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PubMed2026

Insights from changes in NDEV biomarkers of metabolism: effects of PPARγ and GLP1 receptor agonists on brain metabolism.

BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD). METHODS: We analyzed biological samples from two cohorts of clinical trial participants: (1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and (2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups. RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all P ≤ .02) compared with placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; P = .04 and P = .025, respectively) compared with placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test. DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.

Humans↗

PubMed2026

Efficacy and Safety of Mechanical Insufflation-Exsufflation in Invasively Ventilated Critically Ill Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) is increasingly used in invasively ventilated adults in the intensive care unit (ICU), yet its therapeutic efficacy and safety remain uncertain due to inconsistent evidence. AIM: To synthesize evidence on the clinical efficacy and safety of MI-E in this population and to examine methodological and clinical heterogeneity underlying reported outcomes. STUDY DESIGN: A systematic review and meta-analysis of randomized studies (including RCTs and randomized crossover trials), conducted following PRISMA guidelines, with risk of bias assessed using the Cochrane risk-of-bias tool. RESULTS: Five randomized controlled trials involving 310 patients were included. Meta-analysis showed that mechanical insufflation-exsufflation (MI-E) significantly increased sputum clearance (SMD = 0.63, 95% CI, 0.32-0.93; p < 0.00011; I2 = 38%) without affecting oxygenation (MD = 0.28, 95% CI, -0.53 to 1.09; p = 0.50; I2 = 9%). Data on respiratory mechanics, ventilation duration and ICU stay could not be pooled. No serious adverse events were reported. CONCLUSIONS: MI-E significantly improves sputum clearance in invasively ventilated critically ill adults, with no severe adverse events reported in the included studies. Its effects on other outcomes remain inconclusive due to limited data and heterogeneity. Standardized protocols and larger trials are needed. RELEVANCE TO CLINICAL PRACTICE: Clinicians may consider MI-E as an adjunct for respiratory secretion management. Application should be guided by structured patient assessment and individualized parameter adjustment. Future research should standardize interventions and target well-defined patient subgroups to inform clear practice guidelines. TRIAL REGISTRATION: The review protocol was registered in the International Prospective Register of Systematic Reviews, with registration number CRD42023403299.

Humans↗

PubMed2026

Pretreatment EBV-DNA/TLG-Based Risk Stratification Is Associated With Survival Outcomes in Nonmetastatic Nasopharyngeal Carcinoma: An Exploratory Study.

Whether combining pretreatment plasma Epstein-Barr virus DNA (EBV-DNA) with 18F-FDG PET/CT-derived total lesion glycolysis (TLG) improves prognostic stratification in nonmetastatic nasopharyngeal carcinoma (NPC) is unclear, particularly in nonendemic populations. We retrospectively analyzed 86 eligible nonmetastatic NPC patients treated with definitive radiotherapy (2010-2024) at a single nonendemic-region institution. EBV-DNA (prespecified cutoff 3500 copies/mL) and TLG (cutoff 200, ROC-derived within this cohort) were dichotomized. Both were available in 59/86 patients (68.6%), who differed from the rest in nodal and overall stage and in RT technique. Baseline PET/CT was in-house in 57 of 86 patients, and a robustness analysis in that subgroup is reported. Given limited events (13 PFS, 9 OS), Cox analyses are exploratory and were supplemented with penalized regression and bootstrap validation. At a median follow-up of 75.5 months, 5-year PFS and OS for the whole cohort (n = 86) were 81.1% and 85.9%. The EBV-DNAhigh/TLGhigh subgroup remained associated with inferior PFS after adjustment in an exploratory model (adjusted HR = 3.97, 95% CI: 1.32-11.93) and, in a single-variable model, with inferior OS (HR = 4.13, 95% CI: 1.10-15.52). Discrimination was comparable to the individual-biomarker model for PFS and lower for OS. Five-year PFS fell monotonically across the four risk groups in the complete-case cohort (n = 59; 89.7%-58.3%). OS differed across groups (log-rank p = 0.044) but was not strictly monotonic, with wide, overlapping confidence intervals. This two-biomarker model is hypothesis-generating and needs prospective, multicenter validation before any consideration of risk-adapted treatment.

Epstein–Barr virus DNA↗

PubMed2026

Nipocalimab Phase 3 Dose Selection for Severe Hemolytic Disease of the Fetus and Newborn.

Nipocalimab, a neonatal Fc receptor (FcRn) blocker, is under evaluation for severe hemolytic disease of the fetus and newborn (HDFN). In the Phase 2 UNITY trial, weekly intravenous antenatal treatment with nipocalimab at dose regimens of 30 and 45 mg/kg prevented fetal anemia requiring intrauterine transfusion (IUT) in 54% of high-risk pregnancies and delayed the need for IUTs versus their previous pregnancies in the remaining 46% of pregnancies. This analysis aimed to select a weekly dose regimen of nipocalimab for the Phase 3 study in severe HDFN (NCT05912517) that maintains FcRn blockade throughout antenatal treatment, including with an unplanned dosing delay of up to 3 days. Observed pharmacokinetic/pharmacodynamic (PK/PD) data from UNITY (i.e., nipocalimab concentrations, FcRn occupancy, and serum IgG) were analyzed using a model-based approach. A PK/PD model originally developed in nonpregnant participants was updated to incorporate gestational weight gain. Nipocalimab PK and FcRn occupancy were described by a two-compartment model with nonlinear, dose-dependent PK, which captured longitudinal PK, FcRn occupancy, and IgG profiles during dosing and return toward baseline postpartum after discontinuation. Both 30 and 45 mg/kg achieved ∼80%-85% reductions in maternal IgG; however, 30 mg/kg showed greater variability in predose trough concentrations, increasing the risk of falling below concentrations required for full FcRn occupancy across antenatal treatment. Simulations incorporating PK/PD variability indicated that 45 mg/kg weekly per current weight maintained full FcRn occupancy in >95% of pregnant individuals, even with dosing delays up to 3 days. Exploratory exposure-response analyses supported 45 mg/kg for the Phase 3 HDFN study.

Humans↗

PubMed2026

Prognostic value of early changes in the frontal QRS-T angle in patients with heart failure and left bundle branch block undergoing cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in selected patients with heart failure (HF). The frontal QRS-T angle (FQTA), reflecting ventricular depolarization-repolarization heterogeneity, has been associated with major adverse cardiovascular events (MACE). We aimed to assess the prognostic value of changes in the FQTA after CRT in predicting long-term MACE. METHODS: A total of 223 consecutive HF patients with left bundle branch block who underwent CRT between 2018 and 2022 were retrospectively analyzed. The FQTA was measured before and after CRT, and the change (ΔFQTA) was calculated. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff value for predicting the primary outcome, MACE. Patients were subsequently stratified according to this cutoff value. Independent predictors were identified using multivariable Cox proportional hazards regression analysis. RESULTS: ROC analysis identified 22.5° as the optimal cutoff value for predicting MACE (AUC: 0.711; 95% CI: 0.642-0.781; p < 0.001). During a mean follow-up of 34.6 ± 17.6 months, patients with ΔFQTA <22.5° had a significantly higher incidence of MACE compared with those with greater angle reduction (44.7% vs. 11.9%; p < 0.001). In multivariable Cox regression analysis, chronic kidney disease (HR: 2.517; p = 0.002) and ΔFQTA <22.5° (HR: 4.56; p < 0.001) were independently associated with MACE. CONCLUSION: A greater reduction in FQTA after CRT is associated with improved long-term outcomes and may serve as a practical electrocardiographic marker for risk stratification.

Humans↗

PubMed2026

ENLIGHTENme: Translating the Benefits of Self-Administered Daytime Light Supplementation to Older Adults in the Real World.

Controlled studies have demonstrated that light supplementation benefits circadian entrainment, sleep and mood. Translating these findings into effective, real-world usage of light supplementation is, however, challenging because naturalistic and supplemental light exposure are shaped by personal habits and environmental light conditions. Bridging this translation gap is especially critical for older adults, given the reduced ocular light sensitivity associated with natural ageing, which exacerbates low daytime indoor light exposure in urban housing. We therefore set out to investigate the determinants of self-directed light supplementation in this population, and what the real-world feasibility and efficacy of daytime light supplementation is. We recruited 202 participants (63-92 years; 139 females) to our interventional, prospective, randomised study in three major EU cities at different latitudes (Amsterdam, Bologna, Tartu). Participants underwent a 2-week baseline assessment of light exposure, rest-activity patterns and sleep through wearables and daily diaries. Participants were then randomised to either 12 weeks of self-implemented indoor light supplementation using a lamp placed in their most frequently used room (> 8000 melanopic EDI, N = 98) or a no-intervention group. A subsequent 2-week reassessment showed that greater naturalistic light exposure was associated with increased daytime activity, consolidated wakefulness, better subjective sleep quality, and reduced metabolic disorder incidence. Individuals with lower naturalistic light exposure self-initiated earlier and longer indoor light supplementation across seasons, in which supplementation onset before 10:00 was associated with greater daytime activity and lower rest-activity fragmentation. These results confirm that this simple, non-pharmacological, and low-cost intervention has broad potential to support healthy ageing in urban settings.

Humans↗

PubMed2026

Safety, Pharmacokinetics, and Pharmacodynamics of Single-Dose Programmed Cell Death Protein 1 Inhibitor, Budigalimab, in People With HIV-1 With Antiretroviral Therapy-Suppressed Viral Load.

BACKGROUND: Blockade of inhibitory immune checkpoint receptor programmed cell death protein 1 (PD-1) on target immune cells is associated with improved HIV-specific immune function and activation of latent HIV. This randomized, placebo-controlled, Phase 1b study assessed low doses of investigational anti-PD-1 monoclonal antibody, budigalimab, for safety, tolerability, pharmacokinetics, and pharmacodynamics in people with HIV (PWH) on antiretroviral therapy. METHODS: Participants received single doses of budigalimab 10 mg subcutaneous (SC), 20 mg SC, 10 mg intravenous (IV), or placebo (n = 8 per arm) and were followed for 24 weeks. RESULTS: Of 32 randomized participants, 22 reported adverse event(s) (AE); most (n = 19) were grade ≤2 and no grade ≥4 AE or treatment-related serious AE. Two participants reported a non-treatment-related grade 3 AE (placebo, n = 1 pneumonia; 10 mg IV, n = 1 elevated aspartate aminotransferase). One reversible immune-related AE (grade 2 lichenoid keratosis) was reported (20 mg SC). Geometric mean maximum serum concentrations were 0.37, 1.57, and 3.2 µg/mL with 10 mg SC, 20 mg SC, and 10 mg IV, respectively. Drug exposure with 20 versus 10 mg SC dosing was more than dose proportional and less variable. Subcutaneous bioavailability was approximately 53%-62%. The PD-1 receptor saturation was ≥95% in most participants (median duration: 20 mg SC, 42 days; 10 mg SC, 14 days; 10 mg IV, 35 days). CONCLUSIONS: Findings suggest an acceptable safety profile for single-dose budigalimab in PWH, with a favorable pharmacokinetic profile for 20 mg SC and 10 mg IV. Further evaluation as a potential component of an HIV treatment is underway.

Humans↗

PubMed2026

Metagenome-scale modeling to assess microbiome metabolic complementarity for precision microbiota transplantation therapies.

Fecal microbiota transplantation (FMT) holds therapeutic promise beyond recurrent Clostridioides difficile infection, but clinical outcomes remain unpredictable and donor-selection strategies remain limited, in part because the role of donor‒recipient metabolic interactions in shaping the post-FMT community remains poorly understood. Here, we leverage metagenome-scale metabolic modeling to quantify metabolic niche complementarity between donor and recipient microbiomes and predict post-FMT community composition. Using MICOM-derived metabolic models, we show that donor genomes whose metabolic flux profiles are more dissimilar from the recipient community colonize at significantly higher rates in a murine FMT model. In a human IBS trial, the same metric predicted post-FMT community composition via leave-one-out cross-validation and captured known disease-associated alterations in short-chain fatty acid, sulfur, and gas metabolism. We then performed 2,548 in silico FMT simulations between IBS-D/M patients and donors from the OpenBiome biobank to evaluate personalized donor screening, identifying super-donors characterized by high taxonomic diversity, broad metabolic niche coverage, and community interaction networks dominated by cross-feeding rather than competition. Together, these results support metabolic niche complementarity as a potential determinant of post-FMT community composition and provide a mechanistic basis for evaluating donor-recipient metabolic compatibility. This framework offers a scalable approach for generating testable hypotheses for personalized donor selection.

Fecal Microbiota Transplantation↗

PubMed2026

BIOCARD framework: integrating fecal bile acids, lipids, and metabolites to assess response to a cardiovascular health intervention.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, particularly in under-resourced populations. Although nutritional interventions are important for CVD prevention, their outcomes are commonly evaluated using conventional clinical and behavioral indicators, which may not fully capture early molecular responses. In this study, we developed the BIOCARD framework, an exploratory fecal multi-omics platform integrating bile acids, lipids, and metabolites to evaluate intervention outcomes related to cardiovascular health. Fecal samples were collected from caregiver-child participants enrolled in a 10-week randomized controlled trial comparing a multicomponent garden-based intervention (SHA) with an education-only control group (MSP). Fecal polar metabolites, lipids, and bile acids were analyzed by UHPLC-HRMS-based approaches and integrated with conventional health indicators. Traditional clinical indicators in the present study showed limited sensitivity for detecting intervention-related differences. In contrast, fecal multi-omics analyzes revealed intervention-associated differences in metabolites, lipids, and bile acids, with children showing more apparent molecular variation than parents. Network analysis further revealed associations between selected molecular features and cardiovascular-related indicators, including blood pressure, body fat, skin carotenoids, and Healthy Eating Index scores. Together, these findings suggest that the BIOCARD framework may serve as an exploratory molecular approach to complement traditional outcome measures and improve the evaluation of nutritional interventions for cardiovascular health.

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

Genome-wide identification, structural characterization, and evolutionary analysis of growth-related gene families in African catfish (Clarias gariepinus).

The somatotropic axis encompassing growth hormone (GH), insulin-like growth factor (IGF), myostatin (MSTN), and prolactin (PRL) signalling cascades is the master regulator of somatic growth, metabolism, and development in vertebrates. African catfish (Clarias gariepinus), a commercially pivotal aquaculture species, now possesses a chromosome-level reference genome (CGAR_prim_01v2); however, a systematic, genome-wide characterization spanning all five interconnected growth-related gene families has not previously been undertaken in this species. Here, we identified and characterized 15 growth-related genes spanning gh1, ghra, ghrb, Igf1, Igf2a, Igf2b, igf1ra, Igf1rb, Igf2r, Mstna, Mstnb, prl, prlra, prlrb, and smtlb distributed across 13 chromosomes. Complete one-to-one orthology with zebrafish confirmed strong dosage-balance conservation across >120 million years of teleost divergence. Physicochemical analysis resolved a clear biochemical dichotomy between compact, basic secreted ligands (19.88-45.81 kDa; pI up to 10.02) and large, acidic, heavily glycosylated membrane receptors (56.82-270.80 kDa; pI 4.85-5.97). Phylogenetic analysis confirmed 3R whole-genome duplication origins for all paralog pairs, while synteny analysis revealed a disruption of the ancestral gh1-prl chromosomal block in C. gariepinus, a finding that warrants further comparative and functional investigation. This genomic atlas provides the sequence and structural information including exon-intron boundaries, domain architecture, and chromosomal coordinates needed as a prerequisite for future marker-assisted selection and CRISPR-based myostatin-editing efforts in African catfish aquaculture, though translation into applied breeding outcomes will require subsequent functional and expression studies.

Animals↗

PubMed2026

Effects of multistrain probiotic supplementation on hepatic function and anthropometric parameters in patients with metabolic dysfunction-associated steatotic liver disease: a double-blind, randomized controlled trial.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent on a global scale. The gut microbiota is integral to its pathogenesis, prompting extensive research into microbiota modulation as a potential adjunctive therapeutic strategy. AIM: The study aimed to evaluate the effect of multistrain probiotics supplementation on hepatic function in patients with MASLD in a double-blind, randomized, controlled trial. The primary outcomes were changes in Fibrosis-4 index (FIB-4) and fatty liver index (FLI). Secondary outcomes included changes in anthropometric parameters, selected biochemical markers, and other liver-related indices. METHODS: A total of 64 patients with MASLD were randomly assigned to two groups receiving either placebo (C) or a probiotic mixture (PRO) containing the following bacterial strains: 50% Lactococcus lactis Rosell-1058, 25% Lacticaseibacillus casei Rosell-215, 12.5% Lactobacillus helveticus Rosell-52, 12.5% Bifidobacterium bifidum Rosell-71 for 12 wk. RESULTS: Significant group × time interactions were observed for FIB-4 (Q = 0.007), with reduction in the PRO group and increase in the C group (-0.05 vs. 0.10; P = 0.002). No significant interaction was found for FLI (Q = 0.942). Significant group × time interactions were also observed for aspartate aminotransferase (-2.87 vs. 1.87 U/L; Q = 0.003) and APRI (-0.03 vs. 0.02; Q = 0.001), favoring the PRO group (P < 0.001 for both). No significant changes were observed in anthropometric parameters, glucose levels, or lipid profile. CONCLUSIONS: In patients with MASLD, the 12-wk probiotic supplementation had a modest but statistically significant effect on FIB-4, aspartate aminotransferase, and APRI, with no significant effect on FLI or anthropometric and metabolic parameters. These findings suggest that this probiotic formulation may have potential benefits for liver function in MASLD. However, long-term studies incorporating imaging-based and histological endpoints are required to determine the clinical significance of these findings.

Humans↗

PubMed2026

Effectiveness of chlorhexidine gluconate-impregnated dressings in preventing central line-associated bloodstream infection in a paediatric intensive care unit: A randomised controlled trial.

OBJECTIVES: To compare the effectiveness and dermatological safety of chlorhexidine gluconate (CHG)-impregnated dressings versus conventional transparent dressings in preventing central line-associated bloodstream infection (CLABSI) in paediatric patients admitted to a PICU. METHODS: A single-blind, randomised controlled trial with a 1:1 allocation ratio was conducted in a tertiary PICU. A total of 250 paediatric patients with a central venous catheter were included (125 per group). Patient characteristics, catheter-related variables, catheter dwell time and skin alterations were recorded. The primary outcome was CLABSI, defined according to CDC/NHSN criteria. Bivariate analyses and multivariable logistic regression were performed, including clinically relevant covariates related to catheter exposure, dressing type, and vaccination status. The trial was registered at ClinicalTrials.gov (NCT07175116). RESULTS: CLABSI incidence was significantly lower in the CHG group compared with the conventional dressing group (2.4% vs. 18.4%; p < 0.001). In multivariable analysis, CHG-impregnated dressings were independently associated with reduced CLABSI risk (OR = 0.15; 95% CI: 0.04-0.58). Longer catheter dwell time (OR = 1.13 per day; 95% CI: 1.04-1.22) and absence of complete vaccination (OR = 8.68; 95% CI: 2.48-30.47) were also associated with increased infection risk. Incomplete vaccination showed a similar trend without reaching statistical significance (OR = 6.48; 95% CI: 0.95-44.20). Skin alterations were more frequent in the CHG group (16.8% vs. 11.2%), predominantly in younger infants. CONCLUSIONS: CHG-impregnated dressings were associated with a significant reduction in CLABSI incidence in critically ill paediatric patients, although their use was linked to a modest increase in mild skin reactions. IMPLICATIONS FOR CLINICAL PRACTICE: CHG-impregnated dressings may be considered as part of a multifaceted infection prevention strategy, alongside appropriate catheter management, minimisation of catheter manipulation and proactive skin monitoring, with cautious and individualised use in infants.

Humans↗

PubMed2026

Reliability, Device Agreement and Validity of Load-Velocity Profiles: A Systematic Review with Meta-analysis.

BACKGROUND: For a valid one-repetition maximum (1RM) prediction via load-velocity (LV) relationships, high reliability and accuracy must be assumed. OBJECTIVE: Since individual study results indicate ambivalent prediction, this systematic review and meta-analysis was designed to provide a updated and comprehensive overview, extending knowledge about the validity and reliability of commercially available velocity sensors in Part I and the validity and reliability of velocity-based 1RM prediction models in Part II. METHODS: A systematic literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus. Validity and/or reliability studies or velocity-based 1RM prediction evaluations were included. Methodological quality was assessed using adapted COSMIN. The analysis was performed for intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC), and Pearson's correlation coefficient (r). The review was preregistered in PROSPERO (CRD42025634595). RESULTS: Sixty-three studies were included for sensor validity and reliability and 38 for 1RM prediction models. Part I: Velocity sensors demonstrated good-to-excellent pooled validity and device agreement (ICC = 0.91-0.92 [0.83-0.97]; k = 55 and 439, respectively); intra- and inter-day reliability were classified as good to excellent with ICC = 0.90-0.91 [0.85-0.95] (k = 228 and 608, respectively), with sensor technology moderating the results. However, substantial heterogeneity and wide ranges of study-level estimates indicated considerable variability across moderators, linear position transducer (LPT) generally showing more consistent performance than inertial measurement units (IMU). Part II: Velocity-based 1RM prediction showed ICCs = 0.90 [0.83-0.94] (k = 124) and ICC = 0.91 [0.72-0.98] (k = 9); for reliability and validity, respectively. DISCUSSION: Commercial velocity sensors generally provide high relative validity and reliability. Results varied depending on exercise complexity, intensity, sensor technology, and modeling approach. While velocity-based 1RM prediction demonstrated high average validity, large heterogeneity in lower body exercises significantly biased the results. Furthermore, the dearth of measurement error and agreement analyses prohibits final conclusions. CONCLUSION: Therefore, velocity-based monitoring and 1RM prediction require cautious interpretation, as sensor- and exercise-specific evidence remains limited.

Load–velocity relationship↗

PubMed2026

A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.

INTRODUCTION: Cancer cell proliferation occurs within the context of persistent genomic instability. In this review, we propose the RS-CCD-CIN axis as a systems-level framework in which replication stress (RS), cell cycle deregulation (CCD) and chromosomal instability (CIN) form an interdependent triad that shapes tumour evolution. This axis represents a constrained metastable state in which genomic instability is tolerated and buffered. The objective of this review is to synthesize the current understanding of how the RS-CCD-CIN axis contributes to tumour heterogeneity, adaptability and therapy response. DISCUSSION: Evidence indicates that RS, CCD and CIN operate as a dynamic, interconnected network rather than as independent processes. Replication stress induces DNA damage and mutagenesis, while partial checkpoint disruption permits cells with unresolved lesions to proliferate. Chromosomal instability generates both structural and numerical alterations, contributing to intratumoural heterogeneity. Together, these processes facilitate adaptation to environmental and therapeutic pressures. Extrachromosomal DNA, micronuclei formation and cytosolic DNA signalling, including the cGAS-STING pathway, connect genomic instability to adaptive responses and immune modulation. Single-cell and spatial profiling reveal temporal and spatial variability in RS, CCD and CIN states, highlighting the limitations of static biomarkers. Therapeutically, targeting individual components often yields limited durability, whereas approaches that simultaneously perturb multiple aspects of the RS-CCD-CIN axis may improve clinical outcomes. CONCLUSIONS: This review highlights the RS-CCD-CIN axis as a fragile and metastable architecture that supports cancer evolution, while also being susceptible to collapse. A deeper understanding of this interconnected framework may inform the development of therapeutic strategies and enhance the management of resistance.

Humans↗

PubMed2026

Evaluation of intravenous sedation in dental implant surgeries: A prospective cohort study.

PURPOSE: This study aimed to evaluate the impact of intravenous sedation on patient-centered outcomes during implant and bone augmentation surgeries. METHOD: A prospective observational cohort study included 40 patients undergoing placement of ≥3 implants, with or without bone augmentation. Patients underwent surgery under either intravenous sedation (n = 20) or local anesthesia alone (n = 20), according to routine clinical decision-making and patient preference. The sedation group received intravenous sedation with a multimodal regimen comprising remimazolam, dexmedetomidine, alfentanil, and low-dose esketamine, whereas the control group received local anesthesia only. Patient-reported outcome measures, hemodynamic parameters (SBP, DBP, HR, SpO2), postoperative pain (0-10 scale), and OHRQoL (OHIP-14) were recorded from baseline through 7 days post-surgery. RESULTS: Intravenous sedation was associated with significantly lower intraoperative pain (0.5 [IQR: 0∼2.75] vs. 3.25 ± 2.40, p = 0.003), anxiety (1 [IQR: 0∼2.75] vs. 4 [IQR: 3∼6], p = 0.001), and experienced discomfort (2 [IQR: 1∼3.75] vs. 4.15 ± 2.16, p = 0.016), and shortened perceived treatment duration (2.90 ± 2.34 vs. 5 [IQR: 4∼5], p = 0.020). Early postoperative pain was lower in the sedation group from Days 1-4 (p = 0.003-0.010). Hemodynamic parameters were more stable under sedation, with lower SBP (116.42 ± 13.32 vs. 144.11 ± 17.42 mmHg, p < 0.001), DBP (73.21 ± 10.28 vs. 82.37 ± 11.03 mmHg, p = 0.012), and HR (71.00 [IQR: 62.50∼79.25] vs. 85.00 ± 10.72 bpm, p = 0.021). OHRQoL scores favored the sedation group in swallowing, diet, malaise, and daily activities, particularly during the first three postoperative days (p=0.006-0.040). CONCLUSION: Intravenous sedation may enhance the patient experience during implant and/or bone augmentation procedures by reducing intraoperative pain and anxiety, improving hemodynamic stability, and promoting better early-postoperative recovery and OHRQoL. These findings suggest that intravenous sedation provides a safe and effective alternative for implant dentistry surgery, particularly for anxious or pain-sensitive individuals.

Humans↗

PubMed2026

Tissue origins of the plasma proteomic response to glucose ingestion in humans.

AIMS/HYPOTHESIS: Circulating proteins act as important hormonal signals of nutrient intake. We aimed to systematically characterise the time-resolved proteomic response to glucose ingestion in humans, and to assess its robustness following prolonged complete caloric restriction. METHODS: We conducted oral glucose tolerance tests (OGTTs) in 11 healthy volunteers before and after 7 days of complete caloric restriction and measured the response of >2900 targets through high-resolution plasma protein profiling. RESULTS: We identified a signature of 44 proteins that changed significantly following glucose ingestion, which was reproducible after 7 days without food, and was strongly (20-fold) enriched for 'stomach-specific' proteins. We report that annexin A10 (ANXA10) shows the most significant post-glucose change observed, similar to the trajectories of secreted hormones. We present observational human evidence from multiple sources suggesting that ANXA10 is secreted upon sensing an increase in gastric pH, with the stomach as the major contributing tissue. Despite a profound metabolic shift after 7 days of complete caloric restriction, characterised by delayed insulin secretion and postprandial hyperglycaemia, only four proteins showed robust evidence for a differential trajectory during both OGTTs. This included plasma levels of tryptophanyl-tRNA synthetase 1 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease. CONCLUSIONS/INTERPRETATION: Our exploratory study identifies the proteomic response to glucose ingestion and demonstrates its reproducibility despite major shifts in glucose homeostasis. We characterise the gastrointestinal origin of these changes, and hypothesise a hitherto under-recognised role for sensing of changes in gastric pH on the plasma proteome.

Humans↗

PubMed2026

Skeletal Muscles Do Not Compete for Growth: Activating Additional Muscle Mass Does Not Compromise Changes in Muscle Size.

Kataoka, R, Yamada, Y, Hammert, WB, Sallberg, RW, Kang, A, Song, JS, Kassiano, W, Metcalf, EE, and Loenneke, JP. Skeletal muscles do not compete for growth: Activating additional muscle mass does not compromise changes in muscle size. J Strength Cond Res 40(9): 1043-1049, 2026-This study investigated whether the magnitude of muscle size and strength differed based on the amount of muscle recruited during training sessions. One hundred five untrained individuals were randomly assigned to 1 of 3 groups: low-load unilateral elbow flexion exercise (a) to failure (LL-Failure, n = 36), (b) to failure and low-load knee extension exercise to failure (LL-Failure + Legs, n = 33), or (c) a time-matched nonexercise control (CON, n = 36). Training groups completed 18 supervised sessions over 6 weeks (2 sets at 30% 1 repetition maximum [1RM] to failure). LL-Failure + Legs group performed 4 additional sets of knee extension exercise in each leg (20-30 RM). Muscle thickness on the anterior upper arm (60 and 70% sites) and elbow flexor 1RM strength of the trained arm were measured at pretesting and posttesting. Changes were compared using the ANCOVA function of Bayes Factors for Informative Hypotheses (prevalues as the covariate). Specific hypotheses were evaluated by comparing Bayes factors and the posterior probabilities between models. Six weeks of training led to increases in muscle size and strength. However, performing additional leg exercise did not attenuate the muscle growth in the anterior upper arm (0.19 cm) compared with performing only arm exercise to failure (0.18 cm). Changes in 1RM strength also did not differ between training groups (0.32 and 0.25 kg for LL-Failure and LL-Failure + Legs, respectively). Overall, there was no evidence for competition of adaptations in muscle size and strength under uncontrolled nutritional conditions. Whether greater training volume or limited nutrient intake induces a competition for resources warrants further investigation.

Humans↗

Results for “gut&#x2013;muscle axis”

Results for “gut–muscle axis”