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PubMed2026

A polygenic risk score for peripheral artery disease and major adverse limb events.

BACKGROUND AND AIMS: Large-scale genome-wide association studies have identified common genetic variants that predict the risk of peripheral artery disease (PAD). This study assessed whether a polygenic risk score (PRS) is associated with PAD and the incidence of major adverse limb events (MALE) independent of clinical risk factors in patients with established cardiometabolic disease. METHODS: A genetic analysis was performed, pooling individual patient-level data from six TIMI trials. The association of a recently validated PAD PRS with prevalent PAD and the incidence of MALE (acute limb ischaemia, chronic limb-threatening ischaemia, major amputation, or peripheral revascularization) was assessed. RESULTS: A total of 68 816 patients were included in this analysis, with a median follow-up of 2.6 years. Of these, 5986 (8.7%) had known PAD at baseline. After adjusting for clinical risk factors, a higher PAD PRS was independently associated with a 15% greater odds of prevalent PAD (adjusted odds ratio per 1-SD: 1.15 [95% confidence interval 1.12-1.18], P < .0001), a magnitude of risk as strong as established clinical risk factors. A total of 577 patients experienced MALE during follow-up. A higher PAD PRS was associated with a 30% increased risk of MALE (adjusted hazard ratio per 1-SD: 1.30 [1.19-1.42], P < .0001). Adding the PAD PRS to clinical risk factors resulted in a statistically significant but modest improvement in discrimination (area under the curve went from 0.651 to 0.662 P < .0001). CONCLUSIONS: In a broad spectrum of patients with cardiometabolic disease, the PAD PRS is associated with an increased risk of PAD and the incidence of MALE beyond clinical risk factors; however, the improvement in discrimination was statistically significant but clinically modest.

Humans↗

PubMed2026

Unravelling Ovarian Cancer: an analysis of the Influence of LRP1 and PAI1 Genetic Variations.

To assess the potential association between LRP1 (rs715948) and PAI1 (rs2227631, rs1799889) gene variation and ovarian cancer (OC) susceptibility. This study evaluated the genotypic and allelic distributions of LRP1 gene and PAI1 gene variants using Restriction Fragment Length Polymorphism (RFLP) analysis in 134 °C patients and 134 healthy controls. LRP1 (rs715948) showed a significant association with OC risk. The TC genotype was (OR = 3.7823, 95% CI: 2.1732-6.5825, p < 0.0001), and the CC genotype has (OR = 2.1613, 95% CI: 1.0054-4.6459, p = 0.0484). The C allele was significantly more frequent in cases (46%) than controls (32%) (OR = 1.7684, 95% CI: 1.2443-2.5133, p = 0.0015). For PAI1 (rs2227631), AG and GG genotypes showed no significant association (p = 0.3519 and p = 0.1165, respectively). PAI1 (rs1799889) AG genotype was (OR = 5.855, 95% CI: 2.4663-13.9027, p < 0.0001), while GG genotype showed no significance (p = 0.1025). The dominant model of LRP1, (TC + CC) and C alleles, were significantly more frequent in OC cases, indicating a potential risk factor. In contrast, the dominant models (AG + GG) and G alleles of PAI1 (rs2227631, rs1799889) showed no significance with OC susceptibility. Genetic variation in LRP1 (rs715948) significantly associated with increased OC risk, particularly the TC and CC genotypes and C allele. The C allele of this gene is key markers linked to higher OC susceptibility. Whereas in PAI1 (rs2227631, rs1799889), dominant models (AG + GG) show no significance, association suggesting a less prominent role in OC susceptibility. These findings highlight LRP1 as a potential genetic biomarker for OC risk assessment, while the role of PAI1 variants warrants further investigation in larger sample size.

Humans↗

PubMed2026

Long-term motor outcomes after parent-administered early physiotherapy in children born very preterm.

OBJECTIVE: This observational follow-up study investigated whether early parent-administered physiotherapy during the neonatal period was associated with motor outcomes in childhood, and compared these outcomes between two preterm groups and a term-born control group. STUDY DESIGN: This is a follow-up of a pragmatic randomised controlled trial that initially included 153 infants born very preterm (≤32 weeks' gestation), randomised to either early parent-administered physiotherapy or standard care, between 34 and 37 weeks' gestation. At 7-10 years, motor outcomes were assessed in 92 children (intervention, n = 43; standard care, n = 49) and in 83 term-born controls. The primary outcome was the Movement Assessment Battery for Children-Second Edition (MABC-2). Group differences were analysed using linear mixed models adjusted for age, sex, and parental education. Odds ratios (ORs) were calculated for scores ≤5th and ≤ 15th percentiles to estimate the likelihood of having or being at risk for movement difficulties. RESULTS: Mean MABC-2 total score was 9.0 (SD3.0) in the intervention group, 9.6 (SD3.0) in the standard care group, and 10.8 (SD2.9) in the control group. Adjusted mean difference between the intervention and the standard care groups did not differ but both the intervention and standard care groups had lower scores than the control group (-1.2; 95% CI: -2.3 to -0.2 and -0.6; 95% CI: -1.6 to 0.3, respectively). Adjusted ORs for scoring ≤5th or ≤15th percentile did not differ in either preterm group compared with the control group. CONCLUSION: At 7-10 years, motor outcomes did not differ between children born very preterm who received three-week parent-administered physiotherapy and those who received standard care during the neonatal period. However, both preterm groups had lower motor scores than term-born peers.

Humans↗

PubMed2026

Does impulsivity predict treatment outcomes in PTSD with borderline personality disorder features? Results from a randomized clinical trial.

BACKGROUND: Trauma-focused psychotherapies are first-line treatments for posttraumatic stress disorder (PTSD). However, a substantial proportion of clients do not respond adequately or drop out of therapy prematurely. This has sparked interest in identifying individual-level predictors of treatment outcomes, including improvement in PTSD severity and dropout. Impulsivity may be a predictor because it may interfere with key therapeutic processes, such as cognitive restructuring and emotional processing. Consequently, we present a hypothesis-driven secondary analysis of a 15-month randomized clinical trial comparing Dialectical Behavior Therapy for PTSD (DBT-PTSD) and Cognitive Processing Therapy (CPT) in women with childhood abuse-related PTSD and borderline personality disorder features to test whether impulsivity, assessed at baseline, predicts PTSD improvement and dropout. We further explore whether the dimensions of impulsivity (non-planning, attentional impulsivity, and motor impulsivity) differentially affect the outcomes in DBT-PTSD vs. CPT. METHODS: A total of 193 cis women with PTSD related to childhood abuse and borderline personality disorder features were assessed using the Clinician-Administered PTSD Scale (CAPS) and the Barratt Impulsiveness Scale (BIS-10). Separate probit models and general linear models were applied to predict dropout and pre-to-post changes in PTSD severity (ΔCAPS) from total impulsivity and subscale scores, i.e. non-planning, attentional and motor impulsivity. RESULTS: Overall, dropout rates were higher for participants with higher baseline impulsivity scores (p = 0.049), particularly for those with higher non-planning impulsivity (p = 0.012). In participants randomized to CPT improvement in PTSD symptom severity (ΔCAPS) was negatively related to baseline total impulsivity (p = 0.021). In participants randomized to DBT-PTSD this relation was not significant. CONCLUSIONS: The results suggest that impulsivity may predict treatment outcomes. Specifically, patients with elevated impulsivity may be less likely to respond adequately to CPT. If replicated, these findings have implications for personalization of treatment.

Humans↗

PubMed2026

Visualizing the future: impact of holographic visualization on teaching minimally invasive veneer preparation: a randomized controlled trial.

BACKGROUND: Minimally invasive veneer preparation in prosthodontic education requires advanced spatial understanding and psychomotor precision. Although immersive technologies are increasingly used in dental education, evidence regarding the educational effectiveness of holographic visualization in prosthodontics remains limited. This randomized controlled trial evaluated the impact of holographic visualization on preparation quality and student-reported educational outcomes during preclinical training in minimally invasive veneer preparation. METHODS: Sixty undergraduate dental students were randomly assigned to receive either conventional two-dimensional photographic visualization (n = 30) or holographic three-dimensional visualization (n = 30). Following a standardized calibration session and baseline preparation, participants performed a second veneer preparation after exposure to the assigned visualization modality. Preparations were independently assessed by two blinded evaluators using a predefined scoring rubric. Within-group changes were analysed using Wilcoxon signed-rank tests, and between-group differences were assessed using analysis of covariance adjusted for baseline performance. Student-reported outcomes were compared using Mann-Whitney U tests with false discovery rate correction. RESULTS: Both groups showed significant improvements in preparation quality from baseline to post-intervention (both p < 0.001). However, no significant between-group differences were observed (adjusted mean difference: 0.60 points; 95% confidence interval: -0.48 to 1.67; p = 0.269). Overall student-reported outcomes were comparable between groups. Spatial understanding showed the largest between-group effect in favour of holographic visualization, although this difference was not significant after correction for multiple comparisons. Holographic visualization was highly accepted by students, and 70% supported its future integration into dental education. CONCLUSIONS: Although holographic visualization did not significantly improve immediate preparation quality compared with conventional two-dimensional photographs, it was highly accepted by students and showed the largest observed effect for perceived spatial understanding. These findings suggest that holographic visualization may primarily support spatial understanding and represent a valuable adjunct for teaching complex three-dimensional concepts in preclinical prosthodontic education. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00040713, prospectively registered on 22 June 2026.

Humans↗

PubMed2026

Paediatric penile length: a systematic review and meta-analysis.

OBJECTIVE: To assess geographical variation in stretched penile length among prepubertal boys and evaluate temporal trends over the past two decades, as defining reference values for genital organ size remains crucial for early identification of development disorders. METHODS: The PubMed, Cochrane and Scopus databases (no deadlines for publishing were imposed) were searched according to the Preferred Reporting Items for Systematic Review and Meta-analyses statement. Five authors independently extracted individual participant data and assessed the risk of bias. Studies with quantitative penile lengths were included; those involving congenital malformations were excluded. The review protocol was prospectively registered in the International Prospective Register of Systematic Reviews (registration number CRD42022335643). RESULTS: A total of 55 studies from 2000 to 2024 were evaluated, including data from 31 915 boys. Pooled mean stretched penile length estimates were 3.07 cm (95% confidence interval [CI] 2.88-3.26 cm) for the 1-week-old boys, 3.73 cm (95% CI 3.53-3.93 cm) for the 1-year-old boys, 4.69 cm (95% CI 4.49-4.88 cm) for the 2-5 year-old boys, and 5.43 cm (95% CI 5.20-5.66 cm) for the 5-10 year- old boys. When comparing data from the 2000s to the 2020s, stretched penile length decreased by 16.2% (from 3.46 to 2.90 cm), 16.3% (from 4.17 to 3.49 cm), 21.5% (from 5.31 to 4.17) and 26.2% (from 6.46 to 4.77 cm) in the 1-week-old, 1-year-old, 2-5-year-old and 5-10-year-old boys, respectively. Subgroup analysis for those aged >2 years showed significant variations by geographical region (P < 0.001). CONCLUSIONS: The present study observed large variations in penile length across geographical regions and among prepubescent boys of different ages, while also suggesting a possible decline over the past two decades.

Humans↗

PubMed2026

Targeting depression before it starts: An updated systematic review and meta-analysis of preventive interventions in young adults from randomized controlled trials.

INTRODUCTION: Young adulthood is a high-risk period for major depressive disorder (MDD) onset yet is underrepresented in prevention research. This systematic review and meta-analysis examined the effectiveness of psychosocial preventive interventions in adults aged 18-25 years, focusing on symptom reduction, medium- and long-term effects, and MDD onset. METHODS: We conducted a PRISMA-compliant systematic review and meta-analysis (PROSPERO: CRD42024625481) of randomized controlled trials (RCTs) of psychosocial preventive interventions for depression in young adults (18-25) published up to April 15, 2025. Between-group symptom reduction was quantified using Hedges' g and pooled with random-effects models. Outcomes were analyzed at post-intervention, 6-, and 12-month follow-up. Effects on MDD onset were assessed via risk ratio (RR). Risk of bias was assessed with the RoB-2 tool. RESULTS: We included 65 interventions from 58 RCTs (N = 11,333; mean age 20.4; 61.6% female), with 92.8% rated high risk of bias. Interventions at post-test reduced depressive symptoms vs. controls (k = 65; g = -0.52; 95%CI:-0.70;-0.33; p < 0.01), with significant heterogeneity (I2 = 93.0%). Indicated, guided, and face-to-face interventions outperformed universal, selective, self-guided, and online interventions. Effects on symptomatology were highly heterogeneous and non-significant at 6- (k = 8) and 12-month (k = 4) follow-up. Four RCTs were identified evaluating MDD onset risk; pooled effects suggested a reduction in MDD onset (RR = 0.77; 95%CI:0.61;0.97; p < 0.01) though risk of bias was high and samples were highly selective. INTERPRETATION: Psychosocial preventive interventions modestly reduce depressive symptoms at post-test and may lower onset risk in highly selective populations. However, findings remain limited by high risk of bias, scarce data on the long-term sustainability of effects, and unclear mechanisms.

Adolescent↗

PubMed2026

Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults.

BACKGROUND: Guanidinoacetic acid (GAA) supplementation has been reported to increase brain creatine content more effectively than creatine monohydrate (CrM). However, the effects on cognitive function are unclear. PURPOSE: The purpose of this proof-of-concept exploratory clinical trial was to determine whether GAA supplementation with and without CrM affects cognitive function and/or markers of health. METHODS: In a double-blind, randomized, and counterbalanced manner, 58 healthy and active adults (33 females, 35.5 ± 14 years, 76.2 ± 14 kg) ingested a PLA (PLA, 2 × 6 g/d maltodextrin), GAA (2 × 1 g/d) + PLA (2 × 5 g/d), or GAA (2 × 1 g/d) + CrM (2 × 5 g/d) for six weeks. The participants donated fasting blood samples and completed a battery of tests and questionnaires assessing various aspects of function, mood, stress, sleep quality, and markers of health at baseline and after six weeks of supplementation. Data were analyzed using General Linear Model (GLM) multivariate and univariate with repeated measures, and mean changes from baseline with 95% confidence intervals, and Chi-squared analysis, and considered significant when the probability of error was 0.05 or less, and approaching significance (p > 0.05-p < 0.10). RESULTS: GAA supplementation tended to improve overall reaction time (-241.8 ms [-533, 50], p = 0.10) while significant interaction effects were observed in overall reaction time (p = 0.031-330 ms [-629, -31]) and YES reaction time (-290 ms [-484, -96], p = 0.004) while recalled correct reaction time (-178 ms [-374, 21], p = 0.078) and recalled correct YES (7.4 % [-1, 15.8], p = 0.084) approached significance compared to PLA. Limited to no effects were observed on the Delayed Picture Recognition Task Test, Digit Vigilance Task Test, Corsi Block Task Test, or Stroop Color-Word Task Test. The amount of time engaged in moderate physical activity was significantly greater (p < 0.05) in the GAA group compared to PLA. Participants in the GAA group reported a lower frequency of controlling irritations (p = 0.036), and feeling like difficulties are mounting (p = 0.053) on the Perceived Stress Scale. Some positive and potentially undesirable effects were observed in sleep quality assessments. The quality of life assessment revealed that participants in the GAA group reported less frequent feelings of being worn out (p = 0.068) and that their health was excellent (p = 0.092) while those in the GAA + CrM group reported more frequent limitations when bending, kneeling, or stooping (p = 0.053), more often feeling full of life (p = 0.081), and less frequency in feeling downhearted and depressed (p = 0.066). No clinically meaningful changes were observed in blood markers or self-reported side effects among the groups. CONCLUSION: Dietary supplementation with GAA (2 g/d) and the combination of CrM (10 g/d + GAA 2 g/d) for six weeks improved delayed verbal episodic recognition memory and retrieval speed and some measures of perceived stress, sleep quality, and quality of life. However, most cognitive tests were not affected, particularly when comparing the GAA to the PLA group; there were some inconsistencies in the findings, and several differences only approached significance. Additional research is needed before conclusions can be drawn. Clinical trial registration: ISRCTN68542582.

Humans↗

PubMed2026

Five-year outcomes in a randomised controlled trial of prolonged exposure therapy and supportive counselling for post-traumatic stress disorder in adolescents: a task-shifted intervention.

BACKGROUND: Cognitive-behavioural therapies with a trauma focus are effective in reducing posttraumatic stress disorder and other psychological distress in adolescents. Long-term follow-up data on adolescents treated for PTSD remain scarce, with few studies extending beyond 12 months after treatment completion. OBJECTIVE: To evaluate the maintenance of treatment gains in a comparative study of effectiveness of PE-A and SC up to 60 months post-treatment. METHOD: Sixty-three adolescents diagnosed with PTSD were randomly assigned to either treatment, provided by newly trained and supervised non-specialist health workers. The primary outcome measure was PTSD symptom severity, as independently assessed on the Child PTSD Symptom Scale (CPSS). We report on the 60-month post-treatment follow-up, building on post-treatment, 3-month, 6-month, 12-month and 24-month post-treatment data that have been published previously. RESULTS: Participants in both treatment groups maintained a significant reduction in PTSD symptoms up to 60-months post-treatment (F (7, 343) = 2.86, p < .01). Participants receiving prolonged exposure experienced greater improvement on the CPSS at all follow-up assessment timepoints, except for the 60-month FU (p = .28; g = 0.33). CONCLUSION: Adolescents with PTSD continued to maintain treatment gains up to 60-months post-treatment. These data, along with findings from the original RCT, indicate that a brief treatment protocol (averaging 9 sessions of PE-A or SC) in a LMIC, task-shifted to be delivered by nurses without prior psychotherapy experience, led to lasting improvements in PTSD and comorbid symptoms for up to five years. The sustained benefits and improved functioning over the first few years post-treatment support expanding both treatments, especially PE-A, in community settings.

Humans↗

PubMed2026

The impact of supernormal lung function on mortality risk in adults with and without sleep-disordered breathing.

BACKGROUND: In the general population, supernormal lung function is associated with a lower risk of all-cause mortality. RESEARCH QUESTION: It remains unclear whether sleep-disordered breathing (SDB) affects this relationship. METHODS: This cohort analysis included 4,839 adults. Lung function was categorised as supernormal (FEV1 > ULN), normal (LLN ≤ FEV1 ≤ ULN), and below normal (FEV1 < LLN). SDB severity was classified using apnoea-hypopnoea index categories: no SDB (<5 events/hour), mild SDB (5-<15 events/hour), moderate SDB (15-<30 events/hour), and severe SDB (≥30 events/hour). The association between lung function and all-cause mortality was assessed using Cox proportional hazards models with subgroup analyses according to SDB severity and formal testing for interaction. Analyses were repeated using FVC-defined lung function groups as an alternative definition of supernormal lung function. RESULTS: Among the included participants, 4,068 (84.1%) had normal lung function, 369 (7.6%) had supernormal lung function, and 402 (8.3%) had below normal lung function. During 52 421.5 person-years of follow-up (median 11.72 years; IQR, 10.46-12.56), 1,188 deaths occurred. Compared with the normal lung function group, the supernormal lung function group had a lower prevalence of baseline hypertension and cardiovascular disease. The association between lung function and all-cause mortality varied across SDB severity strata (P for interaction = 0.034). A lower mortality risk associated with supernormal lung function was observed in participants without SDB (HR: 0.24, 95% CI: 0.06-0.97), whereas this association was not statistically significant in the mild, moderate, or severe SDB strata. Below normal lung function was generally associated with an increased all-cause mortality risk. Sensitivity analyses using FVC-defined lung function groups yielded broadly consistent findings. CONCLUSION: Supernormal lung function was associated with lower all-cause mortality primarily among individuals without SDB. These findings underscore the importance of considering SDB severity when assessing the health implications of lung function.

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.

Humans↗

PubMed2026

Ketamine assisted psychotherapy to reduce chronic neuropathic pain: A mixed-methods randomized pilot trial.

BACKGROUND: Intravenous ketamine can provide short-term analgesia in chronic neuropathic pain but benefits often wane after treatment. We conducted a randomized pilot trial to assess the feasibility of combining ketamine infusions with psychotherapy to inform future efficacy trials. METHODS: In this single-center, randomized, outcome-assessor-blinded pilot trial at a Canadian tertiary pain clinic, adults with moderate-to-severe chronic neuropathic pain were randomly assigned in 1:1:1 ratio to the ketamine, psychotherapy, or combined ketamine plus psychotherapy arm. Ketamine was delivered as three intravenous infusions over 16 weeks; psychotherapy consisted of 16 weekly cognitive behavioral therapy and mindfulness-based meditation sessions. The primary outcome was feasibility, assessed using prespecified progression criteria. Exploratory outcomes included changes in pain interference (PROMIS 6a T-score), pain intensity, mood, and qualitative interview findings at week 20 (ClinicalTrials.gov: NCT05639322). FINDINGS: Between October 23, 2023, and March 31, 2025, 30 participants were randomized, and 26 (87%) completed 20-week follow-up. Most feasibility criteria, including consent, retention, data completeness, and absence of study-related serious adverse events, were met; adherence targets were partially met. Exploratory pain outcomes showed numerical improvement across groups, with clinically meaningful reductions observed for pain interference and pain intensity. Sixty-four adverse events were recorded, mostly mild and in ketamine-containing groups; no serious study-related adverse events occurred. CONCLUSIONS: Combined ketamine and psychotherapy was feasible and acceptably safe in this pilot trial, supporting evaluation in a larger efficacy-powered study. FUNDING: The study was funded by the St. Michael's Hospital Innovation Fund, The Canadian Pain Society Early Investigator Award and the Physician Services Incorporation Early Career Researcher Award.

Humans↗

PubMed2026

Comparison between the thoracoabdominal rebalancing (TAR) method and the slow expiratory flow acceleration (SEFA) technique in preterm newborns: protocol for a randomised controlled clinical trial.

INTRODUCTION: Preterm newborns (PTNB) present respiratory immaturity and increased susceptibility to muscle fatigue. The thoracoabdominal rebalancing (TAR) method is a physiotherapeutic intervention developed in Brazil that aims to reorganise the synergy of the thoracoabdominal muscles and reduce the effort of the respiratory muscles, a benefit that is particularly important for PTNB; however, the evidence regarding its effectiveness in this population remains inconclusive. Therefore, this study aims to compare the short-term effects of the TAR method and the slow expiratory flow acceleration (SEFA) technique in improving respiratory distress and peripheral oxygen saturation (SpO2) in PTNB admitted to neonatal intensive care unit (NICU). METHODS AND ANALYSIS: The study will be a randomised, controlled, two-arm, parallel-group, single-blind clinical trial. 68 participants will be randomly assigned to one of the two treatment groups. Group 1 will receive four handling techniques of the TAR method for 10 min, followed by the rhinopharyngeal retrograde clearance with saline instillation (RRC+I) technique. Group 2 will receive the SEFA technique for 10 min, also followed by RRC+I. Primary outcomes are respiratory distress and SpO2. Secondary outcomes are respiratory rate (RR), heart rate (HR), pain, behaviour and diaphragmatic excursion. Assessments will be conducted by a blinded researcher at baseline (T0), immediately after the intervention (T1) and at the 30-minute follow-up (T2). Data will be described using measures of central tendency and dispersion and absolute and relative frequencies. An intention-to-treat analysis will be performed, and intragroup and intergroup comparisons will be assessed using generalised estimating equations (GEE). ETHICS AND DISSEMINATION: The Research Ethics Committee of the Faculty of Health Sciences of Trairi of the Federal University of Rio Grande do Norte approved this study (number 8,055,786). The results will be disseminated through peer-reviewed journal publications, scientific conferences presentations and knowledge translation to the public. TRIAL REGISTRATION NUMBER: This study was registered on Brazilian Registry of Clinical Trials (ReBEC) on 9 January 2026 (RBR-3gbsyc2).

Humans↗

PubMed2026

Premeal insulin administration lowers postprandial blood glucose and increases myocardial microvascular blood flow in people with type 1 diabetes: a randomised, crossover clinical trial.

AIMS/HYPOTHESIS: We aimed to evaluate whether prandial insulin timing affects vascular function in people with type 1 diabetes. Our hypothesis was that premeal insulin administration would lead to greater myocardial microvascular blood flow (MBF) via blunting postprandial hyperglycaemia. METHODS: People with type 1 diabetes between 18 and 35 years of age with BMI <30 kg/m2 underwent two protocols with a 1:1 randomised crossover design wherein prandial insulin was injected either 15 min before or 15 min after meal intake began. To provide a physiological comparison, age-, sex- and BMI-matched control participants completed one study where they consumed the same meal but received no exogenous insulin. Glucose, insulin, vascular function (including ultrasound measures of myocardial and skeletal muscle microvascular perfusion, aortic stiffness, brachial artery endothelial function) and biomarkers of systemic inflammation and endothelial dysfunction were assessed at baseline and then 2 h after meal ingestion within each protocol. The primary outcome was change in myocardial MBF within each protocol. Study personnel assessing outcomes were masked to group assignment. RESULTS: Eighteen people with type 1 diabetes and 18 matched control participants were analysed within each protocol. Glucose area under the curve was significantly greater (p=0.015) in the postmeal insulin study compared with the premeal insulin study in participants with type 1 diabetes. Myocardial microvascular flow velocity significantly increased (p=0.031) with premeal insulin administration in people with type 1 diabetes and this consequently led to greater myocardial MBF (p=0.044). There were no changes in myocardial MBF within the other protocols. Changes in vital signs were similar between all protocols. CONCLUSIONS/INTERPRETATION: Appropriately timed premeal insulin led to lower postprandial blood glucose along with increased myocardial MBF in people with type 1 diabetes. Further work is needed to determine the underlying aetiology of these changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04730882.

Humans↗

PubMed2026

Ameliorating Effects and Autonomic Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation on Abdominal Pain in Patients With Functional Dyspepsia and Irritable Bowel Syndrome.

BACKGROUND: Patients with functional dyspepsia (FD) and irritable bowel syndrome (IBS) often experience abdominal pain and reduced quality of life and need effective treatments. This exploratory study aimed to evaluate whether transcutaneous auricular vagus nerve stimulation (taVNS) could improve abdominal pain and quality of life in patients with FD and IBS, and whether the effects were mediated via the autonomic mechanisms. METHODS: A total of 64 patients with abdominal pain (43 FD and 21 IBS) with a pain score of 3 out of 10 or higher were randomized to receive 2 weeks of taVNS or sham-taVNS treatment. The primary outcome was numeric rating scale (NRS) for abdominal pain. The dyspeptic symptom scales (DSS), IBS symptom severity scale score (IBS-SSS), anxiety and depression scores, and the SF36 quality of life scale were assessed before and after the treatment. The electrocardiogram was also recorded for the assessment of autonomic function at baseline and after the treatment. KEY RESULTS: (1) taVNS reduced the abdominal pain score (p < 0.001 for both FD and IBS), the frequency of abdominal pain (p < 0.001 for both FD and IBS), and overall symptom scores in both FD patients and IBS patients (p < 0.001 for FD and IBS). There was no significant difference in the effect of taVNS on abdominal pain between FD and IBS patients. (2) taVNS improved quality of life compared with baseline in both FD and IBS patients. (3) taVNS decreased anxiety (p < 0.001) and depression (p < 0.001). (4) taVNS increased vagal activity. At the end of the taVNS treatment, the vagal activity was negatively correlated with the pain score (r = -0.491, p = 0.004). CONCLUSIONS: Non-invasive taVNS improves abdominal pain, quality of life, and anxiety and depression in patients with FD and patients with IBS, possibly attributed to the enhancement of vagal activity. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2400085697.

Humans↗

PubMed2026

Impact of smoking on structural failure after arthroscopic rotator cuff repair: a systematic review and meta-analysis.

BACKGROUND: Rotator cuff tears cause significant shoulder pain and functional limitation. Arthroscopic rotator cuff repair improves symptoms, yet structural failure rates remain substantial. Smoking may impair tendon-to-bone healing, but clinical studies report mixed findings due to heterogeneous methodology. Therefore, a systematic synthesis of imaging-confirmed outcomes is needed to clarify the association between smoking and structural failure after arthroscopic rotator cuff repair. METHODS: This review followed PRISMA 2020 and was registered in PROSPERO (CRD420251246197). PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 12 December 2025. Comparative clinical studies of adults undergoing arthroscopic rotator cuff repair that reported imaging-confirmed structural integrity (magnetic resonance imaging or ultrasonography) at ≥6 months were included. Two reviewers independently screened studies, extracted data, and assessed quality using the Newcastle-Ottawa Scale. The primary outcome (structural failure) was pooled as risk ratios using a random-effects model with the restricted maximum likelihood estimator and Hartung-Knapp adjustment. Secondary continuous outcomes were synthesized using Bayesian random-effects models; subgroup, sensitivity, and meta-regression analyses explored heterogeneity. RESULTS: Ten cohort studies (1,683 shoulders) were included. Smoking was associated with a higher risk of imaging-confirmed structural failure (risk ratio 1.53; 95% confidence interval 1.13-2.08; P = .011) with low heterogeneity (I2 = 24.7%). Subgroup and sensitivity analyses supported robustness, with no evidence of effect modification by region, follow-up duration, tear size, or smoking definition. Meta-regression showed no significant influence of age, smoking prevalence, or diabetes prevalence on the pooled effect. Secondary outcomes (3 studies) suggested slightly lower postoperative American Shoulder and Elbow Surgeons scores among smokers, while visual analog scale pain scores and forward flexion showed no clear between-group differences. No publication-bias signals were detected for the primary outcome. CONCLUSION: Smoking is associated with a higher risk of imaging-confirmed structural failure after arthroscopic rotator cuff repair. Functional outcomes were broadly similar between groups, with only a small, likely clinically negligible reduction in American Shoulder and Elbow Surgeons scores among smokers. These findings support careful smoking history assessment and perioperative risk modification, including smoking cessation strategies.

Humans↗

PubMed2026

Integrated morphologic, immunophenotypic, and molecular profiling of advanced upper tract urothelial carcinoma across tumor compartments supports biopsy-based testing.

Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with limited molecular characterization in advanced disease. FGFR3 alterations are well established in low-grade urothelial carcinoma, but their prevalence, stability, and biological significance in locally advanced and metastatic UTUC remain only partially defined. We performed an integrated morphologic, immunohistochemical, and molecular analysis of 24 locally advanced and/or metastatic UTUC from 20 patients. FGFR3 status was assessed by RT-PCR across multiple tumor compartments, including biopsies, primary tumors, lymph-node metastases, and distant metastatic sites. Immunohistochemistry included CK20, CK5, GATA3, p53, and mismatch repair proteins. Targeted next-generation sequencing (NGS) was used to characterize co-occurring genomic alterations and to assess concordance with p53 immunophenotype. FGFR3 alterations were identified in 50% of patients and in 54.2% of analyzed tumors. FGFR3 status showed high intra-patient stability, with concordance between primary tumors and distant metastases in 90% of cases, whereas concordance with lymph node metastases was lower (50%), suggesting site-specific clonal divergence. Despite advanced stage, 92.3% of FGFR3-altered tumors displayed papillary urothelial carcinoma morphology, and most showed a luminal immunophenotype (61.5% by CK20/CK5 and 69.2% by GATA3/CK5). Targeted NGS revealed additional pathogenic alterations in 75% of patients, most frequently involving RTK/RAS/MAPK signaling (70%), cell-cycle regulation (25%), and PI3K/AKT pathway components (10%). TP53 mutations co-occurred with FGFR3 alterations in 60% of FGFR3-mutated patients and showed 90.4% concordance with p53 immunohistochemistry. Finally, a few cases exhibited complex, multi-site FGFR3 mutational patterns, consistent with intratumoral clonal evolutions. In conclusion, FGFR3 alterations are frequent and remarkably stable in advanced UTUC, even in high-grade and metastatic disease. These findings support the reliability of FGFR3 testing on limited diagnostic material and reinforce its relevance for therapeutic stratification. UTUC emerges as a molecularly dynamic disease in which early oncogenic drivers such as FGFR3 continue to shape tumor biology and therapeutic vulnerability at advanced stages.

Humans↗

PubMed2026

The Effects of Intermittent Hypoxic Training Strategies on Maximal Oxygen Uptake in Healthy Humans: A Meta-analysis with Meta-regression.

BACKGROUND: Intermittent hypoxic training aims to enhance exercise performance and health, commonly assessed through maximal oxygen uptake (VO2max). Currently applied methods are live-high train-low (LHTL), live-low train-high (LLTH) and passive hypoxic conditioning (PHC). However, within these methods, numerous modes of application exist, and effectiveness is debated. OBJECTIVE: To determine the effect of LHTL, LLTH and PHC on VO2max in healthy participants, and identify factors associated with the amplitude of change in VO2max. METHODS: We conducted a systematic review with random-effects meta-analysis and meta-regression. Studies were identified through PubMed, EMBASE and Web of Science. We included controlled studies, calculating between-group standardised mean differences. Athlete and non-athlete populations were analysed separately. RoB2 was used to assess study quality and publication bias was investigated with funnel plots and the Egger's test. RESULTS: Of the 5244 identified studies, 62 were included for analysis, resulting in a sample size of 1332 participants (610 athletes, 722 non-athletes). LHTL increased VO2max significantly more than control in athletes (mean difference [MD] = 2.17; 95% CI = 0.77, 3.56) but not in non-athletes (MD = 3.1; 95% CI =  - 0.23, 6.43). LLTH did not increase VO2max significantly more than control in athletes (MD = 0.89; 95% CI =  - 0.27, 2.05) but it did in non-athletes (MD = 1.70; 95% CI = 0.85, 2.54). PHC did not increase VO2max significantly more than control in athletes (MD =  - 1.07; 95% CI =  - 3.51, 1.37) but it did in non-athletes (MD = 2.26; 95% CI = 1.00, 3.52). Multivariate meta-regressions identified the severity, duration, and frequency of hypoxic exposure to be significantly associated with the change in VO2max. CONCLUSIONS: LHTL showed a significant effect on VO2max in athletic populations while LLTH and PHC showed a significant effect on VO2max in non-athletic populations only. Future studies should target investigating which characteristics (e.g. severity, duration) of the hypoxic exposure are most beneficial.

Journal Article↗