INTRODUCTION: Anxiety is a common mental disorder with high individual and public health costs. Psychometric scales are frequently applied to describe anxiety severity; however, their subjective nature reduces measurement precision. Heart rate variability (HRV) may serve as a complementary tool for assessing anxiety by adding physiological information beyond subjective symptom ratings. METHODS: We conducted a systematic review and meta-analysis, reported in accordance with PRISMA 2020 (PROSPERO: CRD42024623381). We considered studies on adult populations who had been given validated anxiety scales (BAI, HAM-A and STAI) as well as quantitative HRV parameters (HF, LF, LF/HF, RMSSD, and SDNN). Correlation coefficients quantifying the associations for multiple psychometric scale - HRV parameter pairs were synthesised employing an inverse-variance random- effects meta-analysis framework. RESULTS: A total of 79 studies were included, of which 39 were eligible in a quantitative analysis. Three statistically significant associations were identified: (1) BAI and HF showed a weak negative correlation (r = -0.09, p = .0239), (2) HAM-A and HF had a moderate negative correlation (r = -0.32, p = .0423), while (3) STAI and LF/HF ratio showed a positive correlation (r = 0.39, p = .0017). Other parameters did not show significant associations. CONCLUSION: Selected HRV parameters showed associations with anxiety severity, especially HF with BAI and HAM-A, and LF/HF with STAI. While HRV is not a replacement for psychometric scales, it may contribute as a complementary tool for characterising autonomic regulation associated with anxiety severity.

Dermatophytosis afflicts approximately 25% of the global population, representing a critical public health burden. (), a predominant zoonotic dermatophyte, is a significant contributor to disease morbidity. While the transcriptomic response of keratinocytes-the primary barrier of the skin-to infection is well characterized, the genome-wide translational regulatory mechanisms remain unknown. Here, we employed parallel ribosome profiling (Ribo-seq) and RNA sequencing (RNA-seq) to dissect the genome-wide transcriptional and translational landscape of human keratinocytes during infection. Our analysis revealed extensive but distinct reprogramming at both transcriptional (3,189 differentially expressed genes) and translational (295 differentially translated genes) levels, with only minimal overlap (5.8% of upregulated genes and 0.8% of the downregulated genes), indicating prevalent post-transcriptional control. We further identified and characterized a vast non-canonical translatome, including 17,564 upstream ORFs (uORFs), 188,357 downstream ORFs (dORFs), and 185,704 lncRNA-derived ORFs (lncORFs). Strikingly, both translatable uORFs and dORFs were associated with significantly enhanced translation efficiency (TE) of their host genes, a phenomenon conserved under infection. Moreover, we demonstrated that miRNAs coordinately repress target gene expression at both transcriptional and translational levels. Functional interactions revealed that the presence of translated uORFs or dORFs could significantly attenuate miRNA-mediated TE suppression. This study provides the first comprehensive map of the keratinocyte translatome during fungal infection, establishing uORFs and dORFs as critical dual-layer regulators in the host anti-fungal defense.

ALKBH5, as an m6A demethylase, plays a crucial regulatory role in various kidney diseases such as acute kidney injury, chronic kidney disease, renal fibrosis and renal cell carcinoma. However, its function often exhibits contradictory effects: In renal fibrosis, ALKBH5 has been reported to both promote and suppress fibrogenesis, whereas in renal cell carcinoma most studies support an oncogenic role, but some clinical observations link ALKBH5 downregulation to poor prognosis. These contradictions may stem from differences in cell types, disease stages, and microenvironments. This manuscript systematically reviews the complex function of ALKBH5 in kidney diseases and its underlying mechanisms, explores its potential as a therapeutic target, evaluates its therapeutic potential, and highlights the need for cell- and pathology-specific strategies to enable precise intervention. Future research should focus on its cell and pathological background specificity to achieve precise intervention.

Post-ovulatory aging (POA) reduces oocyte quality, yet effective interventions remain limited. Here we demonstrate that early intervention with vitamin K2 (menaquinone-4 isoform, MK-4) alleviates POA by inhibiting iron-disorder-induced oxidative stress. Western blot revealed that the expressions of ferroptosis suppressor protein 1 (FSP1) and vitamin K epoxide reductase-like protein (VKORC1L1) were significantly decreased in mouse POA oocytes; however, MK-4 attenuated these changes. Further, MK-4 inhibited ferritinophagy by downregulating NCOA4 and LC3II, markedly restored ferritin level, reduced intracellular Fe amount, thus attenuating oxidative stress. These results were characterized by reducing lipid peroxidation marker malondialdehyde (MDA) and acyl-CoA synthetase long chain family member 4 (ACSL4) expression, decreasing γ-H2AX and 8-Hydroxy-2'-deoxyguanosine (8-OHdG), and enhancing expression of the mitochondrial antioxidant enzyme superoxide dismutase 1 (SOD1). Additionally, MK-4 suppressed mitophagy by downregulating PINK1 and Parkin, and upregulating Rab7 improving mitochondrial membrane potential. Consequently, abnormalities in chromosomes, spindles, and the cytoskeleton were significantly ameliorated in POA oocytes receiving early MK-4 intervention. Notably, in vitro-aging oocytes expressed higher FSP1 and VKORC1L1 but lower ACSL4 and MDA versus the in vivo counterparts, suggesting a milder lipid peroxidation in vitro. Collectively, our findings uncover a novel anti-aging mechanism triggered by MK-4, highlighting its potential to establish a preventive strategy for female reproductive aging.

U-wave changes during angina are often not recognized, although a change in U-wave polarity may be the only sign of myocardial ischemia. The appearance of a positive U-wave in leads V1-4 during angina suggests posterobasal ischemia and critical stenosis of the CX or RCA coronary artery. The authors present two examples. Orv Hetil. 2026; 167(31): 1248-1252.

Albuminuria is one of the most important biomarkers of chronic kidney disease and also a target that can be influenced by treatment. The amount of albumin excreted in the urine is an independent predictor of declining kidney function, cardiovascular events, and all-cause mortality. It is most easily determined based on the albumin-to-creatinine ratio (ACR) measured in the first morning urine sample; in the vast majority of cases, 24-hour urine collection is not required. The pathophysiology of albuminuria centers on damage to the glomerular filtration barrier - particularly podocytes - hemodynamic hyperfiltration, inflammation associated with tubular protein reabsorption, and activation of the renin-angiotensin-aldosterone system (RAAS). Modern four-pillar pharmacotherapy - RAS inhibitors (ACE inhibitors/ARBs), SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (finerenone), and GLP1 receptor agonists in type 2 diabetes - acts on these processes through complementary mechanisms. When tailored to the degree of albuminuria and eGFR, this treatment significantly slows the progression of chronic kidney disease and reduces cardiovascular risk. Measuring and monitoring albuminuria must therefore be an essential part of daily clinical practice. Orv Hetil. 2026; 167(31): 1231-1237.

INTRODUCTION: According to epidemiological data from Hungary, cardiovascular diseases cause the greatest loss of health among the population and are responsible for a significant proportion of premature deaths. This reinforces the health policy position that cardiovascular prevention, including improving medication adherence, must be given top priority in patient care. Long-term survival in patients who have experienced acute coronary syndrome depends heavily on medication adherence, particularly regarding statins and anticoagulants; however, domestic surveys indicate deficiencies in the use of preventive medications. OBJECTIVE: The aim of our study was to compare the attitudes and beliefs regarding antiplatelet agents and cholesterol-lowering drugs among patients in the secondary prevention group who underwent percutaneous coronary intervention and those in the primary prevention control group, using the Beliefs about Medicines Questionnaire (BMQ). METHODS: A cross-sectional, questionnaire-based study included 162 secondary prevention patients and 136 primary prevention patients who had undergone percutaneous coronary intervention. Medication attitudes were measured using the specific and general dimensions of the BMQ, and SPSS 27.0 was used for statistical analysis. RESULTS: Among patients in the secondary prevention group, both drug groups were characterized by lower levels of concern and more accepting attitudes, whereas in the primary prevention group, sceptical (p<0.05) and ambivalent attitudes were more common (p<0.001). Based on the analysis of respondents by attitude group and the examination of the BMQ's general subscales, percutaneous coronary intervention significantly influenced beliefs regarding medications. This change was clinically significant in terms of treatment adherence (p<0.001) Discussion and conclusion: Patients who have undergone percutaneous coronary intervention have more favourable attitudes toward medication, which highlights the role of targeted education and psychoeducation in improving adherence in the non-intervention population. However, adherence in the secondary prevention group cannot be considered optimal either, therefore further targeted education is warranted in this patient group as well. Orv Hetil. 2026; 167(31): 1238-1247.

Inflammatory activation is involved in the pathogenesis of heart failure (HF). ATPase H+-Transporting Accessory Protein 2 (ATP6AP2) is an auxiliary subunit of the V-ATPase, and its role in HF is not fully understood. To assess the role and regulatory mechanisms and therapeutic potential of ATP6AP2 in HF, we used a cardiac-specific ATP6AP2 conditional knockout (CKO) mouse model and observed spontaneous cardiac dysfunction, myocardial fibrosis and cardiomyocyte apoptosis in mice. Further studies showed that ATP6AP2 promoted stimulator of interferon genes (STING) degradation through the lysosome-dependent pathway. ATP6AP2 knockdown significantly upregulated STING protein levels, activated the STING-TBK1-IRF3 signaling axis, and promoted pro-inflammatory factor expression and cardiomyocyte apoptosis. In mice with myocardial infarction (MI), myocardial overexpression of ATP6AP2 or treatment with H-151 inhibited the activation of the STING signaling pathway, ameliorated cardiomyocyte apoptosis and inflammatory responses, thereby improving cardiac function. In addition, in macrophages treated with conditioned medium from hypoxia-exposed cardiomyocytes, the levels of pyroptosis-related proteins were markedly increased, whereas ATP6AP2 overexpression or STING inhibition reduced pyroptosis. ATP6AP2 likewise attenuates inflammation and pyroptosis caused by hypoxia in cardiac organoids. In conclusion, activating ATP6AP2 could serve as a promising therapeutic option in HF.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic immune-mediated complication that complicates cardiac surgery because cardiopulmonary bypass requires systemic heparinization. We report a case of acute severe mitral regurgitation (MR) complicated by clinically suspected HIT, in which conventional surgical repair was not feasible. CASE SUMMARY: A 59-year-old man presented with acute severe MR due to chordal rupture and developed cardiogenic shock requiring intra-aortic balloon pump support. While awaiting surgery, his platelet count decreased from 262,000/μL to 23,000/μL. The 4Ts score was 6, and PF4/heparin antibody testing was positive, supporting clinically suspected HIT. Because cardiopulmonary bypass requiring systemic heparinization was considered prohibitively high risk, M-TEER was performed under continuous argatroban infusion. Two PASCAL Ace implants were successfully deployed, reducing MR from severe to trivial without thrombotic or bleeding complications. The patient recovered rapidly with immediate IABP removal and early extubation. DISCUSSION: This case demonstrates that M-TEER under argatroban anticoagulation can be a feasible alternative when conventional surgery is precluded by suspected HIT and the anticipated challenges of anticoagulation during cardiopulmonary bypass. TAKE-HOME MESSAGE: M-TEER under argatroban may serve as a rescue strategy for critically ill patients with acute severe MR and suspected HIT when surgical management is not feasible.

BACKGROUND: Older adults with atrial fibrillation (AF)-associated acute ischemic stroke are prone to disability, depressive symptoms, and falls; the prognostic value of vitamin D status is uncertain. METHODS: We conducted a single-center prospective cohort study of patients aged ≥65 years with ECG-confirmed AF and imaging-confirmed acute ischemic stroke at a tertiary hospital in China (January 2022-August 2024). Serum 25-hydroxyvitamin D [25(OH)D] within 48 hours was modeled per 10 ng/mL decrement and as <20 vs ≥20 ng/mL. Outcomes were 3-month modified Rankin Scale (mRS) shift, Barthel Index (BI), and PHQ-9 ≥10, plus 12-month time to first fall (death as a competing event) and total falls rate. Models adjusted for prespecified baseline confounders. RESULTS: Among 802 participants, median age was 76.2 years (IQR, 71.6-80.6); 60.7% had 25(OH)D <20 ng/mL. Three-month mRS/BI, 3-month PHQ-9, and falls follow-up data were available for 776 (96.8%), 762 (95.0%), and 742 (92.5%) participants, respectively. Each 10 ng/mL lower 25(OH)D was associated with worse 3-month mRS shift (common OR 1.17, 95% CI 1.05-1.31) and lower BI (β -3.9, 95% CI -6.2 to -1.6). Depressive symptoms occurred in 16.8% and were more common with 25(OH)D <20 ng/mL (OR 1.54, 95% CI 1.07-2.22). Among 742 with falls follow-up, low 25(OH)D predicted first fall (HR 1.29, 95% CI 1.07-1.55) and a higher recurrent falls rate (IRR 1.33, 95% CI 1.10-1.61). CONCLUSION: Lower baseline 25(OH)D was consistently associated with poorer functional recovery, greater depressive symptom burden, and higher fall risk and recurrence, supporting 25(OH)D as a pragmatic prognostic marker; multicenter validation and targeted trials are warranted.

BACKGROUND: Children and young people (CYP) with life-limiting conditions (LLCs) comprise a clinically heterogeneous population with diverse disease trajectories and survival patterns. However, studies evaluating long-term survival according to disease group and sociodemographic characteristics remain limited. OBJECTIVES: We assessed long-term survival patterns among CYP with LLCs and evaluated differences in mortality outcomes according to disease group and selected sociodemographic characteristics. DESIGN: Cohort study. METHODS: Using the Korean National Health Insurance database, we identified individuals aged 0-24 years who were newly diagnosed with LLCs between 2011 and 2013. Patients were followed from the date of diagnosis until death or December 31, 2020. Kaplan-Meier survival analyses and Cox proportional hazards models were used to evaluate long-term mortality outcomes according to disease groups and sociodemographic indicators, including insurance premium-based income categories and residential area. RESULTS: In total, 175,813 CYP with LLCs were included. Survival patterns differed significantly across disease groups, age groups, and income levels. Disease group distribution varied by age, with premature and neonatal conditions predominating in infancy. Survival probabilities were lowest among children aged < 1 year and among medical aid beneficiaries. Premature and neonatal disorders and cardiovascular diseases were associated with the shortest observed survival durations. Male patients demonstrated a higher hazard of death from cancer (hazard ratio [HR] 1.83), metabolic diseases (HR 1.61), and neurologic and neuromuscular diseases (HR 1.33) compared to female patients. Higher hazard ratios among medical aid beneficiaries were observed primarily in patients with metabolic, neurologic and neuromuscular diseases, whereas residence-related differences in survival were observed among patients with cardiovascular diseases. CONCLUSION: Distinct survival trajectories exist across disease groups among CYP with LLCs. Early mortality predominates in premature and neonatal disorders and cardiovascular diseases, whereas more prolonged survival patterns are observed in cancer and neurologic disorders. These findings may inform the development of disease-specific integrated treatment strategies, long-term care planning, and supportive care policies for CYP with LLCs and their families.

Noncommunicable diseases (NCDs) remain the leading causes of morbidity and mortality in the United States, yet adherence to recommended physical activity and dietary behaviors remains suboptimal. Authors of this study examined associations between physical activity, diet, and selected NCDs among United States adults. Data were drawn from the 2024 Health Information National Trends Survey, a nationally representative cross-sectional sample of United States adults aged ≥18 years. Survey-weighted analyses examined self-reported diagnoses of diabetes, hypertension, heart disease, and lung disease in relation to aerobic activity, strength training, and fruit and vegetable intake. Bivariate analyses assessed sociodemographic differences, and multivariable logistic regression models estimated adjusted odds of not being diagnosed with each condition. Mean body mass index was 28.8 kg/m, with 35.8% of respondents classified as obese. Few respondents met guidelines for moderate-intensity exercise (36.3%), strength training (38.4%), fruit intake (19.9%), or vegetable intake (28.0%). Meeting aerobic activity guidelines was associated with higher odds of not being diagnosed with diabetes (adjusted odds ratio [aOR] 1.33; 95% CI, 1.04-1.69) and hypertension (aOR 1.49; 95% CI, 1.15-1.93). Strength training was inversely associated with lung disease (aOR 0.66; 95% CI, 0.49-0.89). Fruit intake also was associated with lower odds of lung disease (aOR 1.97; 95% CI, 1.17-3.30). Younger age, healthy weight, and higher income were consistently associated with lower odds of NCD diagnoses. Aerobic physical activity demonstrated the most consistent protective associations with diabetes and hypertension, while diet and strength training showed condition-specific relationships. Improving adherence to lifestyle guidelines may reduce NCD burden and persistent disparities.

INTRODUCTION: Population-based analyses usually classify smoking status at survey enrollment, which combines people who quit before disease recognition with those who continued smoking through diagnosis and quit afterward. This study evaluated whether smoking cessation after a self-reported cardiopulmonary disease diagnosis was associated with subsequent all-cause and cause-specific mortality among adults reconstructed as smoking at diagnosis. METHODS: This secondary analysis pooled ten cross-sectional National Health and Nutrition Examination Survey (NHANES) cycles from 1999-2000 through 2017-2018 and linked survey records to mortality follow-up through 2019. Adults aged ≥40 years with self-reported cardiovascular or chronic lung disease were included when self-reported smoking initiation, diagnosis, cessation, and current-smoking information permitted classification as smoking at diagnosis. Survey-weighted Cox models compared post-diagnostic quitters with persistent smokers. Models were unadjusted, demographic-adjusted, and fully adjusted for prespecified demographic, disease-history, smoking-history, and survey-cycle covariates. RESULTS: Among 2319 participants, 975 were post-diagnostic quitters, and 1344 were persistent smokers. During a median follow-up of 6.33 years, 999 all-cause, 272 heart-disease, and 244 cancer deaths occurred. In the fully adjusted model, post-diagnostic quitting was associated with lower heart-disease mortality (adjusted hazard ratio, AHR=0.59; 95% CI: 0.42-0.82; p=0.001). Associations with all-cause mortality (AHR=0.90; 95% CI: 0.74-1.09; p=0.276) and cancer mortality (AHR=0.72; 95% CI: 0.49-1.06; p=0.100) were not statistically significant. Findings for heart-disease mortality were consistent across landmark, overlap-weighted, smoking-burden-adjusted, disease-restricted, quit-age reconstruction, and leave-one-covariate-out analyses. CONCLUSIONS: Among adults retrospectively classified as smoking when cardiopulmonary disease was diagnosed, post-diagnostic cessation was associated with lower subsequent heart-disease mortality. The findings are observational and remain susceptible to survivor selection, reverse causation, recall and social-desirability bias, exposure changes after enrollment, mortality misclassification, and residual confounding.

Statins are the primary treatment for hypercholesterolemia and a cornerstone of atherosclerotic cardiovascular disease prevention. Although generally safe, serious adverse effects may occur in selected patients, particularly when statins are used at high doses or without medical supervision. We describe a 66-year-old man with hypertension and hyperlipidemia who developed syncope after self-adjusting atorvastatin from 20 mg daily to 80 mg daily for two weeks. On admission, electrocardiography showed sinus arrest with a ventricular escape rhythm, accompanied by acute hepatic and renal dysfunction, electrolyte abnormalities, coagulation abnormalities, and elevated inflammatory markers. Common reversible causes, including thyroid dysfunction, structural heart disease, acute myocarditis, Lyme disease, and the use of negative chronotropic drugs, were not supported by the clinical evaluation. After temporary pacing and supportive treatment, liver and kidney function, electrolytes, and coagulation function returned to normal; however, symptomatic sinus arrest persisted, and a permanent pacemaker was implanted. During follow-up, the electrocardiogram showed recovery of sinus rhythm. Pacemaker interrogation at 1 year showed a pacing burden of approximately 80% when the lower rate limit was programmed at 70 beats per minute; after the lower rate limit was reduced to 50 beats per minute, the pacing burden decreased to approximately 20% at the subsequent follow-up. This finding suggests partial recovery of intrinsic sinus rhythm but persistent or intermittent sinus node dysfunction. The case supports a cautious interpretation of possible atorvastatin-associated severe bradyarrhythmia mediated by multiorgan dysfunction rather than definitive direct statin-induced sinus node injury. Clinicians should carefully educate patients not to self-adjust statin doses and should monitor for serious adverse events when high-dose statin exposure is suspected.

INTRODUCTION: E-cigarette use or 'vaping' is increasing globally. Withdrawal symptoms have been extensively researched in tobacco users, but less is known regarding withdrawal among e-cigarette users. We aimed to explore the type, relative frequency, and severity of withdrawal symptoms experienced by e-cigarette users in Saudi Arabia. METHODS: A cross-sectional survey was administered to e-cigarette users aged ≥18 years residing in Saudi Arabia in 2023, using a convenience sampling frame. The primary outcome is the withdrawal symptoms. Descriptive statistics and correlations were employed to analyze the data. RESULTS: Data from 339 participants were analyzed: 87% males, 66% students, 90% used nicotine-containing e-cigarettes, with 55% using higher strength nicotine concentrations (>18 mg/mL). The most frequently reported psychological withdrawal symptoms were intense cravings for nicotine (43%), anger (29%), restlessness (28%), and poor concentration (20%), while 71% of participants reported experiencing at least one withdrawal symptom. The most commonly reported physical withdrawal symptoms were headache (34%), dizziness (17%), heart palpitations (15%), and breathing difficulties (14%). Approximately 42% of participants reported moderate-to-severe withdrawal symptoms. Notably, 36.9% returned to smoking to alleviate withdrawal symptoms. CONCLUSIONS: E-cigarette users in Saudi Arabia experienced a range of psychological and physical withdrawal symptoms. Psychological symptoms were more commonly reported than physical ones. Further studies are warranted to elucidate the factors influencing the occurrence and severity of these symptoms.

OBJECTIVE: The association between endogenous sex hormones and Cardiovascular-kidney-metabolic (CKM) syndrome remains incompletely elucidated. METHODS: We performed a cohort study using clinical data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Restricted cubic spline Cox proportional hazards models and stratified analyses were employed to analyze the relationships between sex hormone-binding globulin (SHBG), free androgen index (FAI), testosterone-to-estradiol ratio (T: E), and mortality. RESULTS: In a cohort of 2,545 patients with CKM (mean age 51.84 years; 63.65% male) followed for a mean of 4.78 years, stage 2 disease was the most prevalent (56.96%). A significant inverse correlation between advancing CKM stages and serum levels of testosterone-related parameters (all  < 0.05) was observed, alongside reduced estradiol and elevated SHBG. After multivariable adjustments, the association between FAI and all-cause mortality remained significant ( = 0.46, 95% CI: 0.30-0.69,  < 0.001), whereas the effects of SHBG and the T: E ratio were diminished ( > 0.05). However, for CVD mortality, no significant results were observed in multivariable adjustments. In men aged > 60 years, elevated FAI (> 25.91 nmol/L) and T: E ratio (> 1.55) were each independently associated with reduced all‑cause mortality, with adjusted HRs of 0.24 ( = 0.02) and 0.51 ( = 0.01), respectively. CONCLUSIONS: Cox proportional hazards analysis demonstrated an inverse relationship between serum FAI and all-cause mortality in the overall, postmenopausal and men (> 60 years) CKM subgroup. In addition, a higher T: E ratio was inversely associated with all‑cause mortality specifically in men aged > 60 years with CKM.

BACKGROUND: Hypoxemia is a common and serious complication during sedated gastrointestinal endoscopy for out- and in-patients. Though diagnostic and severity scoring systems of obstructive sleep apnea (OSA) and difficult airway assessment (DAA) are widely used to assess hypoxemia risk, there is no exclusively designed prediction model and convenient tool in real-world practice. We aimed to develop and validate a robust and accurate hypoxemia risk prediction model for pre-operative use in this context. METHODS: Using data from out-patients undergoing gastrointestinal endoscopy between May 2020 and November 2023 across seven hospitals in China with diverse regional and ethnic backgrounds, we developed and independently validated a hypoxemia risk prediction model for sedated gastrointestinal endoscopy (HAPPY-12K). The model was developed to pre-operatively predict occurrence of hypoxemia during sedated gastrointestinal endoscopy, defined as SpO falling below 95% for a duration exceeding 10 s. HAPPY-12K was a logistic regression model incorporating eight predictors: body mass index, Mallampati grade, limited jaw protrusion, short thyromental distance, large tongue, history of snoring, short neck with large circumference and pre-operative mean arterial pressure. The model was constructed by a well-established 3-D modeling strategy composed of Double types of effects, Double steps of screening, and Double steps of modeling. The discriminative ability was evaluated using the area under the receiver operating characteristic curve (AUC). The model calibration was examined through calibration slope, expected-to-observed (E:O) ratio and Brier score. For clinical utility, decision curve analysis was performed to assess net benefit (NB) and net reduction (NR). Furthermore, we systematically compared HAPPY-12K with other newly developed models using scores or raw variables from questionaries of OSA and DAA using DeLong's test. This study is registered in the Chinese Clinical Trial Registry (ChiCTR2300074128). FINDINGS: We included 11,957 patients, divided into a Training Set ( = 2,518, hypoxemia rate 10.37%), and five validation sets ( = 9,439, hypoxemia rate raining from 8.40% to 28.45%). HAPPY-12K was developed in a Han Chinese population and exhibited satisfactory discrimination ability with AUCs ranging from 0.818 to 0.895 in external populations of the same ethnicity, and an acceptable AUC of 0.771 in a Uygur Chinese population. Although its Brier scores were satisfactory across all ethnic populations, HAPPY-12K displayed acceptable calibration (calibration slope < 1.2) in external Han Chinese populations, and good calibration (E:O ratio = 0.962) in independent homogenous populations comparable to the training set. The average and were 45.2‰ and 59.5%, respectively. It was estimated that HAPPY-12K would identify over half a million patients with truly developing hypoxemia during sedated gastrointestinal endoscopy and could help avoid over six million unnecessary interventions annually in China. Meanwhile, a head-to-head comparison revealed that HAPPY-12K outperformed other models. HAPPY-12K has been implemented as an interactive online tool available at http://bigdata.njmu.edu.cn/HAPPY-12K/. INTERPRETATION: HAPPY-12K could enable efficient and precise hypoxemia risk assessment before sedated gastrointestinal endoscopy, providing timely alerts for high-risk outpatients. FUNDING: National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; Science and Technology Project of Jiangsu Disease Control and Prevention Administration; Science and Technology Development Project of Nanjing Medical University; Priority Academic Program Development of Jiangsu Higher Education Institutions; and Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.

INTRODUCTION: The evaluation of diastolic function in patients with diabesity (i.e., combined obesity and type-2 diabetes mellitus) undergoing incretin-based therapy could facilitate its early detection and help prevent its progression to heart failure. METHODOLOGY: In this small descriptive study, performed for exploratory and proof-of-concept purposes, a group of 15 diabesity cases with chest x-ray examinations (< 1 month) before and after ≥ 12 months of incretin-based therapy (absent ventricular/valvular dysfunction) were identified. Standard diabesity characteristics (Body Weight (kg), Body Mass Index (kg/m), and Hemoglobin A1c) and AI-model diagnostic predictions of pulmonary venous hypertension (aka "pulmonary congestion") [None; Stage 1: vascular distention/redistribution but minimal interstitial edema; or Stage ≥ 2: vascular congestion with ≥ mild interstitial or alveolar edema] by validated AI-enabled chest x-ray staging, representing mean left atrial pressure in diastolic dysfunction, were evaluated pre- and post-therapy. RESULTS: According to weight-loss response to incretin therapy, cases clustered into equal-sized therapeutic categories as follows: (1) Significant Responders (9-30% decreases); (2) Insignificant Responders (0-2% decreases); and (3) Non-Responders (2-12% increases). Regarding hemoglobin A1c changes: (1) Significant Responders collectively decreased; (2) Insignificant Responders varied; and (3) Non-Responders were largely stable. Pre-therapy, all 15 cases demonstrated AI-enabled chest x-ray pulmonary venous hypertension staging evidence of diastolic dysfunction; post-therapy, 4 improved (especially the cases of greatest weight loss or hemoglobin A1c reduction), 5 were stable, and 6 worsened. Per therapeutic category, AI-enabled chest x-ray signs of functional response were: (1) Significant Responders (all demonstrating unequivocally decreased obesity and improved diabetes) collectively showed stable-decreased dysfunction; (2) Insignificant Responders (all demonstrating at most minimally decreased obesity, but stable-worsening diabetes in most) reflected stable-increased dysfunction in 60%; and (3) Non-Responders (all demonstrating increased obesity, but stable-improved diabetes) showed increased dysfunction in 80%. CONCLUSION: AI-enabled chest x-ray pulmonary venous hypertension staging potentially detects background subclinical diastolic dysfunction in diabesity and monitors its functional response to incretin-based therapy. The confirmation (or disproof), and assessments of durability and generalizability, of these preliminary results await a larger more definitive and controlled prospective study on the subject.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target.

INTRODUCTION: Patients with atherosclerotic cardiovascular disease (ASCVD) and systemic inflammation (SI) or chronic kidney disease (CKD) have poorer outcomes than those without SI or CKD. This study evaluated the impact of both SI and CKD on major adverse cardiovascular events (MACE), healthcare costs, and healthcare resource utilization (HCRU) in patients with ASCVD. METHODS: This retrospective cohort study examined the association between SI and revised MACE, healthcare costs, and HCRU among adult patients with ASCVD from the Komodo Healthcare Map®. CKD stage 3-4 was determined from claims or laboratory data. SI was defined as ≥ 1 high-sensitivity C-reactive protein (hsCRP) value of 2-10 mg/l (without SI, all hsCRP values < 2 mg/l). The primary endpoint, revised MACE, was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. RESULTS: Of 74,884 patients with ASCVD and ≥ 1 eligible hsCRP value, 8.5% had CKD stage 3-4, and 49.2% had SI. Patients with SI had a higher comorbidity index and a greater prevalence of obesity, hypertension, and type 2 diabetes than those without SI. Compared with patients with ASCVD without CKD or SI, SI alone was associated with a 24% higher risk (hazard ratio [HR] 1.24; 95% CI 1.15-1.34), CKD stage 3-4 with a 33% higher risk (HR 1.33; 95% CI 1.16-1.51), and both SI and CKD stage 3-4 with a 62% higher risk (HR 1.62; 95% CI 1.45-1.82) of revised MACE. In patients with ASCVD without CKD, total healthcare costs were $18,002 PPPY with SI vs. $15,070 PPPY without SI. In patients with ASCVD with CKD stage 3-4, costs were $26,089 PPPY with SI vs. $20,753 PPPY without SI. Across groups, SI was associated with higher HCRU. CONCLUSIONS: SI is associated with increased risk of MACE and higher total healthcare costs and HCRU in patients with ASCVD with or without CKD.

Recent awareness that metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition in individuals with type 2 diabetes and carries a significant risk of cirrhosis and extrahepatic disease has called for an examination of its relationship with diabetes-related complications. MASLD, especially at-risk steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH]) with significant fibrosis ≥F2, shares many metabolic abnormalities with type 2 diabetes, including insulin resistance, gluco- and lipotoxicity, chronic subclinical inflammation and mitochondrial impairment. In addition, many cross-sectional and longitudinal observational studies suggest an association between MASLD and micro- and macrovascular complications of type 1 and type 2 diabetes. However, a causal pathogenic relationship has been difficult to confirm given the overlap of cardiometabolic risk factors (CMRFs) in MASLD and type 2 diabetes. Complicating matters further, most of the available evidence has significant limitations. These include shortcomings in participant selection, heterogeneity in study design, use of diagnostic tools with low sensitivity for liver disease and diabetes-related complications, inadequate control for alcohol consumption or CMRFs, and lack of repeat measurements during longitudinal studies. Nevertheless, current evidence suggests that MASLD is a 'risk enhancer' for both micro- and macrovascular disease in diabetes, rather than an independent risk factor. Here, we review the underlying mechanistic pathways and clinical evidence that appear to link both conditions and identify knowledge gaps in need of future research. Until more robust evidence emerges, we hope that a greater awareness about the link between MASLD and diabetes-related micro- and macrovascular complications will prompt clinicians to educate their patients and peers on the potentially heightened health risks of MASLD and encourage clinicians to take a more proactive approach to risk stratification and intervention.

BACKGROUND: The global pandemic of paediatric obesity, unhealthy diets and physical inactivity are important future health challenges. The purpose of this study was to determine 4-year changes in food selection, cardiorespiratory fitness (CRF), and the longitudinal association with the development of adiposity among South African primary school-age children. METHODS: School children aged 5-9 years old in 2017 (n = 950) were followed up for four years. Parents indicated selection from healthy and unhealthy food groups in a validated questionnaire. Weight and height of the children were measured, and WHO BMI z-score (BAZ) was calculated. CRF was determined by the 20 m shuttle run test (20-m SRT). Changes in food selection frequency, CRF and BAZ were assessed. The association between frequency of food group selection, age, household income and CRF with 4-year change in BAZ was determined using mixed linear models. RESULTS: BAZ (p < 0.001) and age-adjusted performance in the 20-m SRT of boys (p = 0.04) increased at follow-up. The frequency of sugar-sweetened beverages (p < 0.001) and milk intake (p < 0.02) decreased, while the intake from fast-foods increased (p = 0.001). Daily intakes of vegetables and milk were associated with decreases in BAZ. A trend of a positive association was found between frequency of SSB intake and BAZ. CRF showed a strong negative association with BAZ over time (p < 0.001). CONCLUSIONS: Higher daily vegetable and milk intakes, as well as higher levels of CRF were protective against increasing adiposity among school-age children. The promotion of healthy eating and measures to improve CRF among school children are important priorities.

UNLABELLED: Obesity is a chronic relapsing disease leading to weight-related health risks for disorders such as cardiovascular diseases, type 2 diabetes, osteoarthritis, and depression. Many studies focus on these weight-related health risks. However, research on current self-reported social impacts and health complaints is limited. This study aims to investigate self-reported social impact and health complaints, received care aiming at lifestyle change, and perceived effectiveness of this care, by children with obesity and their parents. Secondarily, differences concerning sex, age, obesity-severity and frequency of received care were studied. Questionnaires were collected from children and adolescents aged 0-18 years visiting Obesity Center CGG. Data were analyzed regarding their social impacts, health complaints, received care, and perceived care effectiveness (0-10 scale). Children were categorized into sex, age, BMI, and care categories. Descriptive statistics were performed using chi-square tests and post hoc analyses to examine differences between categories. 86.8% of the patients self-reported experiencing social impact and 92.3% reported health complaints. Most frequently reported social impacts were difficulty to find fitting clothes (70.1%), problems in mobility and sports (63.7%), and bullying (41.6%); most reported health complaints were abdominal pain (38.8%), headache (34.8%), and musculoskeletal pain (34.1%). The dietician (64.1%) was most frequently reported as received care, and effectiveness scores ranged between 0 and 4 out of 10. CONCLUSIONS:  A substantial percentage of patients experience social impacts and health complaints affecting their well-being and quality of life. Low perceived effectiveness of interventions calls for a more innovative and comprehensive care framework incorporating these children's needs. WHAT IS KNOWN: • Children with overweight and obesity face a wide range of adverse health consequences and social challenges. • However, the number and types of health issues experienced by children themselves and studying per range of age, BMI-stage or care trajectory have not been systematically investigated. WHAT IS NEW: • A high percentage of children experience social impacts (87%) and health complaints (70%) aff ecting their well-being and quality of life, and perceived eff ectiveness of lifestyle interventions is low. The main reported healthcomplaints abdominal pain, headache, musculoskeletal pain and snoring loudly were mostly observed in girls withobesity aged 12-18 years, who received three or more care types. • The study demonstrated that perceived treatment effectiveness by children and parents declined with increasingobesity severity.

OBJECTIVE: We compared the predictive performance of SLECRISK, an SLE-specific 10-year CVD risk model, to the new PREVENT (Predicting Risk of cardiovascular disease EVENT) model in our SLE cohort. METHODS: Adult SLE patients meeting ACR 1997 and/or EULAR criteria were included. PREVENT and SLECRISK models were used to predict 10-year risk of myocardial infarction, stroke, or cardiac death. Discrimination and model performance were compared. RESULTS: Among 1,243 patients, SLECRISK and PREVENT yielded similar discrimination (AUC 0.74 vs. 0.76; p = 0.64). Using a 7.5% threshold for predicted 10-year MACE risk, SLECRISK demonstrated higher sensitivity (0.74 vs. 0.29), identifying more patients who subsequently developed MACE. 581 patients (46.7%) were classified as moderate/high risk by either model: 490 by SLECRISK only and 91 by PREVENT only or by both PREVENT and SLECRISK. Patients classified by SLECRISK alone were younger (mean 42.5 vs. 57.2 years, p < 0.001) and had lower systolic BP (122.0 vs. 145.0 mmHg, p < 0.001) and creatinine (0.91 vs. 2.63 mg/dL, p < 0.001), while showing higher prevalence of anti-dsDNA (85.7% vs. 73.6%) and anti-RNP (56.1% vs. 28.6%). CONCLUSION: Although overall discrimination was similar, SLECRISK demonstrated better agreement between predicted and observed cardiovascular events and higher sensitivity for identifying patients who developed MACE. In SLE, where younger patients may develop cardiovascular events without many traditional risk factors, failure to identify at-risk individuals may carry greater clinical consequences than overestimating risk. These findings suggest a role for SLECRISK as a diseasespecific tool for cardiovascular risk stratification in SLE.