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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

The Interrelationship between Cadmium, Smoking, and Migraine in the ELSA-Brasil Study.

This study explored the relationship between serum cadmium (Cd), smoking exposure, and migraine in the ELSA-Brasil cohort (2008-2010). The analysis included 2,750 participants whose serum Cd levels were measured using inductively coupled plasma mass spectrometry. Smoking exposure was assessed using self-report data of active smoking and second-hand smoke. Migraine, including definite and probable migraine, was diagnosed according to the International Classification of Headache Disorders, 3rd edition (ICHD-3). Logistic regression was used to estimate the odds of migraine across serum Cd quintiles, using the third quintile as the reference category, while linear regression examined the relationship between smoking exposure and Cd levels. Polynomial contrasts tested linear trends. Participants had a mean (SD) age of 53.2 (9.0) years and 53.1% were women. Migraine prevalence was 29.1% (including probable migraine). Individuals with migraine had slightly higher median serum Cd levels than controls [0.050 µg/L (IQR 0.035-0.077) vs. 0.048 µg/L (0.035-0.066); p = 0.021], although smoking exposure scores did not differ between groups. Smoking exposure showed a strong positive association with serum Cd concentrations (p-trend < 0.001). Participants in the highest Cd quintile had greater odds of migraine [aOR 1.51 (95% CI 1.09-2.08), p = 0.011] after adjustment for smoking exposure and sociodemographic and clinical confounders. Sex-stratified analysis yielded even stronger associations among males [aOR 1.84 (95% CI 1.07-3.16), p = 0.027]. However, in the sensitivity analysis including definite migraine cases only, this association was no longer significant [aOR: 1.14 (0.71, 1.83), p = 0.579]. Main findings suggest that Cd exposure from smoking may contribute to migraine occurrence, particularly in males. However, other sources of Cd that could influence migraine should not be disregarded, and future investigation in this field is warranted.

Cadmium↗

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

A Conserved 3'UTR Stem-loop Directs UPF1/eIF4AIII-Dependent Regulation of GABARAPL1 mRNA.

RNA-binding proteins (RBP) interact with mRNA untranslated regions containing cis-regulatory elements to govern mRNA localization, stability, and translational efficiency. Among these trans-regulatory factors, RNA helicase UPF1 is a central factor which play a role in multiple mRNA decay pathways, including nonsense-mediated mRNA decay (NMD). NMD is triggered when an exon-junction complex (EJC) is located downstream of a premature termination codon. However, in some cases, NMD can be activated in an EJC-independent manner through mechanisms involving the 3'UTR. In the present study, we focused on the GABARAPL1 3'UTR, as previous studies had shown that this region plays a key role in NMD targeting, although the underlying molecular mechanism had not yet been elucidated. Unlike canonical NMD targets such as SC35, we found that the chemical inhibition of eIF4AIII helicase activity did not affect GABARAPL1 transcript levels, indicating that this transcript is regulated through its 3'UTR via an EJC-independent mechanism. We therefore investigated the potential presence of cis-regulatory element within the 3'UTR of GABARAPL1 which can regulate mRNA and protein levels in a UPF1-dependent manner. Furthermore, we identified a conserved RNA region spanning nucleotides 364-421 involved in GABARAPL1 targeting and used biochemical analysis to demonstrate the direct binding of UPF1 and eIF4AIII to this RNA region, to analyse its secondary structure in solution, and to map the protein-binding sites. By complementing these approaches with molecular modelling, we showed that this stem-loop adopts a stable global fold but a local flexibility and dynamic behaviour properties. Together, our results support the role of UPF1 and eIF4AIII as specific regulators of GABARAPL1 transcript and reveal a novel RNA regulatory element within its 3'UTR, which provides a completely unexpected binding site for these factors.

3' Untranslated Regions↗

PubMed2026

Effects of Transcranial Direct Current Stimulation and Individualized Physical Therapy on Pain and Function in Individuals With Chronic Knee Pain: A Pilot Study.

BACKGROUND AND PURPOSE: Noninvasive brain stimulation is a promising neuromodulatory intervention for chronic pain. This study aimed to determine the impact that transcranial direct current stimulation (tDCS) in combination with individualized physical therapy (PT) has on pain and function in individuals with chronic knee pain. METHODS: This study was a preliminary pragmatic, triple-blinded, randomized, and sham-controlled clinical trial performed in an outpatient orthopedic physical therapy clinic. Participants participated in 5 sessions of active or sham tDCS followed by individualized PT intervention. Pain outcomes included the Numeric Pain Rating Scale, Movement-Evoked Pain, pressure pain thresholds (PPT), and the Central Sensitization Inventory. Functional outcomes included the 2-minute walk test, 5-time sit-to-stand test, quadriceps strength, knee range of motion, Patient Specific Functional Scale, and the Lower Extremity Functional Scale. RESULTS: Thirty participants with chronic knee pain completed the study. There were no significant differences observed for primary patient-centered pain and functional outcomes. For secondary outcomes, the active tDCS group had a significant effect (p < 0.05) on percent change in lateral joint line PPT and a significant multivariate effect of group on PPT change scores for 3-site and 5-site clusters (p < 0.05). Exploratory responder analyses demonstrated that the active tDCS group was 12.8 times more likely to achieve the minimum detectable change in quadriceps strength improvement compared with the sham tDCS group (p < 0.05). DISCUSSION: There were no significant between-group differences for primary pain and functional outcomes. However, the active tDCS group showed improvements in pain sensitivity, as measured by PPT, and quadriceps strength, which were superior to those seen in the sham tDCS group. These preliminary findings provide insight into possible mechanisms of tDCS in addressing pain as opposed to efficacy. Given that there were no clear between-group differences in patient-centered outcomes, there is insufficient evidence for routine tDCS use for chronic knee pain. TRIAL REGISTRATION: NCT06132412.

Humans↗

PubMed2026

Cardiometabolic Multimorbidity Increases the Risk of Hip Fracture: A Longitudinal Cohort Study Based on CHARLS.

BACKGROUND: Cardiometabolic Multimorbidity (CMM) is defined as the co-occurrence of two or more conditions among heart disease, diabetes mellitus, stroke, and hypertension. Previous studies have shown associations between cardiometabolic diseases and fragility fractures; however, the relationship between CMM and hip fractures remains unclear in the Chinese population. This study therefore aims to investigate this association in a Chinese cohort to inform fracture prevention strategies. METHODS: This prospective cohort study used data from the China Health and Retirement Longitudinal Study (CHARLS) collected from 2011 to 2020. Participants from the 2011 baseline survey cohort were initially included. Subsequently, individuals were sequentially excluded if they were under 45 years of age, had incomplete baseline CMM information, had a history of hip fracture, lost to follow-up, or had missing data on confounders. Kaplan-Meier survival analysis, Cox proportional hazards regression, subgroup analyses, and sensitivity analyses were performed to evaluate the association between CMM and the risk of hip fracture. RESULTS: A total of 6314 participants aged 45 years and older were included, of whom 544 had CMM. Over a 9-year follow-up period, 287 incident hip fractures (4.55%) were identified. Among these, 36 participants had been diagnosed with CMM at baseline, whereas 251 had not. The incidence of hip fracture was significantly higher in participants with CMM than in those without CMM (13% vs. 8%, p = 0.015). After full adjustment for confounders, multivariable Cox regression showed that CMM was associated with a 70% increased risk of hip fracture (HR = 1.70, 95% CI: 1.318-2.47; p = 0.005). Subgroup analyses indicated that age and history of falls were significant effect modifiers. The association between CMM and hip fracture was more pronounced in participants under 60 years old (P for interaction = 0.048) and those with a history of falls (P for interaction = 0.014). CONCLUSION: These findings suggest that CMM increases the risk of hip fracture, particularly among relatively younger individuals and those with a history of falls.

Humans↗

PubMed2026

The radiographic effect of cage subsidence on neuroforamina after anterior cervical discectomy and fusion.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: The objective of this study is to investigate the effect of cage subsidence on neuroforaminal area after anterior cervical discectomy and fusion (ACDF) utilizing computed tomography (CT). SUMMARY OF BACKGROUND DATA: Restoration of disc height via implantation of an interbody device provides an indirect decompression of the cervical neuroforamina. Interbody cage subsidence is a potential postoperative occurrence, but the effect of this on neuroforaminal area has yet to be characterized. METHODS: A retrospective review was conducted of patients who underwent one- to four-levels of ACDF utilizing an interbody device with anterior plating. Cage subsidence, neuroforaminal area, height and width were measured on CT scans preoperatively and at least 6 months postoperatively. Levels with a cumulative sum of cranial and caudal subsidence greater than 4 mm were classified as severely subsided, while levels with cumulative subsidence less than 4 mm were classified as non-severely subsided. RESULTS: A total of 83 patients (151 levels) were included in this retrospective analysis. Average endplate subsidence was 3.2 ± 1.9 mm. Non-severely subsided levels demonstrated a greater perioperative increase in neuroforaminal area (7.9 vs 2.1 mm2, p < 0.001), neuroforaminal height (1.1 vs 0.4 mm, p < 0.001) and neuroforaminal width (0.7 vs 0.1 mm, p < 0.001) compared to severely subsided levels. Interbody subsidence significantly predicted a decreased change in neuroforaminal height, width and area (p < 0.001). Severe subsidence was associated with an increased rate of pseudarthrosis, but similar reoperation rates and recurrent neurologic deficits between the two groups. CONCLUSIONS: Severe subsidence of interbody cages after an ACDF was associated with a decreased perioperative change in neuroforaminal dimensions. This decrease in the size of the neuroforamen may reduce the effect of indirect decompression of the nerve root.

Humans↗

PubMed2026

Safety of a quadrivalent meningococcal conjugate vaccine (MenACYW-TT) administered concomitantly with routine pediatric vaccines in healthy infants and toddlers in USA and Puerto Rico: Results from a Phase III, randomized, active-controlled study.

MenACYW-TT, a quadrivalent meningococcal tetanus toxoid-conjugate vaccine, is approved for prevention of invasive meningococcal disease in infants ≥ 6 weeks of age in the USA. This Phase III study (NCT03673462; September 17, 2018 - March 16, 2023) evaluated the safety of MenACYW-TT compared with a licensed quadrivalent meningococcal oligosaccharide diphtheria CRM197-conjugate vaccine (MenACWY-CRM) when administered concomitantly with routine pediatric vaccines in healthy infants and toddlers in a four-dose series (3+1 schedule). Participants were randomized 3:1 to receive MenACYW-TT (Group 1; n = 2080) or MenACWY-CRM (Group 2; n = 697) at 2, 4, 6, and 12 months of age, with concomitant administration of routine pediatric vaccines (DTaP5-IPV/Hib, PCV13, rotavirus, hepatitis B, MMR, and varicella vaccines). Safety assessments included immediate unsolicited adverse events within 30 minutes post-vaccination, solicited injection site and systemic reactions within 7d, unsolicited AEs within 30d, serious adverse events (SAEs) including adverse events of special interest (AESIs), and medically attended adverse events (MAAEs) throughout the study. MenACYW-TT and MenACWY-CRM were overall well tolerated, and safety profiles were comparable. Solicited injection site reactions occurred in 84.9% and 84.6% of participants in Groups 1 and 2, respectively; solicited systemic reactions in 87.1% and 88.2%, respectively. During the entire study, 5.2% in Group 1 and 3.0% in Group 2 experienced at least one SAE; 0.9% and 0.1%, respectively, reported at least one AESI. Three deaths occurred in Group 1. All SAEs, AESIs, and deaths were unrelated to study vaccines. This study supports the safety profile of MenACYW-TT in infants and toddlers aged ≥ 6 weeks.Study registration: Clinicaltrials.gov: NCT03673462; EudraCT: 2019-004459-35.

Child, Preschool↗

PubMed2026

Beyond predictive performance: A systematic review and critical methodological appraisal of AI/ML and conventional modelling strategies in breast, colorectal, and pancreatic Cancer.

BACKGROUND: Predictive modelling for cancer risk, treatment-related complications, and survival is central to precision oncology. Conventional logistic regression (LR) and Cox proportional hazards (CoxPH) regression remain widely used but are limited when modelling nonlinear interactions, high-dimensional imaging features, and multimodal clinical-metabolic predictors. Artificial intelligence (AI) and machine learning (ML) methods offer expanded capability through automated feature extraction, ensemble learning, and flexible survival modelling, but the evidence on when AI/ML adds value over conventional models across cancer sites and predictive tasks remains fragmented. OBJECTIVE: To systematically evaluate the methodological performance, validation strategies, and translational limitations of AI/ML models compared with conventional statistical models in published predictive-modelling studies for breast, colorectal, or pancreatic cancer. METHODS: PubMed, Scopus, and Web of Science were searched for studies published between January 2019 and March 2025. Two reviewers independently conducted title-and-abstract screening, full-text eligibility assessment, and PROBAST risk-of-bias assessment. Sixty-five studies (n = 907,567 participants) were narratively synthesised by cancer site, predictive task, model family, comparator, validation strategy, predictor modality, and calibration or explainability reporting. RESULTS: The 65 studies comprised breast cancer (n = 35), colorectal cancer (n = 21), and pancreatic cancer (n = 9). AI/ML superiority over LR and CoxPH was task- and data-dependent. CNN- and U-Net-based models predominated in imaging and body-composition tasks, tree-based ensembles consistently outperformed LR for tabular perioperative complication prediction, and CoxPH remained competitive, and in the largest pancreatic risk study, superior to XGBoost (C-index 0.802 vs 0.723) in well-structured datasets. PROBAST analysis-domain risk was moderate in 54 of 65 studies (83%), driven by limited external validation, sparse calibration reporting (11/65), and few decision-curve analyses (7/65). CONCLUSION: AI/ML adds the most methodological value in imaging-derived feature extraction and nonlinear perioperative prediction, while conventional regression remains preferable in large, structured datasets with linear predictors. Clinical translation requires standardised body-composition definitions, external validation, calibration assessment, decision-curve analysis, and explainability, in line with TRIPOD+AI and CLAIM standards.

Humans↗

PubMed2026

Glaucoma filtering surgery combined with phacoemulsification in the era of new aqueous humor filtration devices: A systematic review.

We evaluate the efficacy and safety of filtering glaucoma surgeries combined with phacoemulsification (PCE)-including new aqueous humor drainage devices-compared to standalone procedures. We performed a systematic search up to March 23, 2025, including all comparative studies assessing trabeculectomy (TRAB), non-penetrating deep sclerectomy (NPDS), Xen® Gel Stent (XEN), or Preserflo® MicroShunt (PMS) combined with PCE, versus the same surgery alone. Key exclusion criteria include inadequate follow-up (less than 12-month), absence of a defined success criterion, more than 50% of loss to follow-up at 12-month, and lens extraction performed without PCE. Main outcome was surgical success at ≥ 12 months. Secondary outcomes included intraocular pressure (IOP) reduction, decrease in hypotensive medications, and rates of complications. A total of 27 studies were included for analysis. Among studies comparing TRAB/PCE with standalone TRAB, half reported similar success rates, while others favored standalone TRAB, particularly using strict IOP thresholds. Safety profiles were comparable. For NPDS/PCE, data mostly showed equivalent outcomes versus standalone NPDS, with comparable safety. In studies on XEN/PCE and PMS/PCE, results suggested similar rates of surgical success, efficacy in IOP and medication reduction, and safety compared to their stand-alone procedures. Small differences occasionally favored standalone procedures under stricter success definitions. Current evidence suggests that combined filtering glaucoma surgery provides long-term efficacy and safety comparable to standalone, though some subgroups and outcome thresholds may slightly favor standalone approaches. The limited availability of high-quality prospective trials underscores the need for further large-scale robust studies.

Humans↗

PubMed2026

Efficacy, Safety, and Pharmacokinetics of Upadacitinib Among Patients in East Asia With Moderately to Severely Active Ulcerative Colitis: A Post Hoc Subanalysis of Randomized Phase 3 Studies.

BACKGROUND AND AIM: Upadacitinib, a selective Janus kinase 1 inhibitor, is approved to treat moderately to severely active ulcerative colitis (UC). This post hoc subanalysis evaluated the efficacy, safety, and pharmacokinetics of upadacitinib in patients in East Asia. METHODS: U-ACHIEVE (UC1; NCT02819635) and U-ACCOMPLISH (UC2; NCT03653026) were Phase 3, multicenter, randomized, double-blind, induction studies evaluating upadacitinib 45 mg or placebo daily in adults with moderately to severely active UC. Clinical responders to 8 weeks of upadacitinib induction were eligible to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo daily in the 52-week U-ACHIEVE maintenance study (UC3; NCT02819635). Efficacy outcomes, safety, and pharmacokinetics were evaluated among East Asian patients. RESULTS: A higher proportion of East Asian patients achieved clinical remission with upadacitinib than placebo at induction Week 8 (UC1: n = 127, 31.4% vs. 7.3%; UC2: n = 114, 31.2% vs. 2.7%) and maintenance Week 52 (UC3: n = 184, upadacitinib 15 mg, 52.4%; upadacitinib 30 mg, 53.8%; placebo, 10.7%). Rates of endoscopic outcomes were higher with upadacitinib than with placebo across studies. No new safety signals were identified. Herpes zoster occurrences were low (UC1 and UC2: upadacitinib 45 mg, two events [in one patient]; placebo, zero events; UC3: upadacitinib 15 mg, five events; upadacitinib 30 mg, eight events; placebo, zero events). Pharmacokinetics and trends in the relationship between upadacitinib exposure and efficacy were consistent in the East Asian and global populations. CONCLUSION: Upadacitinib was generally well tolerated and effective for treating moderately to severely active UC in patients in East Asia, with a favorable benefit-risk profile consistent with the global population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02819635, NCT03653026.

Humans↗

PubMed2026

Psychological impacts of APOE genotype disclosure among Latinos in New York City: a randomized controlled trial.

INTRODUCTION: Latinos face increased Alzheimer's disease (AD) risk but are underrepresented in studies of APOE genotype disclosure. We evaluated the psychological impacts of APOE disclosure in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a randomized controlled trial among Latinos in New York City. METHODS: Latino northern Manhattan residents without self-reported AD (mean age 52, 69% women, 49% college graduates) were randomized in the period August 2021 to July 2024 to receive AD risk estimates to age 85 incorporating APOE genotype, family history, and ethnicity (disclosure) or the same factors excluding APOE (non-disclosure). Bilingual genetic counselors delivered risk estimates to both groups, unmasked to randomization. Follow-up surveys were completed 6 weeks, 9 months, and 15 months after risk delivery. Primary outcomes were impact of genetic testing in AD (IGT-AD) and Impact of Event Scale-Revised (IES-R). Secondary outcomes were changes from baseline in depression, anxiety, and perceived AD threat. Analyses used intention-to-treat with multiple imputation. RESULTS: Disclosure (N = 194) and non-disclosure (N = 180) groups did not differ on IGT-AD (mean disclosure-non-disclosure difference [MD] at 6 weeks: -1.5, p = 0.14; 9 months: -1.2, p = 0.35; 15 months: -2.0, p = 0.07), IES-R (MD at 6 weeks: 0.00, p = 0.98; 9 months: 0.01, p = 0.84; 15 months: 0.03, p = 0.64), or change in secondary outcomes. Occurrence of disclosure-related adverse events was similar in the disclosure (N = 2) and non-disclosure (N = 3) groups. DISCUSSION: In this Latino cohort, APOE disclosure did not have clinically significant adverse psychological effects, addressing an important evidence gap. TRIAL REGISTRATION: ClinicalTrials.gov NCT04471779.

Aged↗

PubMed2026

Mitomycin C in the Endoscopic Treatment of Airway Stenosis: A Systematic Review and a Meta-Analysis.

OBJECTIVE: To assess the efficacy of adjuvant MMC in the endoscopic treatment of airway stenoses. DATA SOURCES: PubMed/MEDLINE, Cochrane Library, Scopus, Embase, and Google Scholar databases. REVIEW METHODS: A literature search was conducted following PRISMA guidelines. The PICOS tool was used to determine the eligibility criteria for this study. A single arm meta-analysis was performed for stenosis resolution, the rate of patients requiring multiple endoscopic procedures, and the rate of patients requiring other surgical treatments. RESULTS: A total number of 358 patients (median age: 48.0 years; 95% CI 44.8-50.8) were included. The median follow-up was 25.2 months (n = 244/358; 95% CI 15.4-38.3). Overall, the cumulative stenosis resolution rate was 76.37% (n = 187/254; 95% CI 59.72-89.64), the rate of patients requiring multiple endoscopic procedures was 52.33% (n = 131/260; 95% CI 32.03-72.25), and the rate of patients requiring other surgical treatments was 4.08% (n = 26/310; 95% CI 0.37-11.48). The median intervention-free interval was 366 days (n = 155/358; 95% CI 270-696). CONCLUSIONS: Current evidence does not allow definitive conclusions regarding the efficacy of adjuvant MMC in reducing recurrence or prolonging intervention-free intervals in airway stenosis. Further well-designed prospective studies are needed to clarify the role of MMC and to inform evidence-based guidelines for patient selection and treatment use. LEVEL OF EVIDENCE: NA.

Humans↗

PubMed2026

Adjuvant CDK4/6 inhibitors in early-stage breast cancer: Clinical evidence and considerations for risk stratification and treatment selection.

Hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high-risk, early-stage disease. Cyclin-dependent kinase 4 and 6 inhibitors, initially established as a standard component of first-line therapy in the metastatic setting based on improvements in progression-free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease-free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high-risk, early-stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment-related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin-dependent kinase 4 and 6 inhibition is modest, especially among the favorable-risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision-making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.

Humans↗

PubMed2026

Sodium-glucose cotransporter-2 inhibitors and gastrointestinal neoplasm risk in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

The potential carcinogenic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) remain controversial, particularly regarding site-specific gastrointestinal (GI) neoplasms. This systematic review and meta-analysis aimed to determine the relationship between SGLT2 inhibitors and the risk of GI neoplasms in patients with T2DM. We searched PubMed, EMBASE, Cochrane CENTRAL, Scopus, and Web of Science through March 17, 2025, for RCTs in T2DM comparing SGLT2 inhibitors with placebo or active comparators. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. The primary outcome was GI neoplasms reported in publications, supplementary materials, or trial registries, usually as adverse events rather than centrally adjudicated cancer endpoints. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in Stata 17.0. In 48 RCTs (n = 48,765), SGLT2 inhibitor therapy was not associated with overall GI neoplasm risk (OR = 1.10, 95% CI: 0.84-1.44; p = 0.46; I² = 0%). Site-specific analyses showed no statistically significant association for esophageal (OR = 1.12, 95% CI 0.37-3.45), gastric (1.20, 0.65-2.23), hepatic (0.62, 0.31-1.22), pancreatic (0.91, 0.51-1.64), colonic (1.28, 0.78-2.08), colorectal (0.76, 0.27-2.17), and rectal neoplasms (0.98, 0.49-1.97), with all p-values > 0.05. Subgroup analyses by agents (e.g., canagliflozin, dapagliflozin, empagliflozin), baseline age, body mass index (BMI), HbA1c, treatment duration, and dose were also non-significant (all p > 0.05). Approximately half of the trials had follow-up of one year or less, limiting our ability to evaluate long-term risk. Available RCT evidence does not show a clear increase in GI neoplasm risk with SGLT2 inhibitors in T2DM. However, limited follow-up, low event counts, and non-cancer-specific outcome ascertainment, the findings should be interpreted as reassuring but not definitive evidence of long-term oncologic safety.Systematic review registration: PROSPERO No. CRD42024619019.

Humans↗

PubMed2026

Evidence-based insights into medial pedicle reduction mammaplasty: A systematic review and meta-analysis.

BACKGROUND: Breast reduction relieves the physical and psychosocial burden of macromastia. Medial pedicle reduction mammaplasty may enhance vascular reliability, preserve nipple-areola complex (NAC) sensation, and sustain upper pole fullness, even in large-volume reductions. The purpose of this study was to assess the outcomes of medial pedicle breast reduction. METHODS: A search across ScienceDirect, Cochrane, and PubMed was conducted. Included studies reported on perioperative outcomes and complications of medial pedicle breast reduction. Data on demographics, surgical variables, complications, sensory recovery, volumetric changes, and patient satisfaction were extracted. Proportion meta-analysis was performed, and odds ratios were calculated for comparison with inferior pedicle breast reduction. RESULTS: Twenty-five studies comprising 1033 patients met the inclusion criteria. Mean BMI ranged from 27 to 42 kg/m2, with mean resection weights between 412 and 3828 g. Mean surgical times ranged from 104 to 204 min. Pooled complication rates were low: infection 1%, seroma 1%, hematoma 1%, fat necrosis 2%, NAC necrosis 1%, dehiscence 8%, and reintervention 5%. Odds of complications did not differ significantly from inferior pedicle reductions. NAC sensation typically recovered by 6-12 months, with no long-term deficits. Volumetric analyses demonstrated stable breast shape after the first postoperative year, with superior upper pole tissue maintained. Patient satisfaction ranged 75-100%, with higher ratings for scar appearance and overall aesthetics in medial pedicle reductions. CONCLUSION: Medial pedicle breast reduction is a well-established and reproducible technique, preserving NAC sensation, achieving stable long-term shape, and enhancing upper pole fullness. It offers satisfactory aesthetic outcomes compared to other traditional methods, even in large-volume reductions.

Humans↗

PubMed2026

Quantitative N-glycoproteomic analysis reveals glycosylation signatures of plasma immunoglobulin G in sepsis.

INTRODUCTION: Sepsis is a life-threatening condition resulting from organ dysfunction due to a dysregulated immune response to infection. Immunoglobulin G (IgG) plays a role in modulating immune responses. However, the precise IgG subclass-specific N-glycosylation profiles in patients with sepsis remain poorly characterized. METHODS: This study aimed to define the site-specific N-glycosylation signatures of plasma IgG subclasses in sepsis patients with different prognoses using quantitative glycoproteomics. By employing our established GlycoQuant strategy, we quantified the intact N-glycopeptides (IGPs) of IgG subclasses in 40 healthy controls and 40 sepsis patients with a clear prognosis. RESULTS: We identified 12 IGPs with altered abundances between patients with sepsis and healthy controls. After Benjamini-Hochberg (BH) correction of the 31 outcome-stratified IGP comparisons, IGP24 and IGP25 remained significant and met the prespecified fold-change criterion. Global BH correction across 124 IGP-clinical parameter correlations retained positive associations of IGP19, IGP22, and IGP23 with procalcitonin (PCT). In exploratory outcome-stratified ROC analyses, candidates were selected using the original unadjusted P-value and fold-change screen; five IGPs were evaluated, with IGP25 and IGP24 yielding the highest individual AUCs. Collectively, our findings underscore the potential of IgG subclass-specific glycosylation profiling as a novel translational approach for clinical applications in sepsis management. SIGNIFICANCE: Sepsis remains a leading cause of global mortality, with patient outcomes heavily dependent on timely diagnosis and accurate prognosis. The dysregulated host immune response, particularly involving immunoglobulins, is central to its pathophysiology. This study provides a significant advance in the field of clinical glycoproteomics by applying a quantitative, site-specific strategy to delineate the plasma IgG subclass N-glycosylation landscape in sepsis. We report, for the first time, a panel of subclass-specific intact IgG N-glycopeptides (IGPs) that are significantly altered in sepsis patients compared to healthy controls. The identified IGPs not only demonstrate diagnostic and prognostic potential but also show a significant correlation with procalcitonin, a key clinical severity index. These findings bridge a critical knowledge gap by moving beyond bulk IgG glycosylation analysis to subclass-resolved profiling, offering novel molecular insights into sepsis immunopathology. The identified glycosylation signatures hold substantial translational promise as a foundation for developing innovative, glycan-based biomarker panels to improve the precision management of this heterogeneous and life-threatening syndrome.

Humans↗

PubMed2026

Efficacy and Safety of Ultra-Low Starting Dose Febuxostat Titration in Male Patients With Primary Gout.

BACKGROUND: Since gout is a common metabolic arthritis caused by urate crystal deposition, urate-lowering therapy (ULT) is clearly indicated, but the initiation of ULT frequently causes paradoxical acute flares that in turn impair patient adherence. OBJECTIVE: This study sought to assess the effectiveness and safety of an ultra-low-dose initiation strategy for febuxostat (10 mg/day) compared to the standard starting dose (20 mg/day) in reducing initiation-related flares while maintaining long-term urate control. METHODS: 120 male patients with primary gout presenting with acute arthritis were randomly assigned to initiate febuxostat at 10 mg/day (Group A) or 20 mg/day (Group B), with protocol-mandated biweekly titration. The primary outcomes were gout flare frequency over 24 weeks (assessed using Poisson regression), serum uric acid (SUA) target attainment, and the incidence of adverse events. RESULTS: Although both groups achieved comparable target SUA levels by week 24, Group A demonstrated a significantly lower overall flare incidence (36.7% vs. 70.0%; p < 0.001), along with a greater percentage of flare-free patients (70.0% vs. 46.7%; p = 0.016). Multivariable Poisson regression revealed that Group B had an approximately twofold higher risk of flares compared to Group A (Incidence Rate Ratio = 1.95; p = 0.012), with obese patients deriving the most pronounced benefit from the ultra-low-dose approach. To avert one additional flare, the calculated number needed to treat was 4.3. Additionally, the occurrence of clinically significant liver injury (ALT/AST > 3× ULN) was low in both groups, with 3.3% in Group A and 1.7% in Group B. Multivariable regression analysis confirmed that LDL-C is an independent predictor of ALT (β = 12.90, p = 0.009), while febuxostat dosage was not linked to hepatotoxicity. CONCLUSION: Initiating febuxostat at a dose of 10 mg/day with gradual titration demonstrates a superior safety profile by effectively reducing early acute flares without compromising long-term urate control, which is particularly advantageous for high-risk cohorts, including obese patients.

Humans↗