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PubMed2026

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 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 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↗

PubMed2026

Clinical accuracy and short-term outcomes of intraoral photogrammetry for complete-arch implant rehabilitation: A retrospective multicentre study on 35 patients.

OBJECTIVES: To evaluate the clinical accuracy and short-term outcomes of complete-arch implant-supported fixed dental prostheses (ISFDPs) fabricated using an intraoral photogrammetry (IPG) based digital workflow in completely edentulous patients. METHODS: This multicenter retrospective clinical study included 35 patients rehabilitated with 52 complete-arch ISFDPs (10 FP1, 18 FP2 and 24 FP3 restorations) supported by 221 implants. All definitive prostheses were designed and fabricated using a fully digital workflow initiated by IPG acquisition with the Aoralscan Elite IPG® (SHINING 3D). The primary outcome was clinical accuracy, assessed at definitive prosthesis delivery through evaluation of passive fit using the Sheffield test and radiographic verification. Secondary outcomes included biologic and prosthetic complications, as well as implant and prosthesis survival rates during the follow-up. RESULTS: Passive fit was achieved in all definitive restorations (100%). Radiographic evaluation confirmed accurate marginal adaptation at the implant-prosthesis interface in all cases. No statistically significant differences in clinical accuracy were observed according to treated arch, number of supporting implants, or prosthetic design (P > .05). During a mean follow-up period of 12.1 ± 3.5 months, biologic and prosthetic complications were limited and generally minor. Implant survival was 99.5%, and prosthesis survival was 100%. CONCLUSIONS: Within the limitations of this retrospective clinical study, the IPG based workflow demonstrated high clinical accuracy and predictable short-term outcomes for complete-arch implant rehabilitation, consistently enabling passive fit and favorable prosthetic performance. CLINICAL RELEVANCE: IPG may represent a clinically reliable and predictable approach for complete-arch digital implant impression acquisition. The high rates of passive fit, together with the low incidence of biologic and prosthetic complications observed in this multicenter clinical study, support the use of IPG based workflows for the fabrication of complete-arch ISFDPs.

Humans↗

PubMed2026

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

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

Humans↗

PubMed2026

Low-carbohydrate diet score subtypes and all-cause mortality in general and chronic disease populations: a systematic review and meta-analysis of prospective cohort studies.

OBJECTIVES: To examine associations of overall, healthy and unhealthy low-carbohydrate diet (LCD) scores with all-cause mortality in general and chronic disease populations. Healthy and unhealthy subtypes were compared with assess whether the observed associations depend on macronutrient quality rather than carbohydrate restriction alone. DESIGN: Systematic review and pairwise category meta-analysis. DATA SOURCES: PubMed, MEDLINE, ProQuest Medical Database and Web of Science Core Collection were searched from inception to 12 May 2026. ELIGIBILITY CRITERIA: Prospective cohort studies of adults assessing LCD adherence using a validated three-macronutrient composite score and reporting HRs for all-cause mortality were eligible. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed study quality using the Newcastle-Ottawa Scale (NOS). Random-effects meta-analyses compared each higher reported LCD category with the lowest category, stratified by LCD score subtype and population type. Certainty of evidence was assessed using NutriGrade. RESULTS: 18 prospective cohort studies included 779 158 participants and 219 457 deaths; all scored 7-9/9 on the NOS. In chronic disease populations, the highest healthy LCD category was associated with lower mortality than the lowest category (HR 0.72, 95% CI 0.69 to 0.76; I²=0%; high certainty), as was the highest overall LCD category (HR 0.85, 95% CI 0.75 to 0.96; I²=68%; high certainty). In the general population, the highest healthy LCD category was not associated with lower mortality than the lowest category (HR 0.93, 95% CI 0.85 to 1.01; I²=69%; moderate certainty), and neither was the highest overall LCD category (HR 0.96, 95% CI 0.90 to 1.03; I²=87%; low certainty). Unhealthy LCD scores were not associated with mortality in either population. CONCLUSIONS: Healthy LCD adherence was associated with lower all-cause mortality, particularly among individuals with chronic diseases. Unhealthy LCD scores were not associated with mortality in either population, suggesting that macronutrient quality and source may matter more than carbohydrate reduction alone.

Humans↗

PubMed2026

Increasing gut short-chain fatty acids protects intestinal barrier function but does not spare muscle glycogen or impact aerobic performance.

Animal studies suggest gut microbiota-derived short-chain fatty acids (SCFA) provide an intestinal barrier-protecting, glycogen-sparing energy source that increases aerobic endurance performance, but confirmation in humans is needed. This study aimed to determine whether increasing colonic SCFA availability impacts intestinal barrier function, substrate metabolism, muscle glycogen and aerobic performance in healthy adults. Using a randomized, double-blind, crossover design 12 active men (age 18-30 years;40.0 ± 7.1 mL/kg/min) performed prescribed exercise and consumed a provided diet supplemented with acetylated and butyrylated high-amylose maize starch engineered to deliver SCFA to the colon (HAMS-A/B) or low-amylose maize starch (LAMS) for 7 days, separated by a 2 week washout. Indirect calorimetry, stable isotopes and blood, muscle and urine biomarkers were measured on intervention day 8 while participants completed 90 min of steady-state cycle ergometry (ExSS; 60 ± 5%) followed by a 5 km treadmill time trial. HAMS-A/B, relative to LAMS, increased faecal and serum SCFA. Multiple markers of intestinal barrier damage and permeability were lower, and the respiratory exchange ratio during ExSS was higher (0.02 [95% confidence interval (CI): 0.01, 0.03], Ptreatment < 0.001) following HAMS-A/B versus LAMS. However no between-treatment difference in glucose turnover, muscle glycogen depletion (14 µmol/kg/g dry wt. [95% CI: -116, 143], Pinteractio n = 0.613) or TT performance (5 s [95%CI: -44, 54], Ptreatment = 0.816) was observed. Increasing colonic and circulating SCFA modestly altered substrate oxidation and preserved intestinal barrier function during endurance exercise. However effects were not sufficient to spare muscle glycogen or increase aerobic endurance performance, leaving the practical relevance unclear and underscoring challenges inherent in translating promising preclinical findings to humans. KEY POINTS: Animal studies suggest gut microbiota-derived short-chain fatty acids (SCFA) provide an intestinal barrier-protecting, glycogen-sparing energy source that increases aerobic endurance performance, but confirmation in humans is lacking. A gut microbiota-targeted dietary supplementation strategy was used to deliver SCFA to the colon and successfully increased colonic and systemic SCFA concentrations in healthy, physically active adults before and during an endurance exercise bout and aerobic performance test. Increasing colonic and systemic SCFA availability preserved intestinal barrier function but did not impact glucose turnover, alter protein expression in muscle or spare muscle glycogen during endurance exercise. Increasing colonic and systemic SCFA availability did not impact aerobic endurance performance.

Humans↗

PubMed2026

Smoke-Free Home Intervention in Permanent Supportive Housing: A Cluster Randomized Clinical Trial.

IMPORTANCE: Chronic diseases related to tobacco use and secondhand smoke exposure are the leading causes of death among formerly homeless adults living in permanent supportive housing (PSH) in the US. OBJECTIVE: To evaluate the efficacy of a brief, smoke-free home intervention in promoting voluntary smoke-free home adoption among PSH residents. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial, data collection occurred from January 11, 2022, to March 31, 2025. Participants were residents aged 18 years or older who smoked cigarettes at home in 40 multiunit PSH sites in the San Francisco Bay area, randomized to intervention or waiting list control clusters, and housing staff who worked at the study sites. INTERVENTION: Residents in intervention sites received one-on-one in-person coaching from research staff on adopting a smoke-free home; waiting list control site residents received no interventions during the study but were offered the intervention once the intervention group completed follow-up. Staff in both intervention and control sites received training on providing brief tobacco cessation coaching. MAIN OUTCOMES AND MEASURES: Primary outcomes were smoke-free home adoption for at least 90 days and 7-day carbon monoxide-verified point prevalence abstinence (PPA; expired carbon monoxide level ≤5 ppm) at 6 months. Secondary outcomes were any adoption (≥1 day) of a smoke-free home in the past 90 days among residents and changes in Smoking Knowledge, Attitudes, and Practices (S-KAP) scores among staff. RESULTS: The trial enrolled 400 residents (mean [SD] age, 54.5 [10.7] years; 251 [63.1%] male), 191 in the intervention and 209 in the control cluster. At 6 months, 13 residents (6.8%) in the intervention and 10 (4.8%) in the control group adopted a smoke-free home for at least 90 days (odds ratio [OR], 1.45; 95% CI, 0.69-3.07). Few residents achieved 7-day PPA, though more intervention residents (12 [6.3%]) achieved it compared with controls (2 [1.0%]) (OR, 6.94; 95% CI, 1.69-28.45). Intervention residents had greater odds than control residents of any smoke-free home adoption of at least 1 day (121 [63.4%] vs 77 [36.8%]; adjusted OR, 3.83 [95% CI, 2.63-5.57]). Among staff, mean (SD) S-KAP scores increased at 6 months vs baseline for beliefs (by 0.21 [0.55] points) and practices (by 0.24 [0.61] points) pertaining to providing cessation treatment. CONCLUSIONS AND RELEVANCE: In this cluster randomized clinical trial, the brief intervention did not result in a significant increase in smoke-free home adoption for at least 90 days, though more residents in the intervention than the control group attempted adoption for at least 1 day. These findings support the scalability of this approach to reduce smoking in PSH, but more intensive interventions may be needed to sustain intervention effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04855357.

Humans↗

PubMed2026

Pilot randomized trial of intermittent theta-burst stimulation versus H-Coil transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Intermittent theta burst stimulation (figure-8-coil iTBS) and H7-coil repetitive transcranial magnetic stimulation (rTMS) are FDA-cleared treatments for major depression; yet their comparative effectiveness in treatment-resistant depression (TRD) has not been evaluated in randomized trials. This pilot randomized trial was designed to obtain preliminary comparative estimates and to explore whether baseline cognitive functioning relates to early remission. METHODS: Twenty-eight adults with TRD were randomized to six weeks of figure-8-coil iTBS delivered to the dorsolateral prefrontal cortex (DLPFC) (n = 15) or H7-coil rTMS delivered to the dorsomedial prefrontal cortex (DMPFC) (n = 13). The primary outcome was change in 17-item Hamilton Depression Rating Scale (HRSD-17) score from baseline to week 6, analyzed with ANCOVA. Additional outcomes included response, remission, and symptom trajectories through week 18. Exploratory analyses examined the association between baseline cognitive functioning, such as executive functions and memory, and remission. RESULTS: Twenty-five participants completed all 30 sessions. Adjusted week-6 HRSD-17 scores did not differ between groups (mean difference -0.40, 95% CI -5.23 to 4.43; p=.865). Response rates were 40.0% for figure-8-coil iTBS and 50.0% for H7-coil rTMS (p>.60), and remission rates were identical across groups (20.0%). Remitters showed higher baseline executive functioning than non-remitters in exploratory analyses, although these associations were not confirmed in adjusted models. CONCLUSION: In this pilot trial, figure-8-coil iTBS and H7-coil rTMS showed symptom improvement, with no clear between-group differences. Exploratory findings suggest a potential signal involving executive functioning that warrants further investigation. These results inform the feasibility and design of larger comparative trials. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05902312).

Adult↗

PubMed2026

Lateral Femoral Condyle Angle Is an Anatomic Risk Factor for Anterior Cruciate Ligament Primary Injury and Secondary Graft Rerupture.

PURPOSE: To define the lateral femoral condylar angle (LFCA)-a parameter measuring condylar inclination-and assess its predictive capacity for primary and recurrent anterior cruciate ligament (ACL) injuries. METHODS: Patients aged 18 to 50 years who underwent primary ACL reconstruction between 2017 and 2022 were screened. Those with graft rerupture were matched 1:1:1 by sex, age, body mass index, and meniscal status to ACL-intact controls and patients without graft failure during a minimum 48-month follow-up. LFCA was measured as the angle between the long axis of the distal femur and the axis of the lateral femoral condyle, alongside 38 established parameters using preoperative 3.0-T magnetic resonance imaging scans. Intergroup differences were assessed with one-way analysis of variance; multivariate regression and receiver operating characteristic analyses identified independent predictors and evaluated predictive performance. RESULTS: The study included 540 patients (180 per group: primary ACL injury, rerupture, controls). One-way analysis of variance revealed a significant gradient in LFCA across controls (81.3°, 95% CI: 80.8-81.8°), primary injuries (81.9°, 95% CI: 81.5-82.3°), and reruptures (84.2°, 95% CI: 83.7-84.6°) (P < .001). In multivariate models adjusted for baseline factors, LFCA independently predicted primary injury (odds ratio [OR] = 1.27, 95% CI: 1.13-1.42, P < .001; area under the curve [AUC] = .576) and rerupture (OR = 1.46, 95% CI: 1.21-1.76, P < .001; AUC = .704). Combined models incorporating LFCA with tibial slopes, notch angle, and notch height achieved an AUC of .847 for primary injury prediction, whereas models with LFCA, lateral condylar flexion curvature radius, slope asymmetry, and tibial AP distance reached an AUC of .817 for rerupture. LFCA alone with lateral condylar flexion curvature radius yielded an AUC of .777 for rerupture prediction. Sex-stratified analyses confirmed LFCA predicted rerupture in both male patients (OR = 1.44, 95% CI: 1.19-1.75) and female patients (OR = 1.49, 95% CI: 1.16-1.92), and primary injury in male patients (OR = 1.30, 95% CI: 1.15-1.48). CONCLUSIONS: LFCA is an independent predictor of ACL injury, showing particular strength in identifying Asian patients at high risk for graft rerupture. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

Humans↗

PubMed2026

Evaluation of pilocarpine effects on sweat proteome.

BACKGROUND: Sweat is increasingly recognized as a valuable, non-invasive biofluid for biomarker discovery, yet its composition depends on the stimulation method. This study aimed to determine how pharmacological induction with pilocarpine compares to physiologically induced sweat through exercise in shaping the sweat proteome. RESULTS: We analyzed thermoregulatory sweat from exercise, pilocarpine-induced sweat, and combined pilocarpine plus exercise sweat. Total protein concentrations were similar across conditions, but pilocarpine markedly increased proteomic diversity, with combined pilocarpine plus exercise sweat showing the highest number of identifications. The core sweat proteome remained stable, while pilocarpine selectively enriched low-abundance proteins involved in vesicular trafficking, cytoskeletal remodelling, and metabolism. Proteins linked to the canonical M3-Gq-PLC-Ca2+ pathway, including AQP5, CALML5, and CLIC1, were consistently enriched, confirming cholinergic activation. Pilocarpine-induced sweat also contained plasma-derived and immune-related proteins, reflecting enhanced secretion and reduced ductal reabsorption. CONCLUSIONS: Exercise yields a physiologically relevant but less complex proteome, pilocarpine-induced sweat produces a pharmacologically enriched yet biased profile, and combined pilocarpine plus exercise sweat maximizes protein detection at the expense of interpretability. These findings highlight the critical impact of stimulation paradigm on sweat proteomics and provide a reference framework for biomarker research. SIGNIFICANCE: This study employed LC-MS/MS to systematically characterize eccrine sweat and delineate how stimulation paradigms-exercise, pilocarpine, and their combination-shape its proteomic landscape. By demonstrating that pharmacological induction profoundly alters protein diversity and composition compared to physiologically induced sweat, these findings establish a critical benchmark for sweat-based biomarker research and highlight the need for paradigm-aware sampling strategies in clinical and translational contexts. Nonetheless, several methodological constraints warrant consideration: the limited sample size (five individuals per group), the exclusive inclusion of women under combined oral contraceptive treatment (21 active pills followed by 7 pill-free days), which restricts extrapolation to naturally cycling women, and the focus on healthy young adults (18-25 years), limiting generalizability to older or clinically heterogeneous populations. Despite these limitations, this work provides a foundational framework for optimizing sweat collection protocols and advancing precision approaches in non-invasive diagnostics.

Pilocarpine↗

PubMed2026

Effects of antidepressant administration on physical performance and perceived exertion in athletes: systematic review and meta-analysis.

INTRODUCTION: Antidepressants are commonly prescribed in athletes with depressive disorders, yet their potential effects on physical performance and perceived exertion remain unclear, and existing evidence is limited and inconsistent. AIM: This systematic review and meta-analysis aimed to evaluate the effects of antidepressant use on objective physical performance and perceived exertion in athletes. METHOD: A systematic literature search was conducted in PubMed, the Cochrane Library, Web of Science, and SPORTDiscus through March 2025. Eligible studies were randomised controlled trials (RCTs) published in English that enrolled elite, competitive, or recreational athletes; compared antidepressant administration with placebo or no treatment; and reported at least one objective or subjective performance-related outcome. Meta-analyses were performed using random-effects models, and pooled mean differences with 95% confidence intervals (CI) were calculated. This systematic review and meta-analysis was registered in PROSPERO (CRD420251123740). RESULTS: Ten crossover RCTs involving 99 male athletes were included. Interventions included a norepinephrine reuptake inhibitor (reboxetine), a norepinephrine-dopamine reuptake inhibitor (bupropion), and selective serotonin reuptake inhibitors (fluoxetine or paroxetine). Acute antidepressant administration was associated with a small increase in rating of perceived exertion (RPE; mean difference 0.52 points on the Borg 6-20 scale, 95% CI 0.01-1.04; p < 0.05). No significant overall effects were observed for time-trial performance, mean power output, heart rate or blood lactate. However, subgroup analyses showed that reboxetine significantly impaired time-trial performance (mean difference 3.62 min, 95% CI 0.18-7.06; p < 0.05) and reduced mean power output (mean difference - 19.97 W, 95% CI - 36.87 to - 3.06; p < 0.05). CONCLUSION: Short-term antidepressant administration in athletes was associated with a small increase in perceived exertion, without consistent impairment in objective physical performance. As the current evidence derives exclusively from male athletes and acute exposure, further research should clarify its relevance to female athletes and to longer-term antidepressant treatment in athletes with depressive disorders.

Humans↗

PubMed2026

Conduction System Pacing Versus Right Ventricular Pacing in Patients With Atrioventricular Block and Anticipated High Pacing Burden.

Right ventricular pacing (RVP) in patients with atrioventricular (AV) block and high anticipated pacing burden is associated with pacing-induced cardiomyopathy (PICM) in approximately 12% to 20% of patients, whereas conduction system pacing (CSP) preserves more physiologic ventricular activation and may mitigate these consequences; the totality of contemporary randomized evidence has not been systematically pooled. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing CSP with RVP in patients with AV block or anticipated high ventricular pacing burden and a minimum 6-month follow-up, with co-primary outcomes of PICM incidence and change in left ventricular ejection fraction (ΔLVEF) and secondary outcomes of heart failure hospitalization (HFH), all-cause mortality, composite clinical endpoint, and paced QRS duration (PROSPERO CRD420261400227); random-effects meta-analysis used DerSimonian-Laird estimation. Five RCTs (LBBP-FAVOUR, CSPACE, Prague CSP, PACE-HF, STAY; N = 806) met inclusion criteria. CSP significantly reduced PICM (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.18 to 0.48; p <0.001; I² = 0%; k = 4), was associated with greater LVEF preservation (pooled mean difference [MD] +4.41%, 95% CI +1.82 to +6.99; p = 0.001; I² = 87%; k = 5), and reduced HFH (HR 0.24, 95% CI 0.12 to 0.48; p <0.001; I² = 0%; k = 5). CSP shortened paced QRS duration (MD -27.5 ms, 95% CI -32.6 to -22.5; p <0.001; k = 5). All-cause mortality was numerically lower with CSP but did not reach significance (HR 0.57, 95% CI 0.29 to 1.12; p = 0.10; k = 4). In a prespecified sensitivity analysis restricting to multicenter trials with N ≥ 150, all findings were concordant with the primary analysis. In conclusion, CSP substantially reduces PICM, preserves LVEF, and reduces HFH compared with RVP in patients with AV block and anticipated high pacing burden, supporting its consideration as the preferred pacing strategy in appropriately selected patients.

Humans↗

PubMed2026

Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock.

BACKGROUND: Whether treatment with balanced crystalloid fluid leads to better outcomes than 0.9% saline in children treated for septic shock is debated. METHODS: In this pragmatic clinical trial conducted at 47 emergency departments in five countries, patients (2 months to <18 years of age) with suspected septic shock and abnormal perfusion were randomly assigned to receive fluid resuscitation with either balanced fluid or 0.9% saline for up to 48 hours. The primary outcome was a major adverse kidney event (a composite of death, new renal-replacement therapy, or persistent kidney dysfunction) at 30 days after enrollment or hospital discharge, whichever occurred first. RESULTS: Of 9041 enrolled patients, 277 (6.1%) in the balanced-fluid group and 282 (6.2%) in the 0.9%-saline group withdrew from the trial, leaving 4235 and 4247 patients, respectively, for analysis. A primary-outcome event occurred in 137 patients (3.4%) in the balanced-fluid group and in 124 (3.0%) in the 0.9%-saline group (difference, 0.4 percentage points; 95% confidence interval [CI], -0.5 to 1.3; risk ratio, 1.10; 95% CI, 0.88 to 1.40; P = 0.85). The median number of hospital-free days during 28 days after enrollment was 23 (interquartile range, 19 to 25) in both groups. Hyperchloremia occurred in 868 patients (31.4%) in the balanced-fluid group and in 1383 (49.0%) in the 0.9%-saline group; hypernatremia in 52 (1.8%) and 89 (3.1%), respectively; and hyperlactatemia in 260 (19.8%) and 228 (16.7%). No differences in other safety outcomes or adverse events were seen. CONCLUSIONS: Among children treated for septic shock, no significant difference was seen in the incidence of death, new renal-replacement therapy, or persistent kidney dysfunction when fluid resuscitation was administered with balanced fluid as compared with 0.9% saline. (Funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; PRoMPT BOLUS ClinicalTrials.gov number, NCT04102371.).

Adolescent↗

PubMed2026

Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.

BACKGROUND: Impaired cognitive functioning is a severe symptom in major depressive disorder (MDD). Recent evidence suggests it may be a central characteristic in its treatment resistant form (TRD), potentially constituting a clinical marker for treatment resistance and a target amenable to intervention. To date, cognitive functioning in TRD remains poorly understood and longitudinal investigations are scarce. METHODS: This observational prospective cohort study, including 320 patients diagnosed with MDD from the multicentre PROMPT study, examined differences in cognitive functioning between 118 TRD and 202 non-TRD patients over a period of twelve weeks in a real-world setting, using linear mixed modelling. Patients that failed to respond to at least two prior antidepressants trials at baseline were classified as TRD. RESULTS: TRD patients showed significantly poorer baseline performances than non-TRD patients in attention/processing speed (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) and verbal memory (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003). Significant time × group interactions were observed in motor speed and verbal fluency tasks. Post-hoc-analyses revealed stagnation in TRD patients and significant improvement in non-TRD patients. Across all other tasks improvement was observed in both groups, and random effects showed large heterogeneity between patients, indicating notable individual differences in cognitive performances. CONCLUSIONS: The results suggest distinct recovery patters between non-TRD and TRD patients, and diminished functioning in TRD patients at the domain level. However, intact and diminished performances likely occur in both groups, warranting further investigation of cognitive heterogeneity. These short-term findings highlight the need for more comprehensive longitudinal research on cognition in TRD.

Humans↗

PubMed2026

Surgical outcomes and complications of fixation strategies for distal tibial fractures: a systematic review and network meta-analysis.

BACKGROUND: Multiple fixation options exist for distal tibial fractures, but the optimal approach remains controversial. Common techniques includeopen reduction and internal fixation(ORIF), minimally invasive plate osteosynthesis (MIPO), external fixation combined with limited open reduction and internal fixation (EF + LORIF), intramedullary nailing (IMN), and retrograde tibial nailing (RTN). METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched through March 19, 2026. Network meta-analysis (R v4.5.1) assessed operation time, fracture healing time, malunion, delayed union/nonunion, and infection, reporting MDs or RRs with 95% CIs. RESULTS: Eleven randomized controlled trials and 18 cohort studies (2145 patients) were included. MIPO was associated with a longer operative time and a longer time to union than IMN-IP (MD = 8.23, 95% CI 0.44-16.01; and MD = 1.02, 95% CI 0.10-1.93, respectively). For malunion, ORIF had a lower risk than MIPO (RR = 0.30, 95% CI 0.11-0.82), whereas MIPO had a higher risk than EF + LORIF (RR = 3.26, 95% CI 1.08-9.80) and IMN-SP (RR = 4.03, 95% CI 1.30-12.48). ORIF, EF + LORIF, and IMN-SP also showed lower malunion risk than IMN-IP. No significant differences were observed for delayed union and nonunion. Infection risk was generally higher with ORIF and MIPO than with several comparators, particularly EF + LORIF and intramedullary nailing-based strategies. CONCLUSIONS: No single strategy was consistently superior. Operation time and impaired union ( delayed union and nonunion) did not differ significantly among techniques. MIPO may be associated with longer time to union than IMN-IP and higher malunion risk than EF + LORIF and IMN-SP. Infection risk appeared higher with ORIF and MIPO in network estimates, although several comparisons remained uncertain. Findings should be interpreted in light of imprecision and study-level heterogeneity. PROTOCOL REGISTRATION: INPLASY2025120055.

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PubMed2026

The impact of acute sleep fragmentation on muscle blood flow responses to handgrip exercise.

Sleep fragmentation is reported to impair resting vascular function. The aim of this study was to test the hypothesis that acute sleep fragmentation would impair muscle blood flow during exercise. Twenty adults (10 females and 10 males) participated in a randomized crossover study that included one night of habitual sleep and one night of fragmented sleep. Sleep was assessed at home using wrist actigraphy. Arousals from sleep were increased by an audio alarm sounding every 30 min. The morning following each sleep condition, participants performed single handgrip contractions and rhythmic handgrip exercise at 15%, 30%, and 45% MVC. Forearm blood flow (FBF) was measured using Doppler ultrasound. Nightly awakenings and wake after sleep onset significantly increased by 18% and 43%, respectively, after fragmented sleep, leading to lower sleep duration (P < 0.001). Peak FBF and total hyperemic responses following single contractions were similar between sleep conditions (all P > 0.05). During rhythmic handgrip exercise, brachial artery dilation was reduced after fragmented sleep (main effect: 5.5 ± 4.8 vs. 3.3 ± 3.7%; P = 0.01), leading to a lower FBF response to rhythmic exercise (main effect: 122 ± 58 vs. 110 ± 56 mL/min; P = 0.04). Endothelial sensitivity to shear rate was similar between sleep conditions (habitual vs. fragmented: 0.039 ± 0.024 vs. 0.042 ± 0.031%/s-1; P = 0.77). In summary, acute sleep fragmentation decreases skeletal muscle blood flow during exercise. This finding suggests that blunted oxygen delivery may be a contributing factor for exercise performance deficits after disturbed sleep.NEW & NOTEWORTHY We demonstrate that one night of fragmented sleep decreases steady-state blood flow and vascular conductance during low- to moderate-intensity handgrip exercise. This impairment was not due to an impaired rapid vasodilation to single contractions nor altered endothelial sensitivity to shear rate as these variables were unchanged after acute sleep fragmentation. These results reveal a negative impact of disrupted sleep on the steady-state muscle vasodilatory response to rhythmic contractions.

Humans↗

PubMed2026

Prognostic effect of serum glial fibrillary acidic protein and neurofilament light chain for predicting progression independent of relapse activity in multiple sclerosis: A systematic review.

BACKGROUND: Progression independent of relapse activity (PIRA) is increasingly appreciated as one of the important factors contributing to disability accumulation in MS. sGFAP and sNfL could represent markers reflecting two separate biological processes related to relapse-independent progression in MS. OBJECTIVE: To perform a systematic review of the literature on blood GFAP and/or NfL measured in relation to PIRA or other similar relapse-independent progression endpoints in people with MS. METHODS: PubMed, Scopus, and Web of Science databases were searched from inception to 1 June 2026. The eligible studies were original human studies measuring blood GFAP and/or NfL concentrations in serum, plasma, or any other type of blood-derived material and assessing PIRA, PIRMA, CDP/CDW without relapses, relapse-free EDSS progression, non-inflammatory progression, or comparable relapse-independent disability worsening outcomes. Methodological quality was assessed according to the Newcastle-Ottawa scale and the QUIPS instrument for bias detection in the body of evidence on prognostic factors. Due to heterogeneity of outcomes, biomarker measurements and effect estimates, results were synthesized qualitatively rather than quantitatively. RESULTS: After removing duplicates, 1206 records were screened, followed by full-text review of 120 reports. A total of 18 reports were included. Overall, sGFAP was associated more frequently with PIRA or PIRA-like disability progression, particularly in cohorts with suppressed or limited overt inflammatory activity. Evidence for sNfL was more variable and context-dependent: several studies reported associations with PIRA-like or relapse-independent disability worsening when acute inflammatory activity was absent, suppressed, or analytically separated, whereas other studies reported negative or inconclusive findings. Negative or inconclusive results were reported by several articles, particularly when broad outcomes were evaluated or the study population was small. CONCLUSION: Blood GFAP and NfL give complementary but non-interchangeable information concerning PIRA in MS patients. The existing evidence base does not allow us to perform meta-analysis because of heterogeneity in terms of outcomes, standardization of biomarkers, and treatment context. Further prospective investigations with uniform criteria will be necessary for their use as biomarkers of PIRA in clinical settings.

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PubMed2026

The tunica vaginalis flap as a rescue procedure in testicular torsion: Quantifying salvage rates with matched cohorts.

INTRODUCTION: Testicular torsion is the most common urological emergency in children, and the role of tunica albuginea fasciotomy with tunica vaginalis flap (TVF) in its treatment is controversial. The objective of this study was to evaluate the outcomes among patients undergoing TVF, standard orchiopexy (SO), and orchiectomy, with attention to symptom duration. METHODS: We performed a retrospective review of boys aged 1 month-18 years who underwent surgery for testicular torsion at a single centre from 2010 to 2024. Clinical, ultrasonographic, and operative variables were abstracted, and testicular salvage was defined as a follow-up volume ≥50% of the contralateral testis with blood flow. Propensity score matching for age, symptom duration, and parenchymal heterogeneity generated TVF-SO and TVF-orchiectomy cohorts. Salvage was further stratified by duration of symptoms (<6, 6-12, 12-24, >24 h). RESULTS: Among 157 patients, 31 (20%) underwent orchiectomy, 39 (25%) TVF, and 87 (55%) SO. Overall salvage was 54%, differing by procedure (SO 82%, TVF 36%, orchiectomy 0%; p < 0.001). In the TVF-SO matched cohort (n = 64), salvage was 38% for TVF and 59% for SO (p = 0.133). In the TVF-orchiectomy matched cohort (n = 38), salvage was 32% in the TVF group and 0% in the orchiectomy group (p = 0.02). Salvage after TVF declined steeply with ischemia time, with higher rates observed within 6 h of presentation. DISCUSSION: These findings suggest that TVF is used predominantly in high-risk torsion with adverse ultrasound features. When viewed descriptively, the TVF cohort showed lower follow-up viability than the SO cohort, but this difference must be interpreted in the context of the different intraoperative and preoperative risk profiles underlying procedure selection. We highlight TVF as a valuable additional consideration compared to outright orchiectomy. CONCLUSION: In this retrospective cohort, TVF was used in clinically severe torsion and was associated with follow-up viability in a subset of cases. These descriptive findings support further prospective study but should not be interpreted as evidence of equivalence or comparative benefit of TVF.

Humans↗

PubMed2026

Vesicoureteral reflux and anorectal malformations.

BACKGROUND: Renal and urinary tract anomalies are frequently associated with anorectal malformations (ARMs) and may adversely affect long-term renal outcomes, if not detected early. However, reliable clinical predictors for significant urologic abnormalities across different ARM phenotypes remain poorly defined. OBJECTIVE: To determine the prevalence and grade distribution of vesicoureteric reflux (VUR) in neonates with ARMs, and to explore its association with renal and urinary tract anomalies, the complexity of the ARM phenotype, and other factors are associated with high-grade VUR. METHODS: In this retrospective cross-sectional study, medical records of 64 neonates diagnosed with ARMs and managed at a tertiary children's hospital between 2018 and 2025 were reviewed. All patients underwent renal and urinary tract ultrasonography. Voiding cystourethrography (VCUG) was performed for all neonates according to our institutional protocol, regardless of ultrasound findings or ARM phenotype. Demographic characteristics, ARM phenotype (less-complex vs. complex), urologic findings, urinary tract infection (UTI) history, and associated anomalies were analyzed. Multivariable logistic regression models were used to identify independent predictors of complex ARM phenotype and high-grade VUR. RESULTS: The cohort consisted of 64 neonates (75% male) with a mean gestational age of 37.36 ± 1.83 weeks and a mean birth weight of 2940 ± 601 g. Renal and urinary tract anomalies were common, with hydronephrosis observed in 48.4%, VUR of any grade in 39.1% and hydroureter in 35.9%,of patients. High-grade VUR was identified in 21.9% of patients, and a documented history of UTI was present in 18.8% of the entire cohort. In multivariable analyses, birth weight, presence of VUR, and UTI history were not independently associated with complex ARM phenotype. Additionally, no demographic or clinical variables reliably predicted high-grade VUR. The predictive performance of the regression model for high-grade VUR was limited (AUC = 0.60). CONCLUSION: Renal and urinary tract anomalies are highly prevalent among neonates with ARMs, with VUR representing a prominent finding. The lack of robust clinical predictors for complex ARM phenotype or high-grade VUR underscores the limitations of selective screening strategies and supports the role of comprehensive urologic evaluation in neonates with ARM, regardless of anatomic subtype.

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