SEARCH · Search PubMed

Results for “Metered Dose Inhalers”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

250 records · Page 12Linked to original sources

PubMed2026

Neuromodulation for Subjective Tinnitus: A Systematic Review and Meta-Analysis of Randomized Trials.

OBJECTIVE: To evaluate the effectiveness and safety of neuromodulation and bimodal stimulation for chronic subjective tinnitus in randomized controlled trials (RCTs). DATA SOURCES: PubMed/MEDLINE, Web of Science, and EMBASE (January 2015-December 2025) searched per PRISMA 2020. REVIEW METHODS: Adult RCTs (≥ 18 years) with chronic subjective tinnitus (> 3 months) assessing validated outcomes (THI, TFI, TQ) for neuromodulation/bimodal interventions vs. sham/controls. Two-stage screening, Cochrane RoB-2 risk-of-bias assessment. Random-effects meta-analyses (REML) were performed when ≥ 3 comparable trials were available; effects reported as standardized mean differences (SMD) with 95% CIs. Main Outcomes and measures included change in tinnitus severity (THI/TFI/TQ) while secondary outcomes included loudness (VAS/NRS), durability, and adverse events. RESULTS: Twenty-six RCTs (n = 1576) met criteria: tES (11; n = 372), rTMS (8; n = 432), acoustic coordinated reset (1; n = 100), vagus nerve stimulation (2; n = 90), and bimodal stimulation (4; n = 582). Meta-analysis showed a nonsignificant pooled effect for tDCS (SMD -0.36; 95% CI -0.75 to 0.02; I 2 = 51%) and rTMS (SMD -0.15; 95% CI -0.37 to 0.07; I 2 = 0%). Single-trial evidence for coordinated reset showed no advantage over broadband noise. VNS demonstrated modest benefits with safety concerns limited to implanted approaches. Bimodal stimulation yielded consistent, clinically meaningful reductions (often ≥ 10-20 points on THI/TFI), with durability up to 12 months. Adverse events were mild/transient across noninvasive modalities. CONCLUSIONS: Noninvasive neuromodulation appears safe with average benefits; among modalities, bimodal stimulation shows the most consistent and durable clinical improvements. Standardized, adequately powered RCTs with harmonized protocols and long-term follow-up are needed to refine targets and dosing.

Humans↗

PubMed2026

Immunogenicity and safety of inactivated TZ84- vs. HM175-based hepatitis A vaccines in pediatric populations: A systematic review and meta-analysis.

Individual studies indicate stronger and persistent long-term immunogenicity with TZ84-based than HM175-based hepatitis A vaccines. This systematic review and meta-analysis compared immunogenicity and safety of inactivated TZ84- and HM175-based hepatitis A vaccines in children and adolescents. Studies involving adults, immunocompromised populations, non-comparative designs, non-English publications, and studies with non-extractable outcomes were excluded. MEDLINE/PubMed, Google Scholar, other electronic databases, and grey literature were searched (September-October 2025). Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, and meta-analyses were performed where appropriate. Seven publications arising from four randomized cohorts (total participants: 3,282) reporting seroconversion rates (SCRs), geometric mean concentrations (GMCs), long-term seroprotection, and adverse events (AEs) were identified. Pooled analyses demonstrated higher SCRs and GMCs with TZ84 than HM175-based vaccines following both one and two doses. SCRs at 1 month [odds ratio (OR): 3.05; 95% confidence interval (CI): 1.88-4.96] and GMCs at 7 months [standardized mean difference (SMD): 0.88; 95% CI: 0.18-1.58; p = .01] both favored TZ84-based vaccines. Long-term follow-up (up to 186 months/15.5 y) showed higher reported anti-HAV antibody concentrations for TZ84-based vaccines. The AEs were comparable between vaccine types (RR: 0.95; 95% CI: 0.76-1.20; p = .69). Evidence was limited by the small number of unique randomized cohorts, geographic concentration in China, heterogeneity across studies, and reliance on surrogate immunogenicity outcomes. Overall, available evidence suggests that TZ84-based hepatitis A vaccines (HAPIBEV™/HEALIVE®) are associated with higher reported antibody responses and greater reported antibody persistence than the HM175-based vaccine (HAVRIX®) in children and adolescents, with comparable safety profiles.Registration: PROSPERO CRD420251154480.

Humans↗

PubMed2026

Intravenous Tranexamic Acid Reduces Perioperative Blood Loss in Reduction Mammoplasty With Immediate Implant-Based Reconstruction: A Randomized, Triple-Blinded, Placebo-Controlled Trial.

BACKGROUND: Postoperative hematoma and oozing can compromise outcomes after reduction mammoplasty with immediate reconstruction. Intravenous (IV) tranexamic acid (TXA) is antifibrinolytic, but prospective evidence in this setting is limited. OBJECTIVES: The aim of this study was to determine whether a single pre-incision dose of IV TXA reduces perioperative blood loss and fibrinolytic activation vs placebo. METHODS: In this randomized, triple-blinded, placebo-controlled trial, 60 women (American Society of Anesthesiologists I/II, 18-75 years) undergoing bilateral reduction mammoplasty with immediate implant-based reconstruction received TXA 10 mg/kg in 100 mL saline or placebo 10 min before incision. The primary outcome was total blood loss within 24 h (intraoperative suction + swab plus drain output). Secondary outcomes were perioperative changes in hemoglobin, D-dimer and fibrinogen, and complications within 30 days. Intention-to-treat analyses were performed. RESULTS: All patients completed follow-up. Total blood loss was lower with TXA than with placebo (mean ± standard deviation: 221.1 ± 72.4 vs 298.1 ± 90.6 mL; mean difference -77.0 mL; 95% CI, -122.4 to -31.6; P = .001). Intraoperative loss and 24 h drain output were also reduced. Postoperative D-dimer rise was attenuated with TXA (0.31 ± 0.15 vs 0.49 ± 0.22 µg/mL; P = .002); hemoglobin decline was smaller. No thromboembolic, neurologic, or allergic events occurred; no skin-flap necrosis was observed. CONCLUSIONS: Pre-incisional IV TXA safely reduces perioperative bleeding and fibrinolytic activity after reduction mammoplasty. These findings support incorporation of IV TXA into perioperative protocols. LEVEL OF EVIDENCE: 2 (THERAPEUTIC): For image description, please refer to the figure legend and surrounding text.

Humans↗

PubMed2026

Effect of renin-angiotensin system inhibitors on survival in glioma patients: A systematic review and meta-analysis.

PURPOSE: To evaluate the effect of renin-angiotensin system inhibitors (RASIs) on the survival outcomes of glioma patients, determine whether using RASIs correlates with survival benefit, and provide evidence-based guidance for the clinical treatment. METHODS: Studies assessing the effects of using RASIs versus non-use in glioma patients were retrieved from the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to April 17, 2024. The included studies reported hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and/or progression-free survival (PFS), as well as the effect on brain edema and steroid dosing in patients. RESULTS: Seven articles involving 2660 patients were included in this study. Pooled results indicated there was no significant difference in OS (HR = 0.89, 95% CI 0.75-1.06, P = 0.204) or PFS (HR = 0.98, 95% CI 0.82-1.18, P = 0.847) between RASIs-treated patients and non-RASIs-treated patients. Sensitivity analysis identified the ACEIs-focused trial reported by Happold et al. as a major contributor to inter-study heterogeneity. Subgroup analyses revealed that in recurrent glioblastoma, pooled OS was significantly longer in RASIs-treated patients than non-RASIs-treated patients (HR = 0.70, 95% CI 0.54-0.92, P = 0.01). Similarly, compared with bevacizumab monotherapy, bevacizumab combined with RASIs significantly extended OS in glioblastoma patients (HR = 0.73, 95% CI 0.63-0.86, P < 0.001). CONCLUSION: The results revealed that treatment with RASIs may show a trend toward prolonged overall survival (OS) in patients with glioma. For patients with glioblastoma, RASI therapy could prolong OS in those with recurrent disease. Furthermore, compared with bevacizumab monotherapy, the combination of RASIs and bevacizumab was associated with improved OS in glioblastoma patients.

Humans↗

PubMed2026

Anti-inflammatory agents after hip and shoulder arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Postoperative inflammation after arthroplasty contributes to pain, delayed mobilization and prolonged hospitalization. Recent randomized trials have evaluated pharmacological anti-inflammatory strategies within contemporary enhanced recovery pathways, but evidence after hip and shoulder arthroplasty remains scattered across different drug classes and perioperative regimens. OBJECTIVES: To synthesize recent randomized controlled trial (RCT) evidence on perioperative anti-inflammatory agents after hip and shoulder arthroplasty. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched for English-language RCTs published from January 2020 to March 2026. The 2020-2026 window was selected to update evidence generated under modern arthroplasty, anesthesia, multimodal analgesia and enhanced recovery after surgery (ERAS) pathways. Eligible trials included adults undergoing hip or shoulder arthroplasty and compared corticosteroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal anti-inflammatory drug (NSAID)-based/local anti-inflammatory regimens, or related anti-inflammatory interventions with placebo, saline, no treatment, or the same regimen without the target component. Weighted mean differences (WMDs) were pooled using random-effects models. RESULTS: Nine RCTs involving 800 patients were included. Anti-inflammatory interventions significantly reduced postoperative C-reactive protein (CRP) [WMD=-32.18, 95% confidence interval (CI) (-41.16, -23.21), P<0.001], interleukin-6 (IL-6) [WMD=-31.25, 95% CI (-41.79, -20.77), P<0.001], rest pain [WMD=-0.41, 95% CI (-0.58, -0.23), P<0.001], activity pain [WMD=-0.56, 95% CI (-0.83, -0.29), P<0.001] and hospital stay [WMD=-0.54, 95% CI (-0.92, -0.15), P=0.006]. CONCLUSION: Recent RCT evidence suggests that perioperative anti-inflammatory interventions can attenuate early inflammatory responses and improve short-term pain and recovery after hip and shoulder arthroplasty. Because data were limited and clinically heterogeneous, the findings should not be interpreted as evidence favoring a specific drug class, dose, route, or timing.

Humans↗

PubMed2026

Validation of the newly introduced Deauville score 5a for patients treated for advanced-stage classic Hodgkin lymphoma.

The Lugano Imaging Committee recently refined the Deauville score (DS), subdividing DS5 into DS5a (>2× liver uptake without new lesions) and DS5b (new lesions). We investigated whether this improves prognostic discrimination at interim positron emission tomography (PET) after 2 cycles (PET-2) in patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) treated in recent German Hodgkin Study Group randomized phase 3 trials. The primary analysis cohort was HD18 postamendment standard arms (uniform treatment with 6 cycles of escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [eBEACOPP]); sensitivity cohorts were HD18 intention-to-treat and HD21 eBEACOPP and brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone arms. Progression-free survival (PFS) was analyzed by landmark Cox models starting at PET-2. DS5a was infrequent (4%-6% across cohorts; 39/639, 67/1745, 33/568, and 29/560). In the primary cohort, DS5 was associated with inferior PFS vs DS1 to DS3 (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.25-7.23) and vs DS1 to DS4 (HR, 2.35; 95% CI, 1.01-5.50). Across sensitivity cohorts, DS5a remained adverse compared with DS1 to DS4 (HR range, 2.57-5.47), whereas DS4 according to the new definition did not consistently separate from DS1 to DS3, which is likely a result of PET-adapted treatment. Overall survival trends were concordant, but interpretation is limited by few events. To our knowledge, this is the first prognostic validation of the refined DS in prospectively randomized trial populations. The newly introduced DS5a isolates a small high-risk AS-cHL, which further supports risk assessment and adaptation using quantitative biomarkers from PET. The HD18 and HD21 trials were registered at www.clinicaltrials.gov as NCT00515554 and NCT02661503, respectively.

Humans↗

PubMed2026

Norgestrel drives mitochondrial collapse and plasma membrane impairment in Pacific oyster (Crassostrea gigas) sperm by triggering premature acrosome reaction.

The toxic mechanisms of norgestrel (NGT), an emerging marine pollutant, on the sperm from externally fertilized invertebrates remain elusive. This study employed an integrated physiological and multi-omics framework to elucidate how NGT (10 and 1000 ng/L) disrupts acrosome reaction (AR) signaling machinery, thereby impairing the functional integrity of Pacific oyster (Crassostrea gigas, also known as Magallana gigas) sperm. Exposure to NGT triggered a significant, dose-dependent premature AR, characterized by elevated acrosin activity and a loss of acrosomal integrity. Multi-omics integration supports a model in which this premature exocytosis is linked to signaling disturbances, including disruption of calcium signaling and reduced transcript abundance of calmodulin (CaM) and the primary recognition protein zonadhesin (Zan). This signaling interference induced an premature AR, subsequently driving a cascade of bioenergetic and structural failures. At the mitochondrial level, NGT induced abnormal mitochondrial permeability transition pore (mPTP) opening and elevated the transcript levels of antioxidant defense genes (e.g., peroxiredoxin-5, PRDX5). These alterations indicate the occurrence of mitochondrial collapse. Concurrently, scanning electron microscopy verified localized plasma membrane wrinkling and pore formation in sperm. In addition, NGT exposure decreased the transcript abundance of cytoskeleton-related genes, including solute carrier family 26 member 6 (SLC26A6), actin (ACT), and tubulin polymerization promoting protein family member 3 (TPPP3). These molecular changes further disrupted membrane phospholipid homeostasis, as represented by altered glycerophospholipid metabolism. At the same time, cumulative cellular stress was associated with decreased transcript abundance of cytoprotective factors (e.g., baculoviral IAP repeat-containing proteins, birc2) and changes in apoptosis-related genes consistent with activation of a caspase-8-mediated apoptotic programme. In conclusion, NGT, as a representative synthetic progestin, exerts reproductive toxicity by interfering with signaling mediators to induce premature AR, which subsequently exhausts metabolic energy and triggers plasma membrane impairment. These findings provide a critical mechanistic basis for the aquatic ecological risk assessment of synthetic progestins.

Animals↗

PubMed2026

Identifying biomarkers of accelerated ageing in cancer patients from routine clinical data.

INTRODUCTION: Cancer and ageing have a bidirectional relationship: age is the strongest risk factor for cancer, and cancer and treatments can accelerate ageing. Therefore, biological age can differ from chronological age; biomarkers are needed to stratify interventions to minimise accelerated ageing. METHODS: PhenoAge was calculated from routine blood test results of patients attending a Geriatric Oncology clinic. PhenoAgeAccel was the residual from a regression of PhenoAge against age. RESULTS: Data were available for 173 patients (62% male). Mean PhenoAge was higher than age (84.3 (12.6) vs 76.2 (7.24), p < 0.001), though the two were correlated (r = 0.579, p < 0.001). Unlike age, PhenoAge and PhenoAgeAccel were associated with one-year mortality (PhenoAge OR=1.083, 95% CI: 1.038-1.136; PhenoAgeAccel OR=1.096, 95% CI: 1.047-1.155). PhenoAge correlated with Clinical Frailty Score and Timed Up and Go (CFS: Rs=0.31, p < 0.001; TUG: Rs=0.25, p < 0.005); there were no correlations with age. PhenoAgeAccel correlated with the number of CGA interventions made (Rs=0.17, p < 0.05), unlike age and PhenoAge. Patients with diabetes mellitus had a higher PhenoAgeAccel compared to those without (3.40 vs -1.71, p = 0.002). In patients receiving systemic anti-cancer treatment, patients with PhenoAgeAccel calculated pre-treatment had less age acceleration than those with PhenoAgeAccel calculated post-treatment, both overall (2.18 vs -2.87; p = 0.048) and in matched samples (n = 21, 7.76 vs -2.87, p < 0.001). CONCLUSIONS: PhenoAgeAccel is a greater predictor of risk than chronological age in older people with cancer. This makes it a promising biomarker to stratify patients for holistic geriatric assessment, dose reductions, or future geroprotective measures which could be integrated within electronic healthcare record systems.

Humans↗

PubMed2026

Impact of creatine supplementation alone or combined with exercise on inflammatory and clinical outcomes in chronic musculoskeletal pain treated in the rheumatological field: a systematic review.

Creatine supplementation has demonstrated ergogenic and anabolic effects in healthy and clinical populations. However, its potential therapeutic role in individuals with chronic musculoskeletal pain treated in rheumatological contexts remains unclear. The aim was to evaluate the efficacy and safety of creatine supplementation on pain, physical function/disability, quality of life, muscle strength, skeletal muscle mass, and inflammatory markers in people with chronic musculoskeletal pain usually treated from the rheumatological field. A systematic review was conducted following PRISMA guidelines. Searches were performed in MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE up to July 2026. Eligible studies were randomized or nonrandomized clinical trials that provided creatine supplementation alone or in combination with exercise as a treatment compared to a control or placebo group. Eight studies (n = 189) were included, encompassing fibromyalgia, osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis. Creatine dosages varied from chronic low-dose to loading protocols (20 g/d, 2-5 g/d). Combined creatine plus resistance training may improve strength, skeletal muscle mass, and quality of life beyond exercise alone in osteoarthritis. Trials on fibromyalgia suggest an increase in muscle strength, but inconsistent effects on pain. Rheumatoid arthritis studies suggest gains in skeletal muscle mass and, in pilot studies, reduced disease activity. No major adverse events were reported. In conclusion, creatine supplementation alone may be insufficient to obtain clinical benefits, while combined with resistance exercise it could offer potential benefits for muscle strength, skeletal muscle mass and certain aspects of quality of life in these clinical conditions. However, evidence on pain and inflammation remains limited; Furthermore, the response across different clinical conditions is heterogeneous, highlighting the need for larger, high-quality trials.

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

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

Biologic-biologic and biologic-JAK inhibitor combination therapy in refractory systemic autoinflammatory diseases.

OBJECTIVES: Systemic autoinflammatory diseases (SAIDs) arise from genetic defects in innate immunity, leading to dysregulated activation of inflammatory pathways, including interleukin (IL)-1, IL-6, TNF, and JAK/STAT. Clinical manifestations range from recurrent fever to severe complications such as encephalitis and AA amyloidosis. Management aims to control inflammation using immunosuppressive agents and targeted monotherapies (biologics or JAK inhibitors). Advanced combination therapy (ACT), defined as the use of biologics and/or JAK inhibitors in combination, has emerged as a strategy for refractory disease. METHODS: In this observational retrospective longitudinal cohort study, patients with SAIDs treated with ACT were included. Demographic, clinical, treatment, and safety data were collected. Treatment response was assessed using a composite outcome incorporating corticosteroid dose, C-reactive protein (CRP), and clinical improvement and categorized as non-response, partial response, or complete response. RESULTS: Thirty-eight patients (median age 30 years [range 4-76]) were included. The most common indications for ACT were pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), mevalonate kinase deficiency (MKD), and undifferentiated SAIDs. Most patients had disease-related complications and were dependent on glucocorticoids and/or opioids to control inflammation and pain, respectively. Following multiple ACT trials, complete response was observed in 21 patients (55.3%), partial response in 12 (31.6%), and no response in 5 (13.1%). Overall, 65 ACT regimens were administered, most commonly combining IL-1 and TNF inhibitors. Thirty-nine regimens were discontinued because of lack of efficacy, secondary loss of response, or adverse events. At the final follow-up, 26 patients (68%) remained on ACT, with a median treatment duration of 60 months (range, 11-186). CONCLUSIONS: ACT offers significant clinical benefits for patients with difficult-to-treat SAIDs, though challenges such as secondary loss of efficacy and infection risks remain.

Humans↗

PubMed2026

Intravesical mitomycin-C administered immediately before transurethral resection of bladder tumor in non-muscle-invasive bladder cancer: Clinical outcomes and molecular predictors from over 3 years of extended follow-up in a phase II trial.

PURPOSE: To evaluate the long-term outcomes and molecular correlates of response after immediate preoperative intravesical chemotherapy (IPeIC) with mitomycin-C (MMC) in patients with non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In this single-center, open-label, randomized phase II trial, 33 patients received two split doses of IPeIC/MMC (40 mg/20 mL), whereas 38 patients underwent transurethral resection of bladder tumor (TURBT) alone. The primary endpoint was 3-year recurrence-free survival (RFS), and secondary endpoints included progression-free survival (PFS). Exploratory RNA sequencing was performed on IPeIC-treated patients (three with recurrence, 25 without) using a Monte Carlo-based resampling strategy. RESULTS: The median follow-up durations were comparable between the intervention (60.0 months) and control arms (60.4 months). IPeIC/MMC reduced recurrence risk by 76.8% versus TURBT alone (p=0.024), yielding a 3-year RFS rate of 90.7% versus 78.6%. On multivariable analysis, IPeIC/MMC independently improved RFS (hazard ratio [HR] 0.266, p=0.044). IPeIC was associated with superior PFS, with 3-year and 5-year rates of 100% versus 92.1% and 85.8%, respectively, in the controls (HR 0.078, p=0.014). Exploratory transcriptomics identified low Glutathione S-transferase Mu 1 (GSTM1) expression as the factor most strongly associated with recurrence. CONCLUSIONS: IPeIC/MMC is associated with improved long-term oncological outcomes compared with TURBT alone and represents a safe prophylactic option for patients with NMIBC who are unable to receive standard immediate postoperative intravesical chemotherapy because of safety concerns or practical constraints. The GSTM1 findings are hypothesis-generating and support future biomarker-driven validation studies.

Aged↗

PubMed2026

A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

PURPOSE: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity. PATIENTS AND METHODS: Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry. RESULTS: Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years. Ten patients had oropharyngeal tumors, of which nine were p16+. Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval (29-71)]. Combination therapy was well tolerated with no unexpected adverse events (AE). Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability. CONCLUSIONS: The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

Humans↗

PubMed2026

A single session of high-definition transcranial direct current stimulation does not modulate effects of knee two-point discrimination training or sensorimotor function in healthy adults: Double-blind randomised controlled trial.

BACKGROUND: Benefits of sensory-training interventions on sensorimotor outcomes are inconsistent, and it is unclear whether transcranial direct current stimulation (tDCS) can enhance proprioception, which is fundamental to neuromuscular control. Existing evidence is dominated by upper-limb studies, so transferability to the knee is unclear. This study investigated whether a single session of anodal high-definition (HD)-tDCS, alone or combined with brief two-point discrimination (TPD) training, enhances knee sensorimotor function and performance in healthy adults. METHODS: In a double-blind randomised-controlled trial, 57 healthy participants received (1) 20-min, 1 mA anodal HD-tDCS over the knee primary somatosensory (S1) map or sham stimulation, and (2) 15-min knee TPD training or no training. Knee somatosensory, sensorimotor, and functional performance measures were assessed pre- and immediately post-intervention. Three-way mixed-design ANOVAs, equivalence testing (smallest effect size of interest η2 = 0.02), Bayes factors, and linear mixed-effects models quantified effects. RESULTS: HD-tDCS, TPD training, and their sequential combination had no effect on any outcome measure (p ≥ 0.05; η2 ≤ 0.015). Confidence intervals spanned equivalence bounds, and equivalence testing results were non-significant (p ≥ 0.05). Bayes factors (<0.33) showed moderate evidence for the null (no effect). Mixed-effects modelling attributed ≤8% of total variance to intervention fixed effects, with the remainder captured by participant-level random effects. CONCLUSION: A single 20-minute session of 1 mA HD-tDCS, with or without brief TPD training, does not acutely modify knee somatosensory, sensorimotor, or functional performance in healthy adults. Existing evidence at the hand may not translate to the lower limb. Future work should investigate higher-dose, multi-session, task-concurrent, or network-targeted strategies in clinical populations.

Humans↗

PubMed2026

The effect of metformin on the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in adults with tuberculosis.

Metformin is under investigation as adjunctive host-directed therapy for tuberculosis (TB), which might interact with first-line TB treatment. We used population pharmacokinetic modeling to assess whether metformin alters first-line TB-drug pharmacokinetics in HIV/TB-coinfected adults without diabetes. Rifampicin, isoniazid, and pyrazinamide pharmacokinetics were investigated in participants from a randomized clinical trial of adjunctive metformin (500 mg twice daily to week 12) in adults starting HIV-associated TB treatment. Antiretroviral therapy (ART)-naïve participants initiated dolutegravir-based ART within 8 weeks. Intensive and semi-intensive sampling was conducted at week 5; concentration-time data were analyzed using non-linear mixed-effects modeling. Data from 78 individuals (43 receiving metformin, median weight 60.8 kg, 62.8% male, 79.5% on ART) were analyzed. Rifampicin and pyrazinamide were described by one-compartment models with linear elimination; typical clearances were 15.8 L/h (95% CI: 13.5-18.7) and 3.88 L/h (95% CI: 3.54-4.08), respectively. Isoniazid followed a two-compartment model with a mixture model for acetylator status; clearance was 10.5 L/h (95% CI: 9.44-11.9) in slow acetylators and 28.8 L/h (95% CI: 25.6-31.0) in fast/intermediate acetylators. Metformin reduced isoniazid bioavailability by 15.6% (95% CI: 4.45-26.4%, P < 0.009) and rifampicin bioavailability by 24.0% (95% CI: 7.83-36.3%, P < 0.007), decreasing the area under the curve from 0 to 24 h from 18.2 to 15.6 mg·h/L and from 35.9 to 27.1 mg·h/L, respectively. No significant effect on pyrazinamide was detected. We found that non-diabetic patients on metformin had lower isoniazid and rifampicin bioavailability. Lowered rifampicin exposure might be clinically relevant; simulations suggest that this could be offset by a single 150 mg rifampicin dose.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04930744.

Humans↗

PubMed2026

Efficacy of afoxolaner (NexGard®) for the treatment of myiasis caused by the zoonotic tumbu fly, Cordylobia anthropophaga, in domestic dogs under field conditions.

Cordylobia anthropophaga is a major cause of furuncular myiasis in dogs and humans in sub-Saharan Africa, yet evidence for pharmacological control remains limited. Current management relies mainly on mechanical larval removal, and no controlled studies have assessed the efficacy of modern antiparasitic agents. This study evaluated the curative and preventive efficacy of a single dose of afoxolaner (NexGard®) in dogs with naturally acquired C. anthropophaga infestation under field conditions and explored a possible indirect protective effect in puppies after maternal treatment. A randomized, blinded, negative-controlled field study was conducted in Samburu County, Kenya, and included 104 naturally infested dogs allocated to a treated group (n = 53) or an untreated control group (n = 51). Clinical evaluations were performed on Days 0, 15 (±2), 30 (±2), and 45 (±2). Efficacy was assessed based on the presence of active nodules and clinical scores. Additional observational data were collected from puppies born to or nursing from treated bitches. Compared to the control group, parasiticide efficacy was 94% on Day 15 and 100% on Day 30. The number of parasite-free dogs reached 86.3% on Day 15, 100% on Day 30, and 95.3% on Day 45. Treated dogs showed a significant clinical improvement from the first post-treatment assessment, whereas infestation persisted in controls (nodules: OR = 0.003, 95% CI 0.001-0.017; skin lesions: OR = 0.010, 95% CI 0.002-0.051; lymph node: OR = 0.013, 95% CI 0.002-0.074; body condition: OR = 0.073, 95% CI 0.027-0.195; all p < .001), with large effect sizes at the final visit for all outcomes (r = 0.521-0.793). No C. anthropophaga infestations were detected in examined puppies from treated dams, including puppies exposed during pregnancy or lactation, up to 4 weeks after birth and up to 11 weeks of age, respectively. Afoxolaner appears effective to control canine cordylobiosis and may offer indirect protection to puppies, warranting further investigation.

Animals↗

PubMed2026

The cellular protein TIAR mediates rapid initiation of West Nile virus genome RNA synthesis.

During the intracellular replication cycle of West Nile virus (WNV), genome RNA synthesis is initially inefficient but increases exponentially as viral replication complexes are sequestered in invaginations in the endoplasmic reticulum. In this study, we investigated the functional role of the cellular protein TIAR (T-cell intracellular antigen-related protein) in the transcription of WNV genome RNA. Close colocalization of cytoplasmic TIAR with viral double-stranded RNA was detected by a proximity ligation assay in WNV-infected cells. TIAR binds specifically to the WNV 3'(-) SL but not to the complementary WNV 5'(+) SL in in vitro RNA binding assays. Only the 3' end of the WNV minus-strand RNA was enriched by immunoprecipitation of infected cell lysates with anti-TIAR antibody. Stable overexpression of TIAR in clonal A549 cells increased the ratio of intracellular viral plus-strand to minus-strand RNA in a dose-dependent manner. TIAR contains three RNA recognition motifs (RRMs). Biophysical data indicated that only RRM2 directly contacts RNA and that up to three TIAR molecules can bind cooperatively to the WNV 3'(-) SL RNA. These data provide additional evidence that TIAR functions as a proviral host factor facilitating exponential amplification of WNV genome production in infected cells.IMPORTANCEWest Nile virus (WNV) is a mosquito-borne orthoflavivirus associated with increasing global human disease incidence. The molecular mechanisms underlying viral replication are not fully understood. In early stages of infection, viral genome transcription is inefficient; however, in late stages, viral genome transcription increases exponentially. T-cell intracellular antigen-related (TIAR) protein is a cellular protein that has been shown to interact with the 3' end of the WNV negative-sense antigenomic RNA. We obtained data showing colocalization of cellular TIAR with viral replication complexes in infected cells and an increased ratio of intracellular genomic to antigenomic viral RNA in TIAR-overexpressing cells, and confirmed preferential binding of TIAR to the 3' end of the WNV antigenome both in vitro and in infected cell extracts. We also demonstrated that multiple TIAR proteins can bind cooperatively to the WNV 3'(-) stem-loop RNA. These data provide supporting evidence for a model of TIAR-mediated rapid initiation of nascent genome RNA synthesis in infected cells.

TIAR↗