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PubMed2026

Long-term consequences of childhood sexual abuse: An umbrella review of diagnostic meta-analyses.

BACKGROUND: Childhood sexual abuse (CSA) is a public health issue with an estimated worldwide prevalence of 12.7%, potentially leading to a host of lifelong and significant mental, physical, and behavioral health. The aim of this study was to comprehensively map the long-term consequences of childhood sexual abuse on physical, psychiatric, and behavioral health outcomes. METHODS: An umbrella review of meta-analyses of observational studies, registered on PROSPERO, was conducted to examine the diverse repercussions of childhood sexual abuse on adult health. Three bibliographic databases (PsycINFO, PubMed and Scopus) were searched from the inception of the respective databases to November 1st, 2022. Thirty-eight meta-analyses representing about 20 million individuals were analyzed, revealing a range of long-lasting consequences associated with CSA. RESULTS: Among physical pathologies, cervical cancer and functional neurological syndromes emerged as the most prominent, exhibiting significantly elevated odds ratios (ORs) of 4.18 IC95% and 3.30 IC95%, respectively. Sleep disorders and borderline personality disorders were the most prevalent mental health disorders associated with CSA, with respective ORs of 16.17 IC95% and 5.96 IC95%. Early sexual initiation (OR=3.59 IC95%, sexual assault (OR=3.36 IC95%, and prostitution (OR=3.24 IC95%) emerged as the most common behavioral consequences. Notably, no significant differences in the consequences of CSA were observed between men and women, except for reproductive health outcomes. DISCUSSION: When faced with certain pathologies, clinicians should consider and discuss sexual abuse with their patients. The consequences of abuse have a multifactorial origin, which is a weakness, as are the problems of defining abuse. The strength of our study is that it lists the consequences published in high-quality studies. CONCLUSION: This umbrella review provides compelling evidence of the profound and far-reaching impact of childhood sexual abuse on a broad spectrum of physical, mental, and behavioral health issues.

Humans↗

PubMed2026

The effects of nitrate and nitrite supplementation on mitochondrial respiration in permeabilized muscle fibres in young healthy adults.

Nitric oxide (NO) is a direct regulator of mitochondrial respiration. Nitrate (NO3-) and nitrite (NO2-) are good sources of NO, but whether their effects on mitochondrial respiration differ between in vivo and in vitro administration remains unclear. In Study 1, 8 participants consumed NO3- -rich beetroot juice (BR) (∼12.8 mmol NO3-) and NO3- -depleted placebo beetroot juice (PL) (∼0.08 mmol NO3-) acutely and chronically for 2 weeks in a randomised, double-blind, crossover design. A substrate-uncoupler-inhibitor titration (SUIT) protocol was used to assess mitochondrial respiration using high-resolution respirometry (oxygen tension: ∼200-450 μM) in permeabilized muscle fibres. In Study 2, skeletal muscle samples were collected from 11 participants. In a randomised, crossover design, different doses (0, 1.5, and 3.0 μM) of sodium nitrite (NaNO2) were administered to permeabilized muscle fibres. Mitochondrial respiration was measured using the same SUIT protocol under lower oxygen tension (∼50-200 μM). Although muscle NO3- concentration significantly increased after both acute and chronic BR supplementation, mitochondrial respiration and exercise performance did not differ between PL and BR in either condition. Similarly, absolute oxygen flux across different respiratory states were not different between different doses of NaNO2. However, the leak control ratio, reflecting the degree of uncoupling of mitochondrial respiration, was significantly higher with 3.0 μM NaNO2 administration (0.12 ± 0.05) compared to 0 μM NaNO2 administration (0.09 ± 0.04, P = 0.03). These findings, involving both in vivo and in vitro administration approaches, albeit in the presence of relatively high oxygen concentrations, suggest that neither NO3- nor NO2- improves mitochondrial respiration, at least in young healthy adults.

Humans↗

PubMed2026

Associations Between Paternal Pre-Conceptional Body Mass Index and Lifestyle Factors and Offspring Weight Development.

BACKGROUND: Evidence suggests that pre-conceptional paternal factors, including BMI and diet, may influence offspring development. OBJECTIVES: We examined the associations between paternal BMI, dietary protein intake, glycemic index (GI), smoking and alcohol consumption and offspring development during the first 5 years of life. METHODS: This secondary analysis of an RCT included 162 father-child pairs from pregnancies among women with pre-pregnancy overweight or obesity. Paternal characteristics were reported at gestational week 15, reflecting the preceding 3 months. Offspring anthropometry was measured at birth, 6 and 18 months, 3 and 5 years. Associations were examined using linear mixed models and linear regression models. RESULTS: No consistent associations were found between paternal characteristics and offspring outcomes from birth to 3 years. At age 5, higher paternal BMI was associated with higher offspring BMI z-score (β = 0.07 (CI: 0.03; 0.10)), fat mass index (β = 0.07 kg/m2 (CI: 0.02; 0.12)) and fat-free mass index (β = 0.05 kg/m2 (CI: 0.01; 0.08)). Lower paternal protein intake was associated with higher offspring BMI z-score (β = 0.54 (CI: 0.07; 1.01)) and fat-free mass index (β = 0.60 kg/m2 (CI: 0.13; 1.07)), while moderately higher protein intake was associated with higher waist-to-height ratio (β = 0.03 (CI: 3.00 × 10-3; 0.05)). Higher paternal GI was associated with lower offspring BMI z-score (β = -0.04 (CI: -0.08; -2.14-10-3)) at age 5. Smoking and alcohol were not associated with offspring outcomes. CONCLUSION: Paternal BMI was associated with offspring outcomes at age 5 years, while findings for paternal dietary factors were less consistent.

Humans↗

PubMed2026

Efficacy and Safety of the Dual Glucagon-Like Peptide-1 and Glucagon Receptor Agonist Mazdutide in Predominantly Chinese Adults With Obesity and/or Type 2 Diabetes: A Systematic Review and Meta-Analysis.

AIM: To assess the effects of mazdutide on body weight, HbA1c, metabolic outcomes, and adverse events in adults with overweight/obesity and/or type 2 diabetes (T2D). METHODS: This systematic review and meta-analysis included randomized controlled trials (RCTs) comparing mazdutide with placebo or active comparators in adults with overweight/obesity and/or T2D, identified through PubMed, Scopus, Web of Science, and ClinicalTrials.gov to 20 February 2026. Co-primary outcomes were percent change in body weight and change in HbA1c. Secondary outcomes included other weight-related and metabolic outcomes, as well as safety. Random-effects models were used to generate pooled mean differences (MDs) or risk ratios with 95% confidence intervals, and the certainty of the evidence (COE) was assessed using GRADE. RESULTS: Nine RCTs (N = 2292; most with low risk of bias) were included. In overweight/obesity without diabetes, mazdutide 3, 4, and 6 mg reduced body weight more than placebo (MDs -6.56%, -9.92%, and -11.1%, respectively; very low COE due to substantial heterogeneity and few trials). In T2D, mazdutide 4 and 6 mg reduced body weight and HbA1c versus placebo (moderate COE) and also outperformed dulaglutide for both outcomes. Mazdutide also improved waist circumference, lipids, liver enzymes, and uric acid levels. Gastrointestinal adverse events were more frequent, but serious adverse events and treatment discontinuation rates were comparable with those of the comparators. CONCLUSIONS: Mazdutide was associated with dose-dependent reductions in body weight and HbA1c, with broader metabolic benefits in predominantly Chinese adults with obesity and/or T2D. Longer-term, multi-ethnic studies are needed to confirm durability, generalizability, and cardiovascular safety.

Humans↗

PubMed2026

Intismeran Autogene Plus Pembrolizumab Versus Pembrolizumab Alone in High-Risk Resected Melanoma: 5-Year Update of the Randomized Phase IIb KEYNOTE-942 Study.

Intismeran autogene (intismeran; formerly V940 or mRNA-4157) is an mRNA-based individualized neoantigen therapy. We report 5-year outcomes of intismeran plus pembrolizumab from the phase IIb KEYNOTE-942 study (ClinicalTrials.gov identifier: NCT03897881). Eligible patients with resected stage IIIB to IV cutaneous melanoma were randomly assigned 2:1 to receive nine doses of intramuscular intismeran 1 mg once every 3 weeks plus 18 doses of intravenous pembrolizumab 200 mg once every 3 weeks or 18 doses of intravenous pembrolizumab 200 mg once every 3 weeks. The primary end point was recurrence-free survival (RFS); secondary end points included distant metastasis-free survival (DMFS) and safety. Five-year analyses were descriptive. Among 157 randomly assigned patients (intismeran plus pembrolizumab, n = 107; pembrolizumab, n = 50), the median planned follow-up at data cutoff (December 15, 2025) was 60.3 (range, 50.5-76.4) months. Intismeran plus pembrolizumab continued to prolong RFS (hazard ratio [HR], 0.510 [95% CI, 0.294 to 0.887) and DMFS (HR, 0.411 [95% CI, 0.200 to 0.843]), with a favorable trend in overall survival (HR, 0.471 [95% CI, 0.165 to 1.345]) versus pembrolizumab. Safety profile continued to be manageable, with no new safety signals. Intismeran plus pembrolizumab was associated with increased T-cell receptor clonality and novel clonotypes versus pembrolizumab; greater novel clone expansion was observed in patients without versus with recurrence in the combination arm. After a 5-year follow-up, intismeran plus pembrolizumab demonstrated sustained, durable treatment benefits versus pembrolizumab alone in resected high-risk melanoma.

Humans↗

PubMed2026

Age-related macular degeneration associated with glucagon-like peptide-1 receptor agonist use: a systematic review.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for diabetes, obesity, and cardiovascular risk reduction. However, their ocular safety profile, particularly regarding age-related macular degeneration (AMD), remains uncertain. This systematic review evaluates the association between GLP-1 RA use and the incidence or progression of AMD including both nonexudative and neovascular subtypes. METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines and registered with PROSPERO (CRD420251183938). MEDLINE, Embase, CENTRAL, Web of Science, and PubMed were searched from inception through 2025 for observational studies and randomized trials evaluating AMD outcomes among adults exposed to GLP-1 RAs. Comparators included nonuse, placebo, or alternative metabolic therapies. Risk of bias was assessed using Risk of Bias in Non-Randomized Studies of Interventions and certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation framework. Due to heterogeneity of outcome definitions, results were synthesized qualitatively. RESULTS: Eight observational studies encompassing 91 408 to 600 816 participants were included. GLP-1 RA use was associated with a reduced incidence of nonexudative AMD across diabetic and nondiabetic populations, with relative risk reductions varying substantially by population, comparator, and follow-up duration. Findings for neovascular AMD were heterogeneous: most studies reported neutral or protective associations, whereas one population-based cohort of older adults with diabetes observed an increased risk (adjusted hazard ratio 2.21, 95% CI 1.65-2.96), with low absolute event rates. Overall risk of bias was moderate to high, and certainty of evidence for all outcomes was very low. CONCLUSIONS: Current evidence does not demonstrate a consistent increase in AMD risk associated with GLP-1 RA therapy and may be associated with a lower incidence of nonexudative AMD, although the certainty of evidence is very low and noncausal explanations cannot be excluded. Prospective studies with standardized endpoints are needed to clarify causal relationships.

Humans↗

PubMed2026

A flipped classroom approach compared with low-interactive online learning for pediatric pain management knowledge and instructional motivation in nursing students: A randomized controlled study.

AIM: This study aimed to compare a flipped classroom approach with low-interactive online learning in terms of nursing students' questionnaire-assessed pediatric pain management knowledge and instructional motivation. BACKGROUND: Pain management in children is a critical and multidimensional nursing responsibility. However, limited curricular time and opportunities for applied learning may restrict nursing students' preparedness in this area. Structured and interactive instructional formats, such as the flipped classroom, may support knowledge acquisition and motivation in pediatric nursing education. METHODS: This study employed a parallel-group randomized controlled trial design with a 1:1 allocation ratio. Eighty-eight third-year prelicensure nursing students were randomized to either the flipped classroom group (n = 44) or the low-interactive online learning group (n = 44). Due to attrition (2 intervention, 2 control), analyses included 42 participants per group (n = 84 in total). Data were collected between February and July 2022 using the Pediatric Pain Management Knowledge Scale for Nursing Students and the Instructional Materials Motivation Survey. This study was prospectively registered at ClinicalTrials.gov (Identifier: NCT07129044). RESULTS: At baseline, the groups were comparable in terms of knowledge and learning motivation. Following the intervention, the flipped classroom group demonstrated greater improvements in questionnaire-assessed pediatric pain management knowledge and instructional motivation than the low-interactive online learning group. Although scores declined from post-test to the three-month follow-up, they remained above baseline in the flipped classroom group. CONCLUSIONS: Within the context of this course, the flipped classroom approach was associated with greater improvement in questionnaire-assessed pediatric pain management knowledge and instructional motivation than low-interactive online learning. The findings should be interpreted as proximal educational outcomes rather than evidence of improved clinical competence or durable long-term effectiveness. Further studies using objective performance-based outcomes and longer follow-up periods are needed.

Humans↗

PubMed2026

One-carbon metabolism and chemotherapy-induced toxicities in patients with stage II-III colorectal cancer: a prospective cohort study.

BACKGROUND: One-carbon metabolism (OCM) is a target of the chemotherapeutic agent capecitabine. OBJECTIVES: We investigated OCM biomarker concentrations in relation to capecitabine-induced toxicities in patients with stage II-III colorectal cancer. METHODS: Within a prospective cohort, 297 patients receiving adjuvant capecitabine-based chemotherapy were included. Pretreatment plasma concentrations of the OCM biomarkers folate, vitamin B2, vitamin B6, vitamin B12, total homocysteine, methionine, serine, and glycine were determined. We also investigated whether associations differed according to methylenetetrahydrofolate reductase (MTHFR) C677T genotypes. Chemotherapy-induced toxicities were defined as toxicity-induced modifications of capecitabine treatment. To allow for inspection of shapes of the associations, restricted cubic splines and Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age and sex. RESULTS: In total, 156 (53%) patients experienced toxicity-induced modifications of capecitabine treatment. Folate was not associated with toxicities in the overall population. Higher folate concentrations were associated with a lower risk of toxicities in patients with MTHFR C677T CT/TT genotype (HRperdoubling: 0.75; 95% CI: 0.57, 0.98) but not in patients with CC genotype (HRperdoubling: 1.17; 95% CI: 0.84, 1.63). Higher concentrations of vitamin B2 were associated with a lower risk of toxicities (HRperdoubling: 0.81; 95% CI: 0.67, 0.99), whereas higher glycine concentrations were associated with a higher risk of toxicities (HRperdoubling: 1.87; 95% CI: 1.18, 2.94). The association between vitamin B6 and vitamin B12 and toxicities appeared nonlinear. Homocysteine, methionine, and serine were not associated with toxicities. CONCLUSIONS: Future studies investigating whether nutrition-guided optimization of OCM biomarkers will result in improved treatment tolerance are warranted.

Humans↗

PubMed2026

Sugar rationing during the first 1000 days and early onset cancer: a natural experiment.

BACKGROUND: The "first 1000 days" of life is a critical window for metabolic programming, while the long-term oncological consequences of nutritional exposures during this period remain understudied. OBJECTIVES: We aimed to evaluate whether restricted sugar intake in utero and during early childhood reduces risk of early onset cancer diagnosis and mortality in adulthood, utilizing a natural experiment. METHODS: We analyzed 63,819 United Kingdom Biobank participants born between October 1951 and March 1956, spanning the end of United Kingdom sugar rationing (September 1953). Leveraging a quasi-experimental birth cohort design, we compared participants exposed to sugar rationing in utero and during infancy with those unexposed. Early onset cancer incidence (≤50 y) and mortality were ascertained via integrated national Cancer Registry and hospital inpatient records. Multivariable Cox proportional hazards models (including Gompertz distribution) were used to estimate hazard ratios (HRs), with exploratory site-specific analyses. RESULTS: Among 63,819 participants (56.3% female), 40,397 were exposed to rationing and 23,422 were unexposed. Early life sugar restriction significantly reduced early onset cancer risk (HR: 0.66; 95% confidence interval: 0.53, 0.81; P < 0.001). A dose-response relationship was observed, with peak protection in individuals exposed for ≤24 mo postnatally. This protection was observed systemically across solid tumors, independent of specific cancer sites. Specificity was corroborated by null associations with negative controls (herpes zoster and cataract). No significant difference was found for cancer-specific mortality. CONCLUSIONS: Restricting sugar intake during the first 1000 days is associated with a reduced risk of early onset cancer, extending the disease-free lifespan. The divergence between reduced incidence and unchanged mortality suggests early life metabolic environments primarily influence tumor latency rather than biological aggressiveness. These findings highlight the potential long-term public health implications of early life dietary guidelines against the rising burden of early onset cancer.

Humans↗

PubMed2026

Safety and Tolerability of Single and Multiple Daily Oral Doses of Dried Kratom Leaf Powder in a Randomized Trial in Healthy Volunteers.

BACKGROUND: Kratom use is rising, increasing the need for safety and tolerability studies of high-quality and well-characterized kratom products in humans. Kratom's risk-benefit ratio, recommended dose, treatment-emergent adverse events (TEAEs), abuse potential, and withdrawal require evaluation. Thus, the safety and tolerability of 4 escalating single and 15 daily dried kratom leaf powder doses in human volunteers were evaluated over 47 days in the largest controlled kratom-administration study to date. METHODS: A randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of MitraLeaf kratom powder after single doses (SD), during 15 daily doses (multiple doses; MD), and a 23-day follow-up was conducted in 116 volunteers (49 MitraLeaf and 67 placebo). Twelve participants each received a SD of either 6.65, 13.3, 26.6, or 53.2 mg (n = 13) mitragynine in 500, 1000, 2000, or 4000 mg of MitraLeaf, respectively, with a 10-day follow-up. The same participants received 15 daily doses at the same concentration of SD mitragynine received, with a 27-day follow-up period. Inclusion criteria were nonsmoking healthy males and females who never used kratom or had not used kratom for ≥12 months, 18-55 years old, and BMI ≥18.5 and ≤29.9 kg/m 2 . Participants were excluded if they had known CYP3A4, CYP2D6, or CYP1A2 genetic polymorphisms. RESULTS: No serious adverse events or deaths were reported. TEAEs after SD or MD generally increased as the dose increased. Dizziness, nausea, and feeling of relaxation were the most commonly reported TEAEs after SD, and headache, feeling hot, increased alanine aminotransferase level, and nausea were most common after MD. CONCLUSIONS: This SD and first MD controlled study shows that Mitragyna speciosa -derived MitraLeaf kratom powder was safe and well tolerated at the dose ranges tested, with no evidence of meaningful abuse potential or withdrawal.

Humans↗

PubMed2026

Phosphorus modulates starch granule development and metabolic partitioning in wheat grain: Insights from SGAP proteomics and nutrition and processing quality.

This study investigates how phosphorus (P) levels are associated with carbon-nitrogen metabolism in wheat grains. Optimal P application (105 kg P₂O₅ ha⁻¹) was associated with enhanced pericarp-endosperm coordination, increased carbon allocation to the endosperm, and early B‑type starch granule formation. Starch granule‑associated protein (SGAP) proteomics showed that optimal P upregulated cytoskeletal and starch‑synthesis proteins bound to starch granules in the endosperm, while reducing storage protein degradation‑related SGAPs in the pericarp. These metabolic adjustments were correlated with increased grain‑filling intensity and duration, and were associated with the highest theoretical grain weight (50.70 mg). Furthermore, optimal P was associated with enrichment of amino acid biosynthesis pathways and with higher levels of essential amino acids (e.g., lysine and threonine by 17.0--26.8%) and an improved essential amino acid profile without altering total protein content. In contrast, excessive P (210 kg P₂O₅ ha⁻¹) was associated with disrupted inter‑tissue coordination but did not simply impair grain filling; instead, HP corresponded to a unique developmental program: it was linked to an early burst of C‑type starch granules (0∼5 µm) at 7 DPA, yet by maturity achieved the highest proportion of large A‑type granules (56.8%) and the highest total starch content (63.5%), together with elevated endosperm phosphorus at 14 DPA and enrichment of spliceosome‑related pathways. HP also showed higher levels of several functional amino acids (glutamate, cysteine, histidine, proline) compared to P0. However, HP was associated with a higher gliadin/globulin ratio and did not improve grain yield. These findings suggest that phosphorus supply is associated with grain quality through tissue‑specific metabolic reprogramming, and that precision management-rather than maximized application-warrants consideration for optimizing both yield and processing quality.

Triticum↗

PubMed2026

Comparison of opioid-free versus opioid-based total intravenous anaesthesia in elderly patients undergoing short-duration surgery: a randomized controlled trial.

INTRODUCTION: Older adults who undergo short-duration surgery are vulnerable to opioid-related complications. It is uncertain whether an opioid-free total intravenous anaesthesia (OFA) can reduce these events. We aimed to determine whether OFA reduces the incidence of major postoperative adverse events compared with standard opioid-based total intravenous anaesthesia (OBA). PATIENTS AND METHODS: This single-center randomized clinical trial was conducted in China. From May to August 2025, 400 patients aged ≥60 years undergoing elective, short-duration surgery (anticipated duration of less than 90 min) were randomized 1:1 to receive either OFA (n = 200) or OBA (n = 200). The primary outcome was a composite of postoperative hypoxemia, delirium, or nausea and vomiting (PONV) within 48 h. RESULTS: A total of 400 randomized patients (mean [SD] age, 69.5 [7.0] years; 125 [31.3%] women). The primary composite outcome occurred in 50 patients (25.0%) in the OFA group and 87 patients (43.5%) in the OBA group (adjusted odds ratio, 0.40; 95% CI, 0.25 to 0.62; p < .001). Among the OFA group had a lower incidence of hypoxemia (15.0% vs 32.0%) and PONV (8.0% vs 16.0%). Intraoperative hemodynamic stability was greater in the OFA group. However, the OFA group had a higher incidence of intraoperative bradycardia (10.0% vs 3.0%; p = .005) and longer extubation times (mean, 9.5 vs 7.2 min; p < .001). CONCLUSION: These findings suggest that OFA is a viable alternative to opioid-based anesthesia for improving postoperative outcomes by reducing the incidence of hypoxemia and PONV in this population, while warranting careful management of its associated side effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2500102550.

Humans↗

PubMed2026

Posterior Segment Risk Factors for Penetrating Keratoplasty Failure.

PURPOSE: To analyze the relationship between intraoperative and postpenetrating keratoplasty (PK) posterior segment variables and PK graft survival. DESIGN: Retrospective clinical cohort study. SUBJECTS: Patients undergoing PK between May 1, 2007 and September 1, 2018 at a single tertiary center. METHODS: Chart review for PKs performed was conducted, and the first PK completed at the institution for each patient was included for analysis. Data collected included demographics, medical and ocular history, preoperative and intraoperative findings, and intraoperative and postoperative posterior segment factors (pars plana vitrectomy [PPV], endolaser, retinal detachment [RD], and vitreous hemorrhage [VH]). After univariable analysis, variables were selected for multivariable Cox regression analysis. MAIN OUTCOME MEASURE: Graft failure, defined as irreversible and visually significant corneal edema, haze, or scarring. RESULTS: Eight hundred and thirty-five eyes of 835 patients were included. Mean age was 57.1 ± 22.0 (range: 0-100) years, and mean time from PK to final follow-up or graft failure was 3.2 ± 2.9 (range: 0.01-16.1) years. Graft failure occurred in 35.0% of cases with a mean onset of 1.9 ± 2.0 (range: 0.04-11.4) years after PK. After multivariable analysis, 9 variables had significant associations with failure. Two posterior segment variables were significant: intraoperative VH at the time of PK (hazard ratio [HR] 6.6, 95% confidence interval [CI] 1.6-27.7, P = .010) and silicone oil (SO) tamponade after the PK (HR 3.2, 95% CI 1.4-7.4, P = .007). CONCLUSIONS: Graft failure is a serious complication of PK. VH at the time of the PK and SO tamponade after the PK were associated with graft failure. In complex eyes that are undergoing PK grafts and that may also require posterior segment interventions, these findings may guide patient counseling and discussion of graft prognosis.

Humans↗

PubMed2026

MIS-TLIF Versus Open TLIF in Combined Lumbar Stenosis and Low-Grade Spondylolisthesis : Of Discharge Timing and Treatment Pricing.

STUDY DESIGN: An open-label, randomized, noninferiority clinical trial. OBJECTIVE: To determine the effectiveness of the MIS-TLIF over the O-TLIF in patients with symptomatic lumbar stenosis combined with low-grade spondylolisthesis by comparing the clinical efficacy and safety. SUMMARY OF BACKGROUND DATA: In patients with combined lumbar spinal stenosis and spondylolisthesis, it remains uncertain whether minimally invasive fusion surgery is noninferior to the open approach. MATERIALS AND METHODS: We conducted an open-label, noninferiority trial involving patients with symptomatic lumbar stenosis combined with low-grade spondylolisthesis. Patients were randomly assigned in a 1:1 ratio to undergo either MIS-TLIF or open TLIF surgery. The primary endpoint was the reduction in the Oswestry disability index (ODI) score from baseline to three months postsurgery, with a noninferiority margin of 12 points. Secondary outcomes included three-month changes from baseline in back and leg pain, neuropathic pain, satisfaction with treatment, intraoperative data, and cost-effectiveness. RESULTS: In the modified intention-to-treat population, the mean difference was 0.4, with the corresponding 90% CI of -5.7 to 6.5, having a lower bound below the noninferiority margin of 12. Similar results were obtained by analysis of the per-protocol population. 82.8% of patients achieved the MCID for the ODI. Results for secondary outcomes (clinical scales, complications) showed no significant differences between the treatment groups (all P >0.05). Although the open TLIF group had a hospital stay that was 1.5 days longer ( P =0.005) and required additional analgesia more frequently ( P =0.026), direct costs were 10.5% higher in the MIS-TLIF group ( P <0.001). CONCLUSIONS: This is the first high-quality study comparing open TLIF and MIS-TLIF with a validated primary endpoint. Among patients with combined lumbar degenerative stenosis and degenerative spondylolisthesis, MIS-TLIF resulted in clinical outcomes at three months that were noninferior to those with open TLIF.

Humans↗

PubMed2026

Same-day initiation of tenofovir alafenamide-based pre-exposure prophylaxis with drug-level feedback for transgender women in Uganda.

OBJECTIVE: To evaluate the feasibility and acceptability of same-day initiation of emtricitabine/tenofovir alafenamide (F/TAF) pre-exposure prophylaxis (PrEP) and test the impact of drug-level feedback on PrEP adherence among transgender women (TGW) in Uganda. DESIGN: Randomized controlled trial. METHODS: HIV-negative TGW were randomly assigned 1 : 1 to intervention (drug-level feedback with tailored adherence counseling) or standard-of-care (SOC), and followed quarterly for 12 months (November 2021-July 2023; NCT04491422). Quarterly clinic visits included demographic and socio-behavioral data collection, PrEP refills, STI testing, and quarterly PrEP adherence assessment using tenofovir levels in dried blood spots (DBS; long-term) and urine (short-term). RESULTS: We enrolled 200 TGW (100 per arm), median age 21 years. Same-day F/TAF PrEP initiation was 100%. Tenofovir detection in urine (intervention arm) was 79, 80, 85, and 70% at the 3, 6, 9, and 12-month visits, respectively. Tenofovir detection in DBS was 46, 40, 35, and 31% at 3, 6, 9, and 12 months, respectively. Median tenofovir DBS concentrations were 40.6 and 47.0 fmol/punch in intervention and SOC arms, respectively. There was no intervention effect on PrEP adherence (DBS tenofovir levels) [adjusted incidence rate ratio (aIRR) 1.06; 95% CI: 0.82-1.37]. Never being harassed by police for being transgender (aIRR 1.66; 95% CI: 1.24-2.23), history of taking daily medication for more than 7 days (aIRR 1.51; 95% CI: 1.18-1.93) and higher monthly income (aIRR 1.44; 95% CI: 1.10-2.04) were associated with PrEP adherence. CONCLUSION: Oral F/TAF PrEP adherence among TGW in Uganda was low and not affected by drug-level feedback or tailored adherence counseling. Long-acting injectable PrEP formulations should be considered for this population.

Humans↗

PubMed2026

Lung function after randomization to metformin, lifestyle intervention or placebo in the Diabetes Prevention Program Outcomes Study (DPPOS).

INTRODUCTION: Metformin and physical activity have been suggested as beneficial for chronic lung disease; however, there are no prior randomized trials. METHODS: The Diabetes Prevention Program (DPP) was a 3-year trial that randomized 3234 individuals at risk for diabetes to metformin, lifestyle intervention or placebo. After the DPP, 88% of participants enrolled in the DPP Outcomes Study that offered lifestyle intervention to all and open-label continuation of metformin. Spirometry was performed at approximately 19 and 22 years post-randomization. Lung function measures were compared in an intention-to-treat (ITT) analysis by original randomization group. Models were unadjusted and adjusted for demographics, body size, smoking and sitting/standing at spirometry. Additional analyses tested prevalence of obstruction (FEV1/FVC <70%), restrictive pattern (FVC < LLN and FEV1/FVC ≥70%), preserved ratio impaired spirometry (PRISm: FEV1 <80% predicted, FEV1/FVC ≥70%) and symptoms (COPD Assessment Test [CAT] score ≥10). RESULTS: The 1888 participants with spirometry were a mean (±SD) age of 68.2 ± 9.3 years, 70% female and 6% currently smoked and 33% had previously smoked cigarettes. Mean follow-up time was 19.0 ± 0.8 years. The mean FEV1 was 2.14 ± 0.60 L, FVC 2.74 ± 0.74 L, FEV1/FVC 78.4 ± 6.4%, mean BMI was 32.4 ± 6.7 kg/m2 and 58% had diabetes. In both unadjusted and adjusted ITT analyses, randomization group was not associated with FEV1, FVC or FEV1/FVC. Likewise, rates of obstruction, restrictive pattern, PRISm or symptoms did not differ by randomization group. CONCLUSIONS: In this long-term follow-up after a randomized trial, we found no significant associations between randomization to metformin or lifestyle intervention and lung function or respiratory symptoms.

Humans↗

PubMed2026

Pembrolizumab-Chemotherapy Versus Pembrolizumab in Head and Neck Squamous Cell Carcinoma: A PD-L1 CPS-Stratified Analysis of Updated KEYNOTE-048 Data.

Based on KEYNOTE-048, pembrolizumab monotherapy and pembrolizumab-chemotherapy are established category 1 first-line treatments for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1. We compared their efficacy using updated trial data. We analyzed 4-year progression-free survival on next-line therapy (PFS2) and 5-year overall survival (OS) data from KEYNOTE-048 by reconstructing time-to-event data using KMSubtraction. Efficacy was compared in CPS 1-19 and CPS ≥ 20 subgroups using Kaplan-Meier estimates, Cox models, restricted mean survival time (RMST), and landmark analyses. Among 499 patients with CPS ≥ 1, 240 (48.1%) had CPS 1-19 and 259 (51.9%) had CPS ≥ 20. In the CPS 1-19 subgroup, pembrolizumab-chemotherapy showed numerically longer median PFS2 (10.1 vs. 8.0 months; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.62-1.06) and OS (12.8 vs. 10.8 months; HR: 0.87; 95% CI: 0.67-1.15) versus monotherapy, without statistical significance. For CPS ≥ 20 patients, efficacy was comparable between regimens, with similar median PFS2 (11.3 vs. 11.7 months; HR: 0.95) and OS (14.7 vs. 14.9 months; HR: 0.96). RMST and landmark analyses showed an early PFS2 benefit and a trend toward OS benefit with pembrolizumab-chemotherapy in CPS 1-19, with comparable outcomes in CPS ≥ 20. Pembrolizumab-chemotherapy showed a trend toward improved outcomes in the CPS 1-19 subgroup, with comparable efficacy in the CPS ≥ 20 subgroup, supporting a refined first-line strategy: monotherapy for CPS ≥ 20 to minimize toxicity, and combination therapy for CPS 1-19 to potentially enhance disease control.

Humans↗

PubMed2026

Multimodal Therapy With Metformin, Inositol and Dietary Restriction Improves Insulin Resistance and Endocrine Outcomes in Women With Polyendocrine Metabolic Ovarian Syndrome: A Randomized Controlled Trial.

INTRODUCTION: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine-metabolic disorder characterized by insulin resistance, hyperandrogenism and ovulatory dysfunction. Metformin, inositol supplementation and lifestyle modification are widely used treatments, but direct comparative evidence remains limited. Multimodal therapy combining metformin, inositol and dietary restriction produces greater metabolic and reproductive improvement than single-modality interventions. METHODS: We conducted a 12-week randomized controlled trial in 192 women aged 18-35 years diagnosed with PMOS according to Rotterdam criteria. Participants were allocated to metformin (1500-2000 mg/day), inositol (myo-inositol 2 g plus d-chiro-inositol 50 mg twice daily), calorie-restricted diet (1200-1500 kcal/day), or combination therapy. Primary outcomes included changes in body mass index (BMI) and insulin resistance assessed by HOMA-IR. Secondary outcomes included testosterone, LH/FSH ratio and menstrual regularity. Analysis was performed using analysis of covariance (ANCOVA), with post-intervention values as dependent variables and corresponding baseline values as covariates. Categorical outcomes were compared using the Chi-square test. RESULTS: All interventions improved metabolic and endocrine parameters. Combination therapy resulted in the greatest reduction in HOMA-IR (- 2.64, 95% CI - 2.82 to -2.46, p < 0.001) and BMI (- 2.8 kg/m2, 95% CI - 3.05 to -2.55, p < 0.001). Menstrual cyclicity improved across all groups, with the highest proportion of participants reporting cycle regularisation in the combination therapy group (85.4%), compared with dietary restriction (72.9%), inositol (64.6%), and metformin (39.6%) (p < 0.001). Given the short follow-up duration, these findings reflect early improvements rather than sustained normalisation. CONCLUSION: Multimodal therapy was associated with superior metabolic and reproductive outcomes compared with single-modality interventions in women with PMOS. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov (NCT07380841).

Humans↗