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PubMed2026

Safety and outcomes of dapagliflozin initiation in critically ill patients with acute kidney injury: A post-hoc analysis of the defender trial.

BACKGROUND: SGLT2 inhibitor use in acute kidney injury (AKI) is controversial due to concerns about hemodynamic instability. We evaluated dapagliflozin initiation in critically ill patients with AKI enrolled in the DEFENDER trial. METHODS: Among 212 patients with AKI at enrollment (100 dapagliflozin, 112 control), we compared 28-day mortality, kidney replacement therapy (KRT), and composite death/KRT. Adjusted risk differences were estimated controlling for age, sepsis, baseline vasopressor use, and creatinine. Physiological trajectories (creatinine, urine output, fluid balance, acid-base parameters) over days 1-5 were analyzed using mixed models. Likelihood ratios quantified compatibility with clinically meaningful harm or benefit. RESULTS: Event rates were similar: 28-day mortality 38% vs 40%, KRT 12% vs 18%, composite 41% vs 42% (dapagliflozin vs control). Adjusted risk differences were - 1.9% (95% CI -14.5 to 10.7) for death, -7.4% (-16.2 to 1.5) for KRT, and - 0.9% (-13.6 to 11.8) for the composite. Physiological trajectories showed no divergence suggestive of hemodynamic or metabolic instability. Likelihood ratios provided limited separation: at 5% absolute effect threshold, LR against harm was 1.47 and against benefit 1.19. CONCLUSIONS: Dapagliflozin initiation in critically ill patients with AKI was not associated with excess mortality, KRT, or physiological derangement. The near-neutral evidential profile indicates neither moderate harm nor benefit can be excluded, supporting feasibility of dedicated trials of SGLT2 inhibitors in AKI.

Humans↗

PubMed2026

ALID score for treatment-effect heterogeneity of adjunctive low-voltage area ablation in persistent atrial fibrillation: A post hoc analysis of SUPPRESS-AF.

BACKGROUND: In persistent atrial fibrillation (AF), the incremental benefit of adjunctive low-voltage area (LVA) ablation beyond pulmonary vein isolation (PVI) remains inconsistent. OBJECTIVE: To examine whether a simple clinical score characterizes treatment-effect heterogeneity of adjunctive LVA ablation among patients with mapped LVA > 5 cm2 and to perform an exploratory supportive analysis in an independent randomized cohort. METHODS: In this post-hoc analysis of SUPPRESS-AF, which included patients with persistent AF and mapped LVA > 5 cm2 after PVI, four variables-age ≥ 75 years, left atrial diameter > 44 mm, estimated glomerular filtration rate < 60 mL/min/1.73 m2, and absence of diabetes-were combined into the ALID score (0-4). Patients were stratified into low (0-1), intermediate (2), and high (3-4) score groups. Because EARNEST-PVI did not use LVA-guided ablation or select patients based on mapped LVA, it was analyzed as an exploratory supportive cohort rather than as an external validation cohort. RESULTS: In SUPPRESS-AF (n = 336), a significant treatment-by-score interaction was observed (P < 0.001). Adjunctive LVA ablation was associated with increased recurrence in the low-score stratum (HR 3.92; 95% CI 1.50-10.20) and reduced recurrence in the high-score stratum (HR 0.48; 95% CI 0.26-0.86). In EARNEST-PVI (n = 494), a qualitatively similar interaction pattern was observed for additional ablation beyond PVI (interaction P = 0.029), although the ablation strategy differed from LVA-guided ablation. CONCLUSIONS: Among patients with persistent AF and mapped LVA >5 cm2, the ALID score identified heterogeneity in response to adjunctive LVA ablation. These hypothesis-generating findings require prospective validation before clinical implementation.

Humans↗

PubMed2026

Efficacy and Hypoglycaemia Outcomes With Once-Weekly IcoSema Versus Comparators in Individuals With Type 2 Diabetes by Kidney and Liver Function: A Post Hoc Analysis of the COMBINE 1-3 Trials.

AIMS: This post hoc analysis of COMBINE 1-3 assessed efficacy and hypoglycaemia outcomes with IcoSema (once-weekly combination therapy of basal insulin icodec and semaglutide [a glucagon-like peptide-1 analogue]) versus comparators in adults with type 2 diabetes (T2D) by kidney and liver function subgroups. MATERIALS AND METHODS: Treatment outcomes were analysed by trial according to kidney (estimated glomerular filtration rate ≥ 90; 60-< 90; 30-< 60; < 30 mL/min/1.73 m2) and liver (total bilirubin ≤ 21 μmol/L or aspartate aminotransferase [AST] ≤ 31/≤ 37 [female/male] U/L; total bilirubin > 21 μmol/L or AST > 31/> 37 [female/male] U/L) function subgroups. RESULTS: In COMBINE 1-3, across kidney and liver function subgroups, there were no statistically significant treatment by subgroup interactions for change in glycated haemoglobin (HbA1c) (baseline to week 52), change in body weight (baseline to week 52) or rates of combined clinically significant or severe hypoglycaemia (not assessed by kidney function for COMBINE 2) (all p > 0.05). There were statistically significant treatment by kidney function subgroup interactions for the achievement of HbA1c < 7.0% without weight gain and without clinically significant or severe hypoglycaemia in COMBINE 3 (p < 0.05) but not COMBINE 1 or 2, and statistically significant treatment by liver function subgroup interactions in COMBINE 1 (p < 0.05) but not COMBINE 2 or 3. For COMBINE 1 and 3, there were statistically significant treatment by kidney function subgroup interactions for mean weekly total insulin dose, but not statistically significant treatment by liver function subgroup interactions. CONCLUSIONS: Efficacy and hypoglycaemia outcomes with IcoSema versus comparators were generally consistent among adults with T2D with mild to moderate kidney impairment or impaired liver function. TRIAL REGISTRATION: The COMBINE 1-3 trials were sponsored by Novo Nordisk and are registered with ClinicalTrials.gov (NCT05352815; NCT05259033; NCT05013229).

Humans↗

PubMed2026

Weight and metabolic changes in patients with schizophrenia treated with paliperidone palmitate 6-month formulation versus paliperidone palmitate 3-month formulation: a post-hoc analysis.

OBJECTIVE: To determine the effect that paliperidone palmitate 6-month long-acting injectable formulation (PP6M) had on metabolic parameters including body weight (BW), and blood lipid profiles, a post-hoc analysis was conducted to assess changes in BW from baseline to the end of study based on age, body mass index (BMI), and changes in blood lipid profiles during a 12-month, phase 3, double-blind (DB) clinical study. Long term effects of PP6M on BW and BMI were further explored during a 24-month extension study in which participants were treated exclusively with PP6M. METHOD: In the 12-month DB phase, participants were randomized to receive PP6M or paliperidone palmitate 3-month long-acting injectable formulation (PP3M). The mean change in BW and abnormal weight percent change from baseline were calculated at endpoint by age, gender, and BMI. Additionally, treatment-emergent shifts from baseline for the four key lipid parameters (fasting low density lipoprotein [LDL], fasting triglycerides [TG], fasting total cholesterol [TC], and fasting high density lipoprotein [HDL]) during DB were assessed. Following this study, participants were given the opportunity to transition to a 24-month extension study and be treated with PP6M. The mean change and percent change in BW, and the mean change in BMI from DB baseline to the end of the extension study (36 months total) were calculated. RESULTS: Participants who were treated with PP6M showed numerically less weight gain, BMI, waist circumference, and more weight decrease compared to PP3M group during 12-month DB phase, though the proportion of participants reporting an abnormal change (≥7% change) in BW did not significantly differ between PP3M and PP6M. The weight differences were more pronounced in the younger age group (18-25 years) and those who were overweight (BMI: 25 to <30 kg/m2. Numerical differences in favor of PP6M were found in fasting blood lipids (HDL, LDL, TG, and TC). The changes in BW and BMI over time remained consistent throughout the 24-month extension, favoring PP6M in each instance. CONCLUSIONS: This post-hoc analysis demonstrated that PP6M was comparable to PP3M in terms of metabolic parameters; however, it may have a beneficial effect on weight gain, especially in young patients. TRIAL REGISTRATION: Post-Hoc Analysis of Studies NCT03345342 and NCT04072575 (ClinicalTrials.gov). Significant outcomes The findings from this study have highlighted that participants who were treated with the 6-month long-acting injectable formulation of paliperidone exhibited less weight gain during treatment overall, and significantly less weight gain in adolescents and young adults. Importantly, this trend continued over the course of long-term treatment, regardless of age. Participants treated with the 6-month formulation also had fewer shifts in blood lipids outside of the normal range and had more favorable changes in body mass index and waist circumference. These results suggest that when considering metabolic dysregulation as a factor in choosing a long-acting injectable antipsychotic, the 6-month formulation is a viable alternative to the 3-month formulation, particularly in younger patients with schizophrenia. Limitations Because this is a post hoc analysis and the study was not powered to test weight and metabolic changes, most endpoints were summarized descriptively and the statistical test was limited to the main endpoint (abnormal percent weight gain and loss).

Adult↗

PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗

PubMed2026

Sex Differences in Postoperative Recovery and Mortality After High-Risk Cardiac Surgery: A Propensity Score-Matched Post Hoc Analysis of the SUSTAIN-CSX Trial.

BACKGROUND: Sex-related differences after cardiac surgery remain controversial because women often present with higher baseline risk and complexity than men. We performed a post hoc propensity score-matched analysis of the SUSTAIN-CSX (Sodium Selenite Administration in Cardiac Surgery) trial to evaluate sex differences in mortality, postoperative complications, and recovery after high-risk cardiac surgery. METHODS: Of 1394 trial participants, 1386 had complete data. Women were matched 1:1 to men using nearest-neighbor propensity score matching based on age and European System for Cardiac Operative Risk Evaluation II (EuroSCORE II), with exact matching on surgical category, yielding 327 female-male pairs. Prespecified sensitivity analyses adjusted for frailty, baseline hemoglobin, renal disease, left ventricular ejection fraction, previous myocardial infarction, preoperative medications, and baseline creatinine. RESULTS: In the primary matched analysis, 180-day survival did not differ between women and men (log-rank P=0.086; unadjusted hazard ratio, 1.80 [95% CI, 0.91-3.55]; P=0.091). In descriptive matched comparisons, women had numerically longer intensive care unit stay (median, 3 days [quartile 1, quartile 3 (Q1, Q3)=1, 6 days] versus 2 days [Q1, Q3=1, 5 days]) and hospital stay (median, 10 days [Q1, Q3=7, 18 days] versus 9 days [Q1, Q3=6, 16 days]; P=0.292), whereas major postoperative complications were similar. In adjusted sensitivity analyses accounting for the matched design and residual imbalance, female sex remained associated with longer intensive care unit stay (adjusted incidence rate ratio [IRR], 1.8 [95% CI, 1.2-2.9]; P=0.009) and hospital stay (adjusted IRR, 1.4 [95% CI, 1.0-1.9]; P=0.031). Mortality sensitivity analyses were model-dependent. CONCLUSIONS: In this propensity score-matched cohort of high-risk cardiac surgery patients, women showed a longer postoperative recovery trajectory in adjusted analyses, whereas mortality findings were sensitive to model specification and should be interpreted cautiously. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002247.

Aged↗

PubMed2026

Making waves: toward systems-level interpretation of hormonal and endogenous biomarkers in wastewater-based epidemiology.

Wastewater-based epidemiology (WBE) has proven invaluable for population health monitoring, most notably during the COVID-19 pandemic. Yet current WBE largely relies on exogenous markers such as drugs, pathogens, and their metabolites, limiting surveillance to what communities are exposed to. We argue for expanding WBE towards endogenous biomarkers, particularly hormones, which provide insights into physiological stress, metabolic function, and endocrine activity. Hormone-based WBE offers new opportunities to capture population-level biological responses to societal and environmental stressors, disasters, and chronic disease burdens at the community scale. This perspective outlines a systems-level framework for integrating hormonal signals in wastewater with clinical data, behavioral indicators, environmental factors, and digital markers to support more robust and context-aware public health surveillance. We highlight key technical considerations, interpretive challenges, and opportunities for translational pilot studies. By moving beyond exposure tracking toward more integrated interpretation of biological responses, hormone-informed WBE may contribute to more resilient, inclusive, and actionable public health infrastructure.

Humans↗

PubMed2026

Effects of Digital Mental Health Screening Alone and With the Online MINDBODYSTRONG CBT-Based Program on Burnout, Depression, Anxiety, Healthy Behaviors, and Suicidal Ideation in at-Risk Nurses at 3- and 6-Months Post-Intervention: An RCT.

BACKGROUND: Burnout and mental distress among nurses are global public health epidemics that adversely affect nurse well-being and healthcare quality. Evidence-based, scalable mental health interventions are urgently needed. AIMS: To evaluate the 3- and 6-month outcomes of a randomized controlled trial (RCT) comparing a psychologically safe, digital mental health screening and referral program alone versus the same screening and referral program combined with the video-based online MINDBODYSTRONG (MBS) cognitive behavioral therapy (CBT)-based skills-building program among nurses at risk for mental distress. METHODS: 501 nurses were recruited from professional organizations and healthcare systems across the United States by email and randomized to either mental health screening and referral (standard care) or standard care plus the MBS cognitive behavioral skills-building intervention (the intervention). All study activities were conducted remotely. Follow-up surveys administered at 3- and 6-months assessed anxiety, depression, suicidal ideation, burnout, healthy lifestyle beliefs, and healthy lifestyle behaviors using valid and reliable scales. RESULTS: Compared with the screening and referral only group, participants in the intervention group had greater reductions in anxiety and depression and significantly greater increases in healthy lifestyle beliefs and behaviors at 3 and 6 months post-intervention. After controlling baseline risk, the intervention group had a lower risk of suicidal ideation than the screening and referral group at 3 months (relative risk ratio [RRR] = 0.717; 95% CI: 0.320-1.606) and 6 months (RRR = 0.329; 95% CI: 0.101-1.072). The intervention group also had a significantly lower risk of burnout at 6 months (RRR: 0.698, 95% CI: 0.528, 0.929, p = 0.012). Nurses who completed more MBS sessions had less suicidal ideation at 6 months and those who completed more MBS skills-building activities had less burnout at 3 and 6 months. LINKING ACTION TO EVIDENCE: Integrating psychologically safe mental health screening combined with the scalable online CBT-based intervention, MBS, can produce sustained improvements in burnout, mental health symptoms, including suicidality, and healthy lifestyle beliefs and behaviors among nurses experiencing mental distress.

Humans↗

PubMed2026

HSK21542 for Postoperative Analgesia in Gynecological Surgery: A Pooled Post-Hoc Analysis of Two Phase III Randomized Controlled Trials.

BACKGROUND: Effective postoperative pain management in gynecological surgery is challenging because of complex visceral-somatic pain interactions and the adverse effects of conventional analgesics. HSK21542, a novel peripherally restricted kappa-opioid receptor (KOR) agonist that selectively targets visceral pain pathways enriched with KORs, may provide adequate analgesia without systemic adverse events. METHODS: We conducted a pooled post-hoc analysis of data from two phase III, multicenter, triple-blinded, randomized controlled trials (Study 301, HSK21542 vs placebo; Study 303, HSK21542 vs tramadol vs placebo). Eligible patients undergoing elective gynecological surgery were included. The primary outcome was the summed pain-intensity difference over 12 and 24 hours (SPID 12h and SPID 24h ). Secondary outcomes were pain-relief quality (proportion of patients relieved from severe pain with a pain numerical rating score ≤ 3 between 0 and 24 hours) and rescue-analgesic requirements (number of doses and time to first rescue analgesic). Adverse events were also assessed. RESULTS: A total of 370 patients were analyzed: 150 received HSK21542, 139 received a placebo, and 81 received tramadol. After inverse probability of treatment weighting (IPTW) adjustment, baseline characteristics were well-balanced across treatment groups (all standardized mean differences [SMD] <0.1; see Table 1 for 95% CIs). HSK21542 produced greater reductions in pain intensity over 12 and 24 hours than placebo (least-squares mean differences -8.1 and -16.3 for SPID 12h and SPID 24h , respectively. Both P < .001) and no statistically significant difference was observed between HSK21542 and tramadol ( P > .05). Significantly more patients in the HSK21542 group were relieved from severe pain at 0 to 12 hours (92.7% vs 82.7%, P < .001) and required fewer rescue doses at 0 to 12 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) and 0 to 24 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) than those in the placebo group, whereas no significant differences with tramadol both in 0 to 12 and 0 to 24 hours. HSK21542 was also associated with significantly lower incidences of nausea (24.7% vs 66.7%) and vomiting (21.3% vs 60.5%) than tramadol. Only one case of dizziness occurred in the tramadol group. CONCLUSIONS: HSK21542 could provide adequate postoperative analgesia with few adverse events in patients undergoing gynecological surgery.

Humans↗

PubMed2026

Effect of adding umbilical cord blood derived stem cells to haploidentical stem cell transplant (haplo-cord) on post-transplant survival and graft-versus-host disease in patients with hematological malignancies: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Haploidentical stem cell transplantation (haplo-SCT) carries a substantial risk of graft-versus-host disease (GvHD), whereas umbilical cord blood (UCB) transplantation offers lower GvHD risk but slower engraftment. The haplo-cord approach combines both graft sources, aiming to mitigate GvHD while ensuring timely engraftment. This meta-analysis compares haplo-cord transplantation with haplo-SCT alone for the treatment of hematological malignancies. METHODS: Four electronic databases and two clinical trial registries were systematically searched. Effect sizes from eligible studies were pooled using odds ratios (ORs) for dichotomous outcomes and hazard ratios (HRs) for time-to-event outcomes. RESULTS: Twelve studies met the inclusion criteria. Haplo-cord was associated with a statistically significant reduction in chronic GvHD (OR = 0.62, 95%-CI: 0.42-0.93), while no significant difference was observed for grade II-IV acute GvHD (OR = 0.75, 95%-CI: 0.52-1.09). Survival outcomes favored haplo-cord, with lower HRs for overall survival (HR = 0.68, 95%-CI: 0.53-0.86) and event-free survival (HR = 0.61, 95%-CI: 0.52-0.72), while non-relapse mortality was not significant. Relapse at 3 years was significantly lower with haplo-cord (OR = 0.54, 95%-CI: 0.35-0.82). Haplo-cord also demonstrated higher day-30 engraftment, along with lower relapse-related and GvHD-related mortality, while CMV and EBV viremia showed no difference between groups. CD34 selection in the haplo graft significantly influenced effect sizes and heterogeneity in both subgroup analyses and meta-regression for acute GvHD. CONCLUSION: Haplo-cord transplantation improves GvHD outcomes, survival, and relapse risk compared with haplo-SCT alone. However, whether protocol optimization, possibly via CD34 selection, confers additional benefit remains uncertain and requires confirmation in future studies.

Humans↗

PubMed2026

Transcriptomic insights into the molecular mechanism of antifouling agent-induced settlement inhibition in the Pacific oyster Crassostrea gigas.

Marine biofouling remains a persistent challenge to maritime industries and marine ecosystems worldwide. In this study, we systematically evaluated the acute toxicity, settlement inhibitory efficacy, and underlying molecular mechanisms of an N-oleyl-1,3-propanediamine-based antifouling agent using pediveliger larvae of the Pacific oyster Crassostrea gigas. The 96 h-LC50 of the agent was determined to be 0.81 mg/L, and exposure to 1.68 mg/L achieved complete larval settlement inhibition without inducing significant acute toxicity. Transcriptomic analysis identified 791 differentially expressed genes, dominated by downregulated genes associated with ribosomal function, translation, cell adhesion, and cytoskeletal organization. The agent exerts its inhibitory effect primarily through the global suppression of protein synthesis, disruption of cell-substrate adhesion and cytoskeletal integrity, and induction of proteotoxic stress responses. These findings reveal a multi-pathway molecular mechanism underlying antifouling agent-induced settlement inhibition in oyster larvae and provide key molecular biomarkers to support the development of eco-friendly antifouling technologies.

Animals↗

PubMed2026

Impact of early nurse-led implementation of an intensive care unit diary following major trauma on quality of life: The QUALITRAU randomized controlled trial.

BACKGROUND: Survivors of major trauma often experience long-term impairments in health-related quality of life (HRQoL) and post-traumatic stress disorder (PTSD). Intensive care unit (ICU) diaries have been proposed to reduce psychological sequelae, but evidence remains conflicting and not specific to trauma patients. OBJECTIVE: To assess whether, in patients with major trauma, a nurse-led ICU diary implemented within the first 48 h after trauma improves HRQoL at 1 year vs. usual care. METHODS: The QUALITRAU randomized controlled trial was conducted in three ICUs of a French tertiary hospital. Adult patients with major trauma (Injury Severity Score > 15) were randomized within 48 h of admission to receive either an ICU diary combined with usual care or usual care alone. The primary outcome was HRQoL at 12 months, assessed with the 4 domains of the WHOQOL-BREF questionnaire. Secondary outcomes included PTSD severity measured with the Impact of Event Scale (IES). Analyses were performed on an intention-to-treat basis. RESULTS: Between November 2014 and November 2016, 208 patients were randomized (101 intervention, 107 control), with primary outcome available for 121 (53 intervention, 68 control). Median age was 35 years [IQR 25-51], 81% were men, and 63% had severe traumatic brain injury. At 12 months, there were no differences between intervention and control groups in the WHOQOL-BREF domains (physical: 5.7 [IQR 4.6-11.4] vs 9.1 [IQR 4.6-13.1],P = 0.16; psychological: 8.0 [IQR 6.7-13.3] vs 11.3 [IQR 6.7-13.3],P = 0.08; social: 5.3 [IQR 4.0-14.7] vs 12.0 [IQR 4.0-14.7],P = 0.10; environment: 8.0 [IQR 5.5-14.5] vs 12.0 [IQR 5.5-15.5], P = 0.05). IES scores were also not different. CONCLUSIONS: Early implementation of nurse-led ICU diaries was not associated with improved long-term HRQoL or reduced PTSD symptoms in patients with major trauma. IMPLICATION FOR CLINICAL PRACTICE: These findings suggest that ICU diaries may need to be integrated into broader, multimodal rehabilitation strategies and may depend on factors such as timing, content, or patient characteristics.

Humans↗

PubMed2026

Integrative quantum and systems biology of cancer: From molecular fluctuations to ecological outcomes.

This review treats cancer as a multiscale adaptive system, asks what the framework must predict to be worth adopting, and separates at each scale what the evidence establishes from what is proposed. It is an expert narrative synthesis, not a systematic review, and states the limits of that design. Proton transfer and tautomeric shifts contribute to spontaneous mispairing but do not license claims of directed or non-random mutation: replication timing, three-dimensional chromatin organization, sequence context and known mutagenic processes explain most mutational heterogeneity, leaving any quantum contribution as a residual against that baseline. The Waddington quasi-potential is bounded: outside detailed balance the dynamics are not gradient-derivable and require a probability-flux term. Hysteresis, rate-limited bimodality and return to state after perturbation distinguish an attractor from a transcriptomic cluster. Single-cell karyotype and live-imaging evidence supports whole-genome doubling as an unstable intermediate of heterogeneous origin and context-dependent consequence, not a uniform adaptive strategy. Systems and synthetic biology, virtual cells and digital twins are assessed against benchmarks, not promise. Tissue-scale ecology is reported with the spatial measurements now quantifying it, including evidence that stromal niche construction is not uniformly tumor-supporting. RNA modification is a layer in its own right, showing that the interpretation of a regulatory signal, not its magnitude, is biologically decisive. A dedicated section states the framework's commitments, the observable and evidence at each scale, and what would falsify them, asking what this adds to somatic mutation theory with clonal evolution and plasticity.

Neoplasms↗

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

Safety and efficacy of Meridian sinew tuina (MST) for post-surgical upper limb lymphedema: a systematic review and meta-analysis.

BACKGROUND: Complex Decongestive Therapy (CDT) is the non-operative standard for breast cancer-related lymphedema (BCRL), but many patients experience persistent subcutaneous stiffness, pain, and restricted mobility. This study systematically reviews the safety and clinical efficacy of Meridian Sinew Tuina (MST) protocols for BCRL. METHODS: Global and regional databases (PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP) were searched from inception to January 15, 2026, with alerts monitored through April 30, 2026. Randomised controlled trials (RCTs) evaluating MST (deep tissue mobilisation along the six-hand meridian sinew [Jingjin] lines via plucking, kneading, and pressing) were included. Two reviewers independently extracted data, evaluated risk of bias using Cochrane RoB 2, and assessed evidence certainty via GRADE using a random-effects model. RESULTS: Fifteen RCTs were included. For the primary anthropometric outcome, MST significantly reduced upper limb circumference compared to controls (SMD = 1.59; 95% CI: 1.44 to 1.74; Z = 20.81; p < 0.0001; I2=0.0%; N = 924; GRADE: Moderate certainty). The Clinical Response Efficacy Rate (≥ 30% swelling reduction and symptom relief) favoured MST (RR = 1.69; 95% CI: 1.54 to 1.87; Z = 10.62; p < 0.0001; I2=0.0%; N = 1,114; GRADE: Moderate certainty). Trial Sequential Analysis confirmed sample size sufficiency. For secondary outcomes (N = 924; GRADE: Low to Very Low certainty due to performance bias and clinical heterogeneity), MST showed favourable 3-month improvements in DASH functional scores (SMD = -1.81; 95% CI: -2.11 to -1.51; I2=45.1%), pain intensity (SMD = -2.44; 95% CI: -2.93 to -1.95; I2=50.4%), and quality of life (SMD = 1.04; 95% CI: 0.79 to 1.29; I2=0.0%). No serious adverse events occurred. CONCLUSIONS: MST protocols are associated with favourable short- and mid-term reductions in upper limb swelling. However, confidence is tempered by unblinded performance bias and control group variations. MST cannot be unconditionally recommended for standalone implementation but represents a promising, optional supportive adjunctive intervention within oncological rehabilitation.

Humans↗

PubMed2026

Divergent trajectories of genome architecture and chromosome evolution in ferns and angiosperms.

Ferns and angiosperms represent the two largest vascular plant lineages but exhibit striking genomic and ecological contrasts. We investigated whether differences in genome size, chromosome architecture, GC content, and stomatal traits reveal divergent evolutionary trajectories between these lineages. We assembled the most comprehensive dataset to date, integrating genome size, chromosome number and size, GC content, and stomatal traits for over 1100 fern species and compared it with an extensive angiosperm dataset. Ferns exhibited markedly lower variability and c. 16-fold slower rates of chromosome size evolution than angiosperms. A persistent positive relationship between genome size and chromosome number in ferns suggests limited cytological post-polyploid diploidization. While ferns generally possess larger stomata, this difference disappears after accounting for genome size, indicating that nucleotypic constraints, rather than lineage-specific physiology, dictate stomatal dimensions. Both groups share a unimodal GC-genome size relationship peaking at c. 14 Gbp. Larger fern chromosomes imply lower genome-wide recombination rates, potentially limiting genetic reshuffling and adaptive potential. Our results highlight fundamentally divergent evolutionary trajectories, likely shaped by meiotic symmetry in ferns and meiotic asymmetry, possibly centromere drive, and post-polyploid diploidization in angiosperms, defining the functional and genomic landscapes of these lineages across deep evolutionary timescales.

Genome, Plant↗

PubMed2026

RNA dysregulation as a determinant of aging and neurodegenerative vulnerability.

In the nervous system, aging causes deterioration of cellular and molecular processes that are associated with declines in cognition, sensory perception, and motor coordination. Aging is also the strongest risk factor for neurodegenerative disease, yet the mechanisms by which aging predisposes neurons to dysfunction remain incompletely understood. While genomic instability, proteostasis decline, mitochondrial dysfunction, and chronic inflammation have dominated prevailing models, recent evidence highlights RNA dysregulation as a central component of age-associated decline. In this review, we summarize recent findings suggesting that aging progressively erodes RNA regulatory fidelity through alterations in RNA-binding protein abundance, localization, biophysical behavior, and RNA interactions. We argue that age-dependent RNA dysregulation represents an important mechanism that converges with genetic risk to drive neuronal vulnerability and neurodegeneration.

RNA dysregulation↗

PubMed2026

Approaches to observational study designs and analytical options to evaluate the safety of multi-dose vaccines: a systematic review.

INTRODUCTION: Observational studies require careful considerations when evaluating the safety of multidose vaccines. We reviewed design and analytical approaches in observational studies evaluating the safety of multidose vaccines in the post-licensure phase. METHODS: EMBASE, MEDLINE, Web of Science, and Scopus (2018-2022) were searched for hypothesis-testing studies evaluating the safety of multidose vaccines. Key features from frequently used designs were extracted. RESULTS: Among 123 eligible studies, cohort (46%) and self-controlled case series (SCCS)/self-controlled risk interval (SCRI) (40%) followed by case-control (12%) were the most common designs, and 15% of studies used multiple designs. Among cohort studies evaluating multiple doses, vaccination date (36%) and cohort entry with time-updated exposure status (32%) were frequent approaches used to define time zero. Twenty-eight percent of cohort studies did not report time zero; all but one evaluated COVID-19 vaccine effect on post-delivery and fertility-related outcomes. For SCCS/SCRI, 64% of studies accounted for event-dependent exposures, mainly by including pre-exposure periods (53%) and modified SCCS model (48%), while 20% employed multiple correction strategies. Among studies using multiple designs, 68% reached consistent conclusions. CONCLUSIONS: SCCS/SCRI and cohort designs dominate multidose vaccine safety studies. Clear reporting on time zero in pregnancy and fertility-related cohort studies, and on addressing event-dependent exposures in SCCS/SCRI studies is needed, along with guidance on interpreting results from multiple designs.

Humans↗