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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

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

Adductor Canal Block and Local Anesthetic Versus Local Anesthetic Alone in ACL Reconstruction: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Effective postoperative analgesia is crucial for early recovery after anterior cruciate ligament reconstruction (ACLR). Local infiltration analgesia (LIA) and adductor canal block (ACB) are common regional techniques, but their combined efficacy remains unclear. PURPOSE: To compare the effectiveness of LIA alone versus LIA combined with ACB in patients undergoing ACLR, with primary outcomes including postoperative opioid consumption and quadriceps function. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A double-blind randomized controlled trial enrolled 100 patients undergoing ACLR under general anesthesia. Patients were randomized into 2 groups: LIA + sham (saline injection) (n = 50) and LIA + ACB (n = 50). The primary outcome was postoperative opioid consumption in the first 24 hours. Secondary outcomes included visual analog scale (VAS) pain score, quadriceps function assessed by straight leg raise (SLR) at 3 hours, Quality of Recovery-15 (QoR-15) score, and Knee Injury and Osteoarthritis Outcome Score (KOOS) at 1 week. Statistical analysis was performed using t tests and chi-square tests with a P value <.05 considered significant. RESULTS: There was no significant difference in 24-hour opioid consumption between the LIA + ACB and LIA-only groups (P = .109). Similarly, VAS pain scores at 24 hours postoperatively showed no significant differences between the groups (P = .0804). Early functional recovery, assessed by SLR performance at 3 hours, was equivalent between groups (P = .6711). Additionally, QoR-15 scores on postoperative day 1 and KOOS values at 1 week demonstrated no significant differences (P = .6486 and P = .9054, respectively). Intraoperative opioid consumption was not different between the groups (P = .127). CONCLUSION: These findings indicate that the addition of ACB to LIA does not yield postoperative analgesic in ACLR. Consequently, LIA alone suffices for routine ACLR, potentially enabling clinicians to optimize perioperative workflows without incurring the additional time, financial burden, and resources associated with routine ACB administration. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04721119.

Humans↗

PubMed2026

Temporal evolution of minimally invasive pediatric urolithiasis treatment over 30 years.

Urolithiasis in children has increased substantially over the past 30 years, and surgical management maintains an important role in treatment. Technological advances such as lasers and miniaturization have broadened treatment options, and researchers investigate the best indications for each procedure. The aim was to identify publication trends in the field and explore reasons why Extracorporeal Shockwave Lithotripsy is being gradually less applied in the treatment of pediatric urolithiasis. A Reverse Systematic Review of the literature was conducted regarding the surgical treatment of urolithiasis in children. Five databases were screened, gathering all articles from inception that were evaluated in systematic reviews. We examined 123 publications, 197 reports, and 15,878 procedures, consisting of the largest studied population in the field. There was an increasing number of publications, although in progressively less prestigious journals. The number of studies on miniaturized percutaneous techniques and flexible ureteroscopy has increased closely with the rise in popularity of these procedures worldwide, mainly driven by studies from Asia, Europe, and North America. A trend of self-renewed interest is fueled by technological innovation and has led to fewer publications on Extracorporeal Shockwave Lithotripsy over the years. This review highlights the fact that, despite positive results in recent studies, the low popularity of ESWL within the scientific community is driving a decline in the technique's indications. Moreover, based on the findings of this study, key research priorities include continued reporting of high-quality outcomes, and technological progress in ESWL would contribute meaningfully to the field.

Humans↗

PubMed2026

Searching for New Genes That Cause Usher Syndrome.

PURPOSE: The purpose of this project was to identify novel Usher syndrome (USH) candidate genes from phenotyping data of 9139 knockout (KO) mouse lines. METHODS: We evaluated phenotype data for concurrent retinopathy and hearing abnormalities in single-gene KO mice generated by the International Mouse Phenotyping Consortium (IMPC). A search was performed to determine whether each gene had been previously associated with retinopathy and/or deafness in humans. Bioinformatic tools were used to predict protein interactions, molecular functions, signaling pathways, and the expression of human orthologues of candidate genes in the retina and inner ear. RESULTS: We identified 18 single-gene KO lines exhibiting hearing abnormality and retinopathy after ear and eye examinations, respectively, and/or by histopathology. The molecular functions and signaling pathways of the human orthologues of the 18 candidate genes partially overlapped with those of USH genes. Particularly, FER and DYRK1B proteins were predicted to interact with proteins encoded by known ciliopathy genes. ADIPOR1, ATP8B1, and MPDZ were associated with retinal degeneration in humans. CHSY1 and IDUA may be pathogenic causes of hearing impairment in people. Furthermore, CHSY1, CSTB, and SPRED1 were located adjacent to unsolved genetic loci related to USH. CONCLUSIONS: A screen of 9139 KO mouse lines revealed 18 candidate genes exhibiting both retinal and inner ear abnormalities consistent with the principal clinical features associated with USH. As the observed phenotypes are attributed to gene deletion in mice, these genes warrant further study to determine the causation of retinal degeneration and hearing loss in patients.

Animals↗

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↗

PubMed2028

Parental son preference in childhood and sex differences in the risk of cardiovascular disease in middle-aged and older adults.

INTRODUCTION: Sex differences in cardiovascular disease (CVD) risk are examined through biological and clinical factors, with less attention to early-life social exposures. This study examined associations of childhood parental son preference with CVD risk, sex differences, and mediation by modifiable risk factors. METHODS: This cohort analysis included China Health and Retirement Longitudinal Study participants aged ≥45 years without baseline CVD. Parental son preference was assessed retrospectively in 2014; incident CVD was self-reported physician-diagnosed heart disease or stroke through 2020. Sampling-weighted, community-clustered Cox models estimated adjusted hazard ratios (aHRs) and 95% CIs. Sex was prespecified as an effect modifier; mediation by 13 risk factors used inverse-odds-ratio weighting. Data were collected from 2011 to 2020 and analyzed from 2025 to 2026. RESULTS: Among 8,079 participants (mean age, 57.5 years; 4,216 women [52.2%]), 1,820 (22.5%) reported parental son preference. Son preference was associated with higher CVD risk overall (aHR 1.23 [95% CI 1.04, 1.46]) and among women (aHR 1.25 [95% CI 1.03, 1.53]); among men, the estimate was 1.16 (95% CI 0.87, 1.56), with limited heterogeneity by sex (ratio of aHRs 1.06 [95% CI 0.72, 1.58]). Among women, risk was concentrated in the highest paternal (aHR 1.47 [95% CI 1.14, 1.90]) and maternal (aHR 1.50 [95% CI 1.12, 1.99]) preference categories. Modifiable risk factors mediated 5.8% (95% CI 1.9%, 9.7%) of the association among women, mainly through socioeconomic and psychosocial factors. CVD risk was highest with both son preference and high risk-factor burden overall (aHR 1.97 [95% CI 1.43, 2.73]) and among women (aHR 2.23 [95% CI 1.61, 3.10]). CONCLUSIONS: Parental son preference was associated with higher incident CVD risk, with the largest estimates in the highest paternal or maternal categories among women. Modifiable risk factors explained a modest proportion, supporting life-course cardiovascular prevention that considers sex-differentiated childhood environments alongside risk-factor modification.

cardiovascular disease↗

PubMed2026

The global potential of freshwater microbes for plastic degradation.

Plastic pollution is becoming increasingly severe on a global scale, and the potential for biodegradation as a treatment method that is environmentally friendly merits greater attention. A significant number of genes that associated the degradation of plastic (PDAGs) have been identified, however, the distribution of these genes among microorganisms in global inland waters remains to be elucidated. A global-scale meta-analysis was conducted, incorporating approximately 1000 metagenome datasets of inland waters across seven continents. A total of 13,109 metagenome-assembled genomes (MAGs) were obtained by means of metagenomics binning, and 22,621 PDAGs were identified from these. Among these recognized PDAGs, phenylacetaldehyde dehydrogenase (PAD) was the most dominant (n = 16,664), followed by catalase (n = 5931). The predominant hosts for PAD and catalase were identified as Gamma-proteobacteria and Bacteroidia, respectively. The largest number of both PAD and catalase was found in MAGs from North America, while the average gene number in single MAG was highest in MAGs from Oceania. In accordance with the prediction of traits, PDAG-carrying MAGs from Europe demonstrated the fastest growth rate and the lowest optimal growth rate. Furthermore, 25 styrene monooxygenase (StyA) enzymes were identified, which were found to cluster into two distinct groups hosted by Alpha-proteobacteria and Gamma-proteobacteria, respectively. Moreover, 11 MAGs were observed to possess the complete pathway of polystyrene degradation. These results explored the potential of inland water microorganisms as a biological resource for plastic degradation and provided valuable microbial reference information that can be used to develop biological treatment technologies for mitigating plastics.

Plastics↗

PubMed2026

Impact of estimated total blood volume on NT-proBNP response to angiotensin receptor-neprilysin inhibition in acute heart failure: Insights from the PREMIER study.

BACKGROUND: Sacubitril/valsartan (Sac/Val) reduces N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in acute heart failure (AHF), particularly in patients with reduced ejection fraction. However, whether estimated total blood volume (TBV), calculated using anthropometric equations, is associated with heterogeneity in biomarker response remains uncertain. METHODS: This post hoc exploratory sub-analysis of the PREMIER randomized trial evaluated whether baseline estimated TBV was associated with heterogeneity in NT-proBNP reduction after Sac/Val compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) therapy. Estimated TBV was calculated using validated anthropometric equations and dichotomized at the median (4.05 L). Patients were further stratified by left ventricular ejection fraction (LVEF <40% vs ≥40%). The primary endpoint was the proportional change in NT-proBNP from baseline to Week 8. RESULTS: Among 376 patients, 372 with baseline estimated TBV data were analyzed. In the high TBV group, Sac/Val was associated with greater NT-proBNP reduction than ACEI/ARB (-56% vs -32%; ratio of change, 0.67; 95% confidence interval, 0.53-0.84; P = .001), whereas no significant difference was observed in the low TBV group (P for heterogeneity = 0.063). In patients with LVEF <40%, Sac/Val was associated with greater NT-proBNP reduction in both TBV groups. In patients with LVEF ≥40%, Sac/Val was associated with greater NT-proBNP reduction in the high TBV group, whereas the point estimate in the low TBV group numerically favored ACEI/ARB. CONCLUSIONS: In this exploratory post hoc analysis, higher estimated TBV was associated with greater NT-proBNP reduction after Sac/Val, particularly among patients with LVEF ≥40%. These findings are hypothesis-generating and require external validation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05164653; Japan Registry of Clinical Trials, jRCTs021210046.

Humans↗

PubMed2026

Understanding and Usefulness of Effect Size and Certainty of Evidence: A Cross-Sectional Survey of Evidence-Based Practice Competencies Among US Registered Dietitians.

INTRODUCTION: Understanding of absolute and relative effect estimates, and determining effect size and certainty of evidence corresponding to effect estimates, represent fundamental evidence-based practice competencies that promote informed clinical decision-making. While research has been conducted in the medical profession, based on our literature review there is no published research on these competencies in the nutrition and dietetics profession. METHODS: Among registered dietitians, our main objectives were to assess (1) their understanding and perceived usefulness of three absolute and two relative effect estimate approaches to determine effect size, (2) their perceived usefulness of certainty of evidence, and (3) factors influencing their understanding and perceived usefulness. We conducted a web-based, cross-sectional survey by recruiting dietitians from the Academy of Nutrition and Dietetics (United States). Participants received effect estimates based on hypothetical dietary interventions vs. usual diet for reducing myocardial infarction risk. RESULTS: Of the 11,050 dietitians who received the survey link, 210 participated, and only completers (n = 114) were included in our analysis. Participants demonstrated a similar understanding of the relative (27.6%) and absolute (27.5%) effect estimates, with Risk Difference being the best understood approach and Number Needed to Treat being the least (30.7% vs. 24.6% correct responses). While perceived usefulness scores were similar between five approaches, they were highest when data was presented as Relative Risk [mean (SD): 4.82 (1.50)]. Dietitians rated the usefulness of certainty of evidence favorably [mean (SD): 5.07 (1.83), on a 7-point scale], and no factors were associated with correct understanding. CONCLUSION: Dietitians may have limited understanding of effect size thresholds presented in our survey, a finding mostly consistent with surveys of other health professionals. To optimize informed decision-making between dietitians and clients, dietetic programs and continuing education platforms should consider additional training on effect estimate approaches (relative and absolute), and determining effect sizes and certainty of evidence for effect estimates.

Clinical nutrition↗

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

Transvalvular Flow Rate is Associated With Mortality Rate and Lifetime Loss in Aortic Valve Stenosis: A Meta-Analysis of Reconstructed Time-to-Event Data.

Low-flow states are associated with adverse outcomes in aortic stenosis (AS), but the prognostic value of transvalvular flow rate (TFR) has not been consistently established across studies. This study is a systematic review and meta-analysis of reconstructed time-to-event data was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses. PubMed/MEDLINE, EMBASE, and Cochrane Library were searched for studies (published by November 14, 2025) comparing low versus normal TFR in AS. Data were collected from Kaplan-Meier curves. The primary endpoint was all-cause mortality. Survival was assessed using pooled Kaplan-Meier curves, Cox regression, flexible parametric survival models, and restricted mean survival time (RMST) analysis. A total of 9 studies including 6,494 patients were analyzed; 2,575 (39.7%) had low TFR. At 8 years of follow-up, estimated survival was 34.1% (95% confidence interval [CI] 24.7% to 47%) in the low-TFR group and 63% (95% CI 58.9% to 67.4%) in the normal-TFR group. Low TFR was associated with higher all-cause mortality (hazard ratio 1.59, 95% CI 1.45 to 1.74, p < 0.001). We observed a progressively greater hazard over time, with the hazard ratio approaching 1.9 by 8 years. At 8 years, RMST in the normal-TFR group was 7.37 years (95% CI 7.21 to 7.53 years) versus 5.07 years (95% CI 4.91 to 5.23 years) in the low-TFR group, representing a lifetime loss of 2.3 years in the low-TFR group (ΔRMST -2.30 years, 95% CI -2.53 to -2.07 years, p < 0.001). In patients with AS, low TFR is associated with significantly higher mortality and lifetime loss. These findings support TFR as a clinically meaningful marker for risk stratification in AS.

Aortic Valve Stenosis↗

PubMed2026

Clinical Performance of Bulk-Fill Versus Incremental Composite Placement Approaches in Vital Posterior Teeth: A 24 Months Randomized Controlled Trial.

BACKGROUND: Composite resin placement technique may influence marginal integrity, polymerization stress distribution, and long-term clinical performance of posterior restorations. This randomized controlled clinical trial evaluated the 24-month clinical performance of four different placement techniques in Class I posterior composite restorations. METHODS: Fifty patients aged 20-35 years presenting with four occlusal carious lesions each were enrolled, resulting in 200 restorations. Cavities (4-5 mm depth) were prepared according to caries extension. Restorations were randomly allocated into four equal groups (n = 50) according to placement technique: stamp technique, snowplow technique, modified incremental "pizza" technique, and bulk-fill technique. All materials were applied following manufacturers' instructions. Clinical evaluation was performed at baseline and after 6, 12, and 24 months using FDI criteria. Functional (fracture/retention, marginal adaptation), esthetic (marginal staining, anatomical form), and biological (postoperative sensitivity, secondary caries) properties were assessed by two calibrated evaluators. Statistical analysis was performed at a significance level of α = 0.05. RESULTS: Thirty-eight patients with a total of 152 restorations were evaluated at the end of the 24 months in line with FDI at the end of the study with 76% recall rates. No statistically significant differences were observed among groups regarding fracture/retention or secondary caries (p > 0.05). Marginal adaptation and marginal staining demonstrated minor deterioration over time across all groups, with statistically significant intergroup differences found (p < 0.05). Postoperative sensitivity was minimal and transient in all groups with no significant difference (p = 0.181). CONCLUSIONS: Within the limitations of this 24-month follow-up, the four placement techniques demonstrated comparable clinical performance in Class I posterior composite restorations. Selection of technique may therefore be guided by clinical preference and procedural efficiency rather than differences in short-term clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07415317.

Humans↗

PubMed2026

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

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

Humans↗

PubMed2026

Association of Early Knee Extension Range of Motion Deficits With Cartilage T2 Relaxation Following Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Anterior cruciate ligament (ACL) injury significantly increases the risk for developing knee osteoarthritis (OA), yet the early contributors to cartilage degeneration remain poorly understood. While range of motion (ROM) deficits after ACL reconstruction (ACLR) are associated with long-term development of radiographic OA, the association between early ROM recovery and cartilage composition has not been established. HYPOTHESIS: Knee extension ROM deficits at 2 months after ACLR would be associated with worsening tibiofemoral and patellofemoral cartilage T2 relaxation times at 6 months. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 30 participants (15-35 years) were enrolled within 1 month of ACL injury and before ACLR. At 2 months post-ACLR, active knee extension ROM was measured in the supine position using a goniometer. An extension deficit was considered >3° less extension in the injured knee compared to the uninjured side. Quantitative magnetic resonance imaging-based T2 relaxometry of the injured knee was performed preoperatively and at 6 months post-ACLR to measure percent change in mean T2 relaxation times in predefined tibial and femoral cartilage regions. Independent t tests were used to compare changes in T2 values between participants with and without an extension deficit. RESULTS: The mean age of the participants was 18.8 ± 3.9 years, and 63.3% were female. Fifteen (50.0%) participants exhibited an extension deficit at 2 months. Those with an extension deficit demonstrated a greater increase in T2 relaxation time in the anterior (mean difference, 10.21% [95% CI, 3.67%-16.76%]; P = .003) and weightbearing (mean difference, 6.14% [95% CI, 2.19%-10.09%]; P = .004) cartilage of the medial femoral condyle. No significant group differences were observed in other cartilage regions (all P > .05). CONCLUSION: Knee extension ROM deficits at 2 months post-ACLR are associated with early compositional changes in the medial femoral cartilage, indicating a potential relationship between limited extension and OA risk.

Humans↗

PubMed2026

Rationale, design, and experiences from the vanguard phase of the bariatric surgery for the reduction of cardiovascular events (BRAVE) trial.

BACKGROUND: Observational studies suggest that metabolic/bariatric surgery (MBS) reduces mortality and major adverse cardiovascular events in patients with obesity, but adequately powered randomized trials (RCTs) are lacking. The Bariatric Surgery for the Reduction of Cardiovascular Events (BRAVE) trial was designed to address this evidence gap. METHODS: BRAVE is an investigator-initiated, multi-center, open-label RCT with blinded endpoint adjudication comparing MBS vs guideline-based medical weight management (MWM) in adults with obesity and high-risk cardiovascular disease (CVD). Eligible participants have a body-mass index ≥35 kg/m² or ≥30 kg/m² with type 2 diabetes or age >55 years, and prior myocardial infarction (MI), coronary intervention, heart failure (HF), atrial fibrillation (AF) with elevated CHA₂DS₂-VASc score, cerebrovascular disease, or peripheral arterial disease. Participants are randomized 1:1 to MBS (sleeve gastrectomy, Roux-en-Y gastric bypass, or duodenal switch) or MWM, which includes dietary, behavioral, and pharmacologic therapies. The primary outcome is the composite of all-cause death, MI, stroke, HF events, coronary revascularization, AF hospitalization, and renal events. A vanguard phase of 200 participants was implemented to optimize recruitment and logistics. RESULTS: As of October 2025, 2,514 individuals have been screened from 17 centers in Canada, Brazil, Italy and Spain, with 444 entered MBS work-up, and 200 have been randomized. The randomized cohort (mean age 59.8 years; 37% female; mean BMI 44.0 kg m⁻²) has high burden of hypertension (82%), diabetes (45%), coronary artery disease (44%), HF (39%), and AF (48%). Recruitment barriers were identified and addressed through targeted education and enhanced patient engagement. CONCLUSIONS: BRAVE is the first large RCT evaluating whether MBS safely reduces major cardiovascular events compared with medical therapy in high-risk patients with obesity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05531474.

Humans↗

PubMed2026

Noncombustible Nicotine or Tobacco Product Use After Smoking Cessation and Major Vision-Impairing Diseases: A Nationwide Cohort Study.

OBJECTIVE: We assessed the risk of major vision-impairing eye diseases among smokers who quit combustible cigarettes (CC) and switch to noncombustible nicotine or tobacco products (NNTPs) compared with those who completely quit using tobacco. DESIGN: Retrospective cohort study. PARTICIPANTS: About 179 273 adults from the Korean National Health Insurance Service who smoked CC in 2011 to 2012 and reported cessation in 2018 to 2019, classified into complete quitters and NNTP switchers. METHODS: This nationwide longitudinal cohort study followed participants for up to 6 years and identified incident major vision-impairing eye diseases (cataract, glaucoma, age-related macular degeneration, diabetic retinopathy, and refractive and accommodation disorders) using standardized diagnostic codes. Propensity score matching was applied to emulate a pseudo-randomized comparison, balanced on key demographic, clinical, comorbidity, and lifestyle characteristics. Subdistribution hazard ratios (SHRs) were evaluated using the Fine-Gray subdistribution hazards model accounting for all-cause mortality as a competing risk. MAIN OUTCOME MEASURES: Adjusted SHRs for incident major vision-impairing eye diseases. RESULTS: Among 32 316 matched participants followed for a mean of 4.6 years, 6328 incident major vision-impairing eye disease events occurred. The incidence was 41.1 and 44.0 per 1000 person-years for complete quitters and NNTP switchers, respectively. Switching to NNTPs was associated with an increased risk of major vision-impairing eye disease (SHR, 1.07; 95% CI, 1.02-1.13). The risk elevation was most pronounced for diabetic retinopathy (SHR, 1.24; 95% CI, 1.00-1.53) and refractive and accommodation disorders (SHR, 1.07; 95% CI, 1.01-1.12). These findings were robust across inverse probability-weighted and Cox proportional hazards models. The association remained consistent in sensitivity analyses and across clinical subgroups. CONCLUSIONS: Transitioning from CC to NNTPs is associated with a modest but consistent increase in the risk of major vision-impairing eye diseases compared with complete nicotine abstinence. These findings challenge the assumption that substituting NNTPs for CCs is visually harmless and indicate that, from an ophthalmic perspective, complete cessation of all nicotine products should remain the preferred cessation goal.

Humans↗