa0;7.9&#xa0;yr) with overweight/obesity (32.5&#xa0;&#xb1;&#xa0;4.6&#xa0;kg&#xb7;m-2) and MetS were randomized to: a) standard health care non-exercise group (CONTROL group, N=58) or b) standard health care plus 16 weeks of HIIT (EXER group, N=170). MetS (MetS z-score), insulin resistance (HOMA-IR), cardiorespiratory fitness (VO2PEAK), maximal cycling power (WPEAK), and body weight/composition were assessed. After intervention, EXER group participants were divided according to their weight loss response to training: i) those achieving the weight loss predicted from estimated exercise energy expenditure (-BW group, n=78; -3.3&#xa0;&#xb1;&#xa0;2.2&#xa0;kg); ii) those not reaching the expected weight loss (=BW group, n=38; -0.7&#xa0;&#xb1;&#xa0;0.5&#xa0;kg); iii) and those who gained weight (+BW group, n=54; 1.1&#xa0;&#xb1;&#xa0;1.0&#xa0;kg). VO2PEAK significantly improved regardless of body weight loss response (-BW, 0.3&#xa0;&#xb1;&#xa0;0.3; =BW, 0.2&#xa0;&#xb1;&#xa0;0.3; +BW, 0.3&#xa0;&#xb1;&#xa0;0.2&#xa0;L&#xb7;min-1; all p&#xa0;<&#xa0;0.001) compared to CONTROL group (0.0&#xa0;&#xb1;&#xa0;0.3&#xa0;L&#xb7;min-1). However, significant improvements in MetS z-score (-0.31&#xa0;&#xb1;&#xa0;0.41) and HOMA-IR (-0.7&#xa0;&#xb1;&#xa0;1.6) were observed only in the -BW group (both p&#xa0;<&#xa0;0.001). CONCLUSIONS: Exercise recommendations should consider that greater improvements in MetS are observed when interventions are accompanied by successful body weight loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05120778.

Humans

Access to palliative care in rural settings: A mixed-methods systematic review.

BACKGROUND: Rural populations experience persistent inequities in access to palliative care. Existing evidence often describes individual barriers separately, with less attention to how access breaks down across the care pathway or how different service configurations shape access. OBJECTIVES: To synthesise evidence on access to palliative care in rural settings and examine how access barriers, service models, and implementation conditions interact across the care pathway. METHODS: A mixed-methods systematic review using a convergent integrated approach searched nine databases (PubMed, Embase, CINAHL, Web of Science, Scopus, PsycINFO, CNKI, WanFang, SinoMed) from inception to 15 March 2026, supplemented by hand-searching. Eligible studies were primary qualitative, quantitative, and mixed-methods studies on access to palliative care for adults in rural or non-urban settings. Two reviewers independently screened studies, extracted data, and assessed quality using the Mixed Methods Appraisal Tool. Findings were mapped to the Levesque access framework, analysed using the updated Consolidated Framework for Implementation Research, and integrated through mixed-methods synthesis, with additional coding of service models. RESULTS: Thirty-four studies were included, of which 26 were conducted in high-income countries and eight in low- and middle-income countries. Service configurations included specialist or hospice-oriented care, generalist or primary-care-oriented care, mixed specialist-generalist models, home-based and caregiver-centred care, nurse-coordinated services, telehealth-supported care, and community or implementation-oriented approaches. Access broke down cumulatively across four interdependent stages: recognition, entry, reach, and use and continuity, with affordability constraining every stage. Recognition was limited by low awareness, poor service visibility, and delayed identification of need. Entry was shaped by stigma, trust, family expectations, and unclear referral processes. Reach was constrained by distance, transport, workforce shortages, limited specialist capacity, and weak infrastructure. Use and continuity were affected by fragmented coordination, weak transitions, unstable follow-up, and reliance on family caregivers. Access problems varied across service configurations. Evidence on service innovations was methodologically less certain, and the overall evidence base remained concentrated in high-income countries. CONCLUSIONS: Access to palliative care in rural settings is best understood as a pathway and service-configuration problem rather than simply a deficit in service availability. Improving access requires earlier recognition, clearer referral routes, stronger specialist-generalist and nursing links, better support for family caregivers, and greater attention to affordability, continuity, and rural settings with limited resources. REGISTRATION: International Prospective Register of Systematic Reviews: CRD420261340783.

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