Metabolism

Polycystic ovary syndrome (PCOS) is linked to adverse pregnancy outcomes and increased cardiometabolic risk in offspring, yet the placental mechanisms underlying these risks remain poorly understood. Metformin is prescribed during PCOS pregnancies despite limited mechanistic justification. Using multi-modal molecular analyses of placentas from healthy controls and women with PCOS randomized to placebo or metformin (PregMet trial), restricted to uncomplicated pregnancies, we characterized direct PCOS associated placental alterations independent of confounding complications. PCOS placentas showed transcriptional downregulation across multiple cell types and shifts in cell type proportions. Specifically, syncytiotrophoblasts exhibited reduced expression activity of growth hormone receptor signaling and glycosaminoglycan biosynthesis. Endothelial cells displayed diminished receptor tyrosine kinase pathway activity, including VEGFC, despite increased cell proportion and hypervascularity. Intercellular communication networks were globally suppressed, including reductions in PDGF signaling from Hofbauer cells to fibroblasts. Notably, metformin did not reverse most PCOS-associated molecular alterations and induced transcriptional changes correlated to birth weight and childhood BMI. These findings indicate that PCOS-associated placental features are driven by cell type specific dysregulation of growth factor, angiogenic signaling pathways that are largely unresponsive to metformin. This underscores the need to develop mechanism based, placenta targeted therapeutic alternatives for future pregnancy management.

Importance: Despite the benefits of statin therapy in individuals with diabetes, fewer than 70% of adults with diabetes meet contemporary guidelines for statin therapy and reducing low-density lipoprotein cholesterol (LDL) to <100 mg/dL. Evidence describing delays in statin initiation after diabetes diagnosis and associated clinical outcomes may motivate process of care interventions to improve guideline recommended care in individuals newly diagnosed with type 2 diabetes mellitus (T2D). Objective: To examine the timing of statin initiation and achievement of LDL <100 mg/dL after diabetes diagnosis, and to determine the association of early LDL reduction among statin initiators with incident atherosclerotic cardiovascular disease (ASCVD). Design: Retrospective observational cohort study using data from 2005-2021 Setting: Veterans Affairs Health Care System (VA) Participants: Individuals with newly diagnosed T2D Exposure: Primary exposure was ASCVD risk based on ACC/AHA Pooled Cohort Equations; secondary exposure was LDL <100 mg/dL in the first year after T2D diagnosis among statin initiators Main Outcomes and Measures: Co-primary outcomes were initiation of statin therapy and achievement of LDL <100 mg/dL within 5 years of diabetes diagnosis; incident 5-year ASCVD was a secondary outcome. Results: Among 100,406 individuals with newly diagnosed T2D, 59,615 were prescribed statin therapy within five years (59.4%), and 44,783 (57.5%) of those with LDL above goal achieved LDL <100 mg/dL within 5 years. Relative to those at low (<7.5%) 10-year ASCVD risk, individuals at intermediate (7.5-20%) and high (>20%) risk were more likely to be initiated on a statin (intermediate: Hazard Ratio [HR] 1.14 [95% CI 1.11, 1.17]; high: HR 1.16 [95% CI 1.13, 1.19]) and to achieve LDL <100 mg/dL (intermediate: HR 1.23 [95% CI 1.19, 1.26]; high: HR 1.34 [95% CI 1.30, 1.38]). Among those prescribed a statin within one year of diabetes diagnosis, achieving LDL <100 mg/dL in the first year after diabetes diagnosis was associated with lower risk of 5-year incident ASCVD (HR 0.84 [95% CI 0.77, 0.92]). Conclusions and Relevance: Gaps in guideline-directed primary prevention of ASCVD arise early following initial diabetes diagnosis. Guideline recommended early LDL lowering among statin initiators was associated with improved clinical outcomes.

Background: Polygenic risk scores (PRS) for coronary artery disease (CAD) are associated with cardiovascular events, but the relationship between inherited risk and routinely reported coronary computed tomography angiography (CTA) findings has not been studied. Objectives: To evaluate associations between a genome-wide PRS for angiographic coronary disease burden and coronary CTA-derived measures of atherosclerotic severity in a real-world clinical cohort. Methods: We studied Penn Medicine BioBank participants with available genotypes and clinically obtained coronary CTA reports. A previously published PRS for angiographic CAD burden was calculated using pgsc_calc. CAD-RADS scores and coronary artery calcium (CAC) values were extracted from radiology reports using the large language model Llama 3.1 8B. Associations between PRS and CAD-RADS severity were evaluated using Bayesian cumulative ordinal logit regression, while associations with log-transformed CAC burden were assessed using Bayesian linear regression. Results: Among 630 participants, median age was 59 years (IQR 49 - 68), 53% were female, 62% were genetically similar to a European reference population, and 34% to an African reference population. LLM-extracted CAD-RADS and CAC values demonstrated near-perfect agreement with manual abstraction. Higher PRS was associated with greater coronary atherosclerotic burden on CTA. Each 1-standard deviation (SD) increase in PRS was associated with a 20% higher odds of belonging to a more severe CAD-RADS category (cumulative OR 1.20, 95% credible interval 1.06-1.44). Higher PRS was also associated with greater CAC burden ({beta} 0.38, 95% credible interval 0.15 - 0.61). Conclusions: Polygenic risk for angiographic coronary disease burden is reflected in clinically reported coronary CTA severity measures, including CAD-RADS and CAC. These findings demonstrate that inherited susceptibility to CAD manifests as greater anatomic atherosclerotic burden at the time of clinical presentation and support further investigation of genetic risk integration into imaging-based cardiovascular risk assessment.

Background: The specific 3D morphological substrates distinguishing the newly defined massive and torrential functional tricuspid regurgitation (FTR) phenotypes from standard severe disease remain under-characterized. Objectives: This study investigates the 3D geometric changes of the tricuspid valve (TV) apparatus across the spectrum of FTR, specifically focusing on the structural definition of massive and torrential grades. Methods: Three-dimensional (3D) transesophageal echocardiography (TEE) was performed in 322 patients with FTR secondary to left-sided heart disease. Patients were stratified into mild-moderate (n=166), severe (n=82), and massive-torrential (n=74) groups. TV geometry, including annular dimensions, leaflet tethering, and subvalvular apparatus, was quantified using 3D modeling software. Results: Patients with massive-torrential TR were characterized by advanced age, female predominance, and atrial fibrillation (75%). 3D analysis demonstrated that massive-torrential TR represents a distinct phenotype defined by extreme annular circularization (ellipticity index 1.0) and planar flattening (P < 0.001). Furthermore, these patients exhibited a critical leaflet-annulus uncoupling, where compensatory leaflet growth (relative length < 80%) failed to match the massive annular dilation. Consequently, the regurgitant orifice in massive-torrential grades appeared highly complex, frequently manifesting as multiple irregular orifices. Conclusions: Massive and torrential FTR are characterized by a unique geometric profile involving extreme annular circularization, severe leaflet tethering, and leaflet-annulus uncoupling. These morphological insights suggest that conventional repair strategies may be insufficient for these advanced phenotypes, highlighting the necessity for pre-procedural 3D TEE to guide device selection.

Background Lifestyle interventions can increase the probability of remission of prediabetes to normal glucose tolerance, but their economic value remains unclear. We assessed the within-trial and lifetime-horizon modeled cost-effectiveness of intensive and conventional lifestyle interventions in risk-stratified participants with prediabetes. Methods A health economic evaluation was conducted alongside the 12-month multicenter PLIS trial (n=1,105). High-risk participants were randomized to intensive (HR-INT) or conventional (HR-CONV); low-risk participants to conventional lifestyle intervention (LR-CONV) or control (only short single consultation; LR-CTRL) with risk stratification based on insulin secretion, insulin sensitivity, and liver fat content. Within-trial analyses estimated incremental costs per additional remission to normoglycemia and per quality-adjusted life year (QALY). Lifetime cost-effectiveness was modelled using a four-state Markov Model. Findings At 12 months, HR-INT and LR-CONV increased remission compared with their respective comparators. The incremental cost per additional remission was {euro}7,081 (95% CI: dominated-47,277) for HR-INT and {euro}4,278 (1,312-11,793) for LR-CONV from a health insurance perspective. A willingness-to-pay of {euro}22,000 (HR-INT) and {euro}7,500 (LR-CONV) per additional remission corresponded to 90% probability of cost-effectiveness. Neither intervention was cost-effective in terms of QALYs gained within the 12-months period. Lifetime modelling suggested that both HR-INT and LR-CONV are not only cost-effective, but also cost-saving, relative to HR-CONV and LR-CTRL, respectively. Also in the probabilistic sensitivity analysis, most simulations indicated dominance (71.7% for HR and 88% for LR). Interpretation Based on short-term economic evaluation, the interventions assessed were cost-effective regarding additional participants with remission, not for incremental QALYs gained. Lifetime modelling suggests cost savings for both risk groups. Targeting populations with lifestyle interventions to achieve prediabetes remission seems to generate good value for money in the long term.

Background: Three-dimensional visualization and quantitative analysis of cerebral arteries on 3DRA are central to endovascular treatment planning, device selection, and cerebrovascular research. Manual segmentation is time-consuming and operator-dependent, yet no open-source deep learning model has been prospectively validated for this task on 3DRA. Methods: A nnUNet v2 model was trained for binary cerebral artery segmentation on 400 consecutive 3DRA acquisitions from three angiographic systems, comparing four configurations across architectures and loss functions. The best-performing configurations were prospectively validated on 40 patients using a dual approach: quantitative metrics (DSC, clDice, HD95, ASD, Precision, Recall), and blinded expert qualitative evaluation by two interventional neuroradiologists assessing 12 arterial segments, a global quality score, and clinical usability across 40 test cases. Results: The ensemble model achieved median DSC 0.917, clDice 0.932, and HD95 1.494 mm. Global quality scores were significantly lower for nnUNet v2 than for expert segmentations (median 4 vs 5, p<0.001), but nnUNet v2 segmentations were rated clinically usable in 88-90% of cases versus 95-98% for expert segmentations, without significant difference on the binary usability criterion. A consistent proximal-to-distal quality gradient was identified, with comparable scores at proximal arteries and the largest differences at distal arterial segments. Conclusion: nnUNet v2 with topology-aware training provides clinically usable cerebral artery segmentations on 3DRA, prospectively validated through both quantitative metrics and structured expert qualitative assessment, and represents a reproducible open-source foundation for endovascular and research applications.

Aims/Hypothesis: Behavioral and phenotypic characteristics do not fully explain variability in African Americans with youth-onset type 2 diabetes (Y-T2D) treated with metformin with or without liraglutide. We hypothesized that biological heterogeneity, including genetic variation in the metformin transporter OCT1, influences metformin pharmacokinetics and hepatic glucose flux. Therefore, we sought to characterize metformin pharmacokinetics in Y-T2D and evaluate genetic variants known to modulate metformin efficacy in adults to determine the mechanisms underlying variation in treatment response. Methods: We evaluated genetic variants related to metformin transport and mechanisms of action in 30 Y-T2D using a candidate-gene approach to evaluate the association of pharmacogenetic variants with fasting glucose and gluconeogenesis. In a subset of Y-T2D randomized to 3 months of metformin (n=11) or metformin and liraglutide (n=8), we constructed a metformin population pharmacokinetic model and evaluated gene variant associations. Results: A one-compartment first-order absorption and elimination pharmacokinetic model provided the optimal fit. Metformin pharmacokinetic parameters were similar by group and not related to glycemia. The rs628031_OCT1 A allele was associated with greater metformin clearance. The rs622342_OCT1 C allele was associated with lower post-treatment fractional gluconeogenesis ({beta} [95% CI] = -8.8 [-14.13, -3.47] %, Adjusted R2 = 0.56, P = 0.003). The rs7903146_TCF7L2 T allele was associated with greater reductions in fasting glucose among those treated with metformin + liraglutide ({beta} = -1.32 [-2.42, -0.22] mmol/L, Adjusted R2 = 0.8, P<0.002), but baseline glucose and gluconeogenesis (P<0.0001) were the strongest predictors of post-treatment glycemia. Conclusion/interpretation: In Y-T2D, OCT1 gene variants rs628031 and rs622342 were associated with metformin clearance and gluconeogenesis, respectively. TCF7L2 variant rs7903146 may contribute to differences in glycemic response in youth treated with metformin and liraglutide. These findings suggest genetic variants may be important for understanding variable metformin response in Y-T2D.

Background. Infectious mononucleosis (IM) with hepatitis is associated with suppression of high-density lipoprotein cholesterol (HDL-C), but the magnitude, specificity, recovery kinetics, and long-term cardiovascular implications of this finding have not been systematically characterised. Methods. Using the TriNetX Global Collaborative Network (<190 million patients, 178 healthcare organisations), we conducted a retrospective real-world evidence study in 1,944 adults with IM and hepatitis. We compared HDL-C distributions at presentation across 14 propensity-score-matched (PSM) comparator cohorts spanning other infectious, metabolic, and immune-mediated conditions. Gaussian mixture modelling characterised the HDL distribution. Longitudinal HDL trajectory was assessed across six post-index time windows, with the number of patients contributing a measurement ranging from 318 (16-30 days) to 2,849 (1-3 years) per window. Long-term major adverse cardiovascular events (MACE) were analysed in PSM cohorts of IM patients with very low HDL ([&le;]20 mg/dL, n = 979 per arm after PSM) versus those without low HDL, over up to 20 years of follow-up, with COVID-19 (n = 83,888 per arm) and pharyngitis (n = 10,618 per arm) as comparators. Results. At presentation, mean HDL in IM hepatitis was 36.7 +/- 22.6 mg/dL (median 33 mg/dL), ~14-17 mg/dL lower compared to pre-illness values. Nearly one quarter (23.9%) had HDL [&le;]20 mg/dL and 43.9% had HDL [&le;]30 mg/dL. HDL suppression was equivalent to CMV hepatitis but substantially greater than pharyngitis and IM without hepatitis, supporting a hepatitis-driven mechanism. Gaussian mixture modelling identified a discrete suppressed subpopulation (mean 16 mg/dL, 41% of patients) absent in non-hepatitis controls. Recovery was rapid in most patients (mean HDL 50.0 mg/dL by 16-30 days) but prolonged among the severely suppressed ([&le;]20 mg/dL), who required 3-6 months to approach baseline. In PSM MACE analyses, IM patients with very low acute HDL had significantly higher long-term event rates for all outcomes (HR 1.92-2.47 versus IM without low HDL), a pattern mirrored in the COVID-19 cohort (HR 2.04-2.70) and, with attenuated effect size, in pharyngitis (HR 1.43-1.69). Conclusions. Very low HDL-C is a prevalent, hepatitis-driven finding in IM affecting approximately one quarter of patients. It identifies a subgroup at elevated long-term cardiovascular risk comparable to that observed after COVID-19. These findings warrant prospective evaluation of cardiovascular follow-up strategies for affected patients.

Background and Aims: Steatotic liver disease (SLD) has high clinical and public health relevance. Robust population estimates of SLD and its subcategories are challenging due to the limitations of ultrasound measurements or non-invasive scores, particularly for low-grade steatosis. We aimed to quantify SLD prevalence using magnetic resonance imaging (MRI) in the population-based German National Cohort (NAKO). Methods: Hepatic multi-echo Dixon MRI was performed at 5 dedicated study sites with identical setup across Germany. Liver fat (proton density fat fraction, PDFF), R2* as proxy for liver iron, and liver volume were assessed. The resulting data of N = 29'842 individuals (age range 20-72 years) were weighted by survey weights for regional representativeness, resulting in a sample of 50% women and a mean age of 45.6 years. SLD was defined as PDFF [&ge;] 5.75%, and sex-specific prevalence according to age, BMI, socioeconomic status and geographic region was calculated. Results: Overall, SLD prevalence was 21.3% in women and 35.7% in men, and the majority were metabolic dysfunction-associated (MASLD, 89.3% of all SLD cases). Prevalence increased with age in a sex-specific pattern, suggesting potential menopausal effects in women. There was a relevant prevalence of SLD in individuals with normal weight (5.3% in women, 13.2% in men) and the age group <25 years (7.5% in women, 11.9% in women). Differences in prevalence between low and high socioeconomic status were more pronounced in women (37% vs 15.8%) compared to men (45.5% vs 30.3%). Conclusions: Data underscore the high public health relevance of SLD and its subcategory MASLD. The considerable prevalence in groups historically considered low-risk, such as younger or lean individuals, emphasizes the need for raising awareness early.

Background: Black adults bear a disproportionate burden of cardiometabolic dysfunction, yet most dietary trial evidence comes from predominantly White cohorts. Objective: To evaluate whether a personalized whole-food dietary intervention improves cardiometabolic outcomes more in Black than White young adults with overweight or obesity. Methods: In this 8-week randomized, controlled trial (ClinicalTrials.gov: NCT04635917), 112 Black and White adults (18-35 years; BMI 25-45 kg/m2) were block-randomized by race to a personalized dietary intervention providing whole foods (PD, n=57) or conventional dietary counseling at baseline (BL) using MyPlate guidelines (CD, n=55). Primary outcomes were Matsuda Index and fasting and OGTT-derived glucose, insulin, and non-esterified fatty acids. Other glucoregulatory, cardiovascular, anthropometric, appetite, and cognitive outcomes were also assessed. Outcomes were analyzed using baseline-adjusted linear models with sensitivity analyses adjusting for baseline BMI and food security score. Results: Compliance with study food consumption was 85-91%. Diet quality was higher in PD than CD (P < 0.05), with larger gains in vegetable-related outcomes among Black participants (group x race, P < 0.05). HOMA-{beta} was lower in PD than CD overall (P < 0.05). In sensitivity analyses, Black PD participants had greater fasting insulin reductions than White, especially in the latter half of intervention (week x group x race, P < 0.05), with a similar tendency for HOMA-IR. Glucose AUC 0-30 min was higher in White than Black PD participants (group x race, P < 0.05). Concentration performance was higher in PD than CD overall (P < 0.05), with larger gains in processing speed and accuracy among Black than White participants (group x race, P < 0.05). No effects were observed for cardiovascular or appetite outcomes. Conclusions: The personalized whole-food intervention produced differential effects in fasting insulin and early-phase glucose handling, and greater benefits in attention, in Black compared with White young adults with overweight or obesity during weight maintenance.

Background: Comprehensive assessment of hypertension-mediated organ damage (HMOD) across multiple organ systems remains limited in sub-Saharan Africa. We aimed to determine the prevalence and predictors of multidomain HMOD in a geographically diverse Ghanaian adult population. Methods: This secondary analysis of the Ghana Heart Study included 1,106 adults from four regions. Multidomain HMOD was defined as a pre-specified 9-domain TOD composite score ?2, based on the ESH/ESC 2018 guidelines framework. Logistic regression and ROC analysis were used to identify predictors and compare discriminative performance. Results: Mean age was 46.9 (17.2) years and 58% were female. Multidomain HMOD prevalence was 21.2% (235/1,106) and increased steeply with age: 8.6% (<45 years), 20.6% (45?59 years), and 44.4% (?60 years). Hypertension prevalence was 73% in the HMOD group versus 28% in those without HMOD (p < 0.001). The strongest independent associations were peripheral artery disease (OR 41.2), valvular burden (OR 14.4), and ECG-LVH (OR 9.0). baPWV showed superior discriminative performance (AUC 0.827, 95% CI 0.794?0.860) compared with the ASCVD Pooled Cohort Equations (AUC 0.466; ?AUC +0.351, DeLong test p < 0.001). Conclusions: One in five Ghanaian adults has hypertension-mediated organ damage in ?2 organ systems. baPWV is the strongest predictor and substantially improves risk stratification beyond conventional scores. These findings support the use of baPWV to guide hypertension management and HMOD assessment in West Africa.

Biological aging is heterogeneous across organ systems, yet whether CT-derived abdominal aging provides prognostic value beyond routine clinical data and whether organ decomposition adds beyond a unified estimate remains untested. We developed and evaluated organ-specific and ensemble biological age models from radiomic features across five abdominal organs in 68,675 CT scans from 32,883 subjects, evaluated on alignment with chronological age of healthy subjects (nested cross validation: MAE=3.68 years, R^2=0.90). In sequential analyses restricted to adults aged 20-60 years which is the stratum of strongest BAG-disease association, ensemble biological age gaps provided incremental prognostic value beyond demographic covariates for all-cause disease and mortality (Delta C-index=0.141, 0.051) and beyond routine blood biomarkers (Delta C-index=0.048), confirming CT-derived aging captures structural information beyond laboratory markers. Organ-specific biological age added incremental prognostic value beyond ensemble selectively for focal diseases: cardiovascular (aorta, Delta C-index=0.091) and hepato-pancreatic (pancreas, Delta C-index=0.096). These findings establish a hierarchical organization of CT-derived biological aging, positioning routine CT as a source that adds prognostic value to existing clinical biomarkers.

Background: People with ischemic heart disease (IHD) remain at high risk of recurrent major cardiovascular events despite contemporary therapy. Over two decades, a translational research program has evaluated pressure pain sensitivity (PPS) as a non-invasive marker of central autonomic dysfunction and a mutual risk phenotype in IHD and type 2 diabetes. A PPS-guided non-pharmacological intervention has been shown to substantially reduce five-year all-cause mortality in IHD. Methods: In a randomized controlled trial, 213 adults with stable IHD and elevated PPS, suggesting ANSD, were allocated to PPS-guided intervention (n=106) or control (n=107). The active group received three months of structured education (daily PPS self-measurement, cutaneous sensory nerve stimulation, supportive mental and physical exercises, telemedical feedback) followed by self-directed continuation. Controls received a booklet on general stress-management. The primary endpoint for this prespecified secondary analysis was a composite of eight major cardiovascular events. Results: Over 5 years, at least one major adverse cardiovascular event occurred in 19.8% of the PPS-guided group versus 43.8% of controls (odds ratio 0.32, 95% CI 0.17-0.62, P=0.0003). Incidence rates were directionally in favor of active intervention across all event categories (P=0.004). Conclusions: A brief PPS-guided non-pharmacological intervention, followed by self-directed continuation, was associated with a marked long-term reduction in major adverse cardiovascular events, complementing previously reported large reductions in all-cause mortality in the same cohort. Within the context of a multi-decade PPS research program, these findings support PPS-guided care as a low-resource autonomic intervention ready for pragmatic scale-up testing as an adjunct to cardiometabolic care.

Objectives: Diabetes affects over 500 million people globally and glycemia is inadequately managed. Metformin is the most frequently prescribed initial treatment for type 2 diabetes globally, yet glycemic response trajectories to metformin in routine real-world care and predictors of treatment response have not been well described. We aimed to identify glycemic response trajectories in adults prescribed metformin monotherapy as initial type 2 diabetes treatment and predictors of poor glycemic response to metformin. Design: Observational cohort study using latent class mixed models to identify hemoglobin A1c (HbA1c) trajectory classes, followed by random forests machine learning to predict trajectory class membership. Setting: US Veterans Affairs Healthcare System Participants: Adults treated with metformin alone for >30 days after diabetes diagnosis with a minimum of two HbA1c measurements from 90 days prior to two years after the first metformin prescription (N=140,413). Exposures: Demographic, laboratory, vital sign, and comorbidity data were included as predictors of metformin response trajectory Main Outcomes and Measures: We included all HbA1c measurements (487,604 total) for two years after metformin initiation to define metformin glycemic response trajectories. Results: We identified three HbA1c trajectories: stably low (89.7% of sample, mean HbA1c decrease from 7.2% to 6.6%), brisk response (7.1% of sample, mean HbA1c decrease from 11.4% to 7.0%), and non-response (3.1% of sample, mean HbA1c increase from 8.9% to 10.8%). Of those in the stably low and brisk response classes at 2 years, 91% maintained HbA1c at approximately 7% on metformin alone for 5 years after drug initiation. Prediction models could accurately predict brisk response (91% accuracy) but not metformin non-response (59% accuracy). Conclusions: Most individuals treated initially with metformin monotherapy have a beneficial and durable glycemic response. Predicting individuals who will not respond to metformin may be challenging but is evident within six months with recommended glycemic surveillance. The findings support current guidelines for HbA1c surveillance when initiating diabetes treatment.

Background: Prostate-specific membrane antigen (PSMA) PET/CT is central to prostate cancer staging and theranostic workflows. To our knowledge, no direct within-patient comparison of [18F]FC303 ([18F]Florastamin) and [68Ga]Ga-PSMA-11 has been reported. We performed a preliminary paired method-comparison study under non-harmonized acquisition protocols. Patients and Methods: Twenty patients with histologically confirmed prostate cancer underwent [68Ga]Ga-PSMA-11 PET/CT (185 +/- 37 MBq, 60 +/- 10 min) followed by [18F]FC303 PET/CT (370 +/- 37 MBq, 105 +/- 15 min) on the same PET/CT system within each patient (median interval, 29.5 days). Index targets were anatomically matched to the biopsied or surgically sampled lesion or target region. The primary malignant set included 18 histologically malignant targets; two histology-negative or indeterminate targets were included only in sensitivity analysis. Fixed [68Ga]Ga-PSMA-11-first scan order and the 45-min uptake-time difference were central interpretive constraints. Results: Across five predefined reference organs, [18F]FC303 showed lower SUVmean than [68Ga]Ga-PSMA-11 (all Benjamini-Hochberg-adjusted p < 0.001; [68Ga]/[18F]FC303 geometric mean ratio [GMR], 1.29-3.89). In the primary malignant set, [18F]FC303 lesion SUVmax was lower than [68Ga]Ga-PSMA-11 (median, 11.3 vs 18.1; paired median difference, -5.50; 95% CI, -6.85 to -2.90; Wilcoxon p = 8.4 x 10-4), with strong rank correlation (Spearman {rho} = 0.90). Passing-Bablok regression yielded {beta} = 1.13 (95% CI, 1.04-1.45), and log-Bland-Altman GMR (FC303/[68Ga]) was 0.75, consistent with proportional non-interchangeability. Tumor-to-liver and tumor-to-mediastinum ratios did not differ significantly (GMR, 1.17 [95% CI, 0.94-1.45] and 0.96 [0.80-1.15], respectively); the study was not powered for equivalence. The n = 20 sensitivity analysis showed consistent directionality. Conclusions: Under non-harmonized acquisition conditions, [18F]FC303 showed lower physiologic reference-organ SUVmean and malignant target-region SUVmax than [68Ga]Ga-PSMA-11, whereas tumor-to-liver and tumor-to-mediastinum ratios were not significantly different. Absolute SUVs were not interchangeable; [68Ga]Ga-PSMA-11-derived SUV thresholds should not be directly transferred to [18F]FC303 without tracer-specific calibration.

1. Background: With the rising prevalence of hypertension, especially among younger populations, there is a critical need to better assess health status and predict associated complications. This study developed a biological age model ("hypertension age") for hypertensive patients to predict the risk and timing of major complications. 2. Methods: Using South Korea's NHIS-NHID data, researchers analyzed 4,535,041 hypertensive patients who underwent health examinations between 2009 and 2010. Patients were followed for an average of 12.40 years (until 2022). Principal Component Analysis (PCA) was used to develop the biological age (cBA) model. The risk and onset timing of complications were analyzed using Cox proportional hazards and multiple regression models, adjusting for variables like medication use and baseline diseases. 3. Results: A 1-standard deviation (SD) increase in the age gap?where biological age exceeds chronological age (cBA - CA)?was significantly associated with an elevated risk for all major complications in both sexes (p < 0.001). Furthermore, a 1-SD increase in this gap significantly accelerated the time to complication onset for nearly all conditions (p < 0.001), with the exception of dementia in women. The impacts of medication use, hypertension duration, and baseline comorbidities varied by specific complication. 4. Conclusions: Lowering "hypertension age" relative to chronological age can significantly reduce the risk and delay the onset of major cardiovascular and related complications. Quantifying this biological age gap serves as a powerful motivational tool for personalized health management and complication prevention in hypertensive patients.

We present the TopBrain 2025 Challenge, the first benchmark for fine-grained multiclass segmentation of the whole brain vasculature in both computed tomography angiography (CTA) and magnetic resonance angiography (MRA). Building on the TopCoW challenge, TopBrain scales vessel annotation from the Circle of Willis to the entire brain, introducing a dataset of 90 annotated volumes across 48 landmark vessel classes spanning arterial and venous systems, of which 50 training volumes are publicly released. Vessel definitions were consolidated from established neuroanatomical references into a unified annotation scheme, and vessel caliber measurements along the centerline are reported for the first time across the whole brain vascular anatomy. To address the unique challenges of multiclass brain vessel segmentation, we propose an evaluation framework that accounts for detection in segmentation performance, assesses anatomical plausibility, and introduces novel contamination metrics that characterize inter-class prediction errors. Fifteen teams from over 220 registered participants submitted algorithms to the benchmark. The top-performing teams built on nnUNet with principled system design choices, achieving around 80% Dice scores, near-zero invalid neighbor counts, over 60% F1 scores for side-road vessels, and below 18% foreground contamination ratio. Larger vessels are easier to segment, while smaller and more complex vessels remain the true bottleneck. The annotated datasets and podium-finish algorithms are made publicly available on Zenodo.

Background: Post-operative hypotension and vasoplegia are well recognised following cardiac surgery but remain poorly characterised after major non-cardiac surgery, despite associations with acute kidney injury (AKI), cardiovascular complications, and increased mortality. Dysregulation of the renin angiotensin aldosterone system (RAAS) may underpin haemodynamic instability in this setting, yet data in abdominal surgery are limited. Objectives: The POLECAT (Perioperative delta Renin) study aims to determine whether changes in circulating renin concentration (delta renin) from pre-operative baseline to the early post-operative period are associated with post-operative vasoplegia in patients undergoing major abdominal surgery requiring intensive care admission. Methods: POLECAT is a single-centre, prospective observational study conducted at a UK tertiary referral hospital. Adult patients undergoing planned or emergency abdominopelvic surgery with anticipated intensive care admission are enrolled. Blood samples are obtained pre-operatively, within four hours post-operatively, and on post-operative day one to measure renin and a panel of endothelial, renal, and immune biomarkers. The primary outcome is post-operative vasoplegia, defined as the requirement for a vasopressor infusion at 08:00 on post-operative day one. Secondary outcomes include alternative vasoplegia definitions, AKI (KDIGO criteria), vasopressor burden, organ dysfunction, cardiovascular complications, length of stay, and mortality. Multivariable regression, receiver operating characteristic analyses, and predefined subgroup analyses will be performed, with sensitivity analyses addressing missing data. Conclusions: This study will clarify the relationship between peri-operative RAAS dysfunction and vasoplegia following major abdominal surgery. Findings may support biomarker-guided risk stratification and inform future interventional trials targeting haemodynamic instability in this high-risk population.

Atherosclerosis is a systemic vascular process linked to cardiovascular, cognitive and renal outcomes. DNA methylation (DNAm)-based scores of atherosclerosis may capture cumulative biological processes underlying vascular aging. Here, we examined associations of DNAm scores for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque), derived from a large study of imaging-based subclinical atherosclerosis, with prevalent and incident outcomes in two population-based cohorts of older adults: the Health and Retirement Study (HRS; n = 3,875) and The Irish Longitudinal Study on Ageing (TILDA; n = 487). Higher DNAm scores were associated with adverse cardiometabolic profiles and socioeconomic indicators. In HRS, higher DNAm-CAC was associated with prevalent cardiovascular disease (odds ratio per SD, 1.16; 95% confidence interval (CI), 1.07-1.26), lower cognitive function ({beta} = -0.50, 95% CI -0.68 to -0.32) and lower estimated glomerular filtration rate (eGFR; -1.7 ml min-1 1.73 m-2, 95% CI -2.6 to -0.8) in unadjusted models. After adjustment for demographic and clinical risk factors, DNAm-CAC ({beta} = -0.29, 95% CI -0.46 to -0.13) and DNAm-cPlaque ({beta} = -0.24, 95% CI -0.42 to -0.06) remained associated with lower cognitive function, and DNAm-cPlaque was associated with incident cognitive impairment or dementia (hazard ratio per SD, 1.16; 95% CI, 1.01-1.32). Associations were attenuated after further adjustment for race/ethnicity and socioeconomic indicators. In TILDA, higher DNAm-cPlaque was associated with worse cognitive performance (incidence rate ratio, 1.11; 95% CI, 1.01-1.21), increased risk of incident cardiovascular disease (hazard ratio, 1.18; 95% CI, 1.00-1.42) and lower eGFR, with consistent associations observed for DNAm-CAC. These findings suggest that DNAm-based scores of atherosclerosis capture systemic vascular processes linked to multiple age-related outcomes across populations. Further work is needed to clarify the biological pathways reflected by these scores and their relation to cumulative and socially patterned vascular risk.

Introduction: Menstrual cycle phase has been proposed as a source of intra-individual variability in resting energy expenditure and the thermic effect of food in premenopausal females, yet studies examining the thermic effect of food across menstrual cycle phases report conflicting findings. Methods: This protocol describes a secondary analysis of prespecified outcomes from a non-randomized, two-period crossover trial primarily designed to assess postprandial plasma triglyceride concentrations across menstrual cycle phases (ClinicalTrials.gov: NCT07459465) in 12 premenopausal females aged 18-30 years, free of chronic disease and hormonal contraceptive use, recruited in Ottawa, Canada. Participants complete two experimental sessions: one in the early follicular phase and one in the mid-luteal phase, each involving consumption of a high-fat meal. Eleven secondary outcomes will be reported: fasting resting energy expenditure, thermic effect of food, respiratory exchange ratio, carbohydrate oxidation rate, lipid oxidation rate, desire to eat, hunger, fullness, prospective food consumption, serum beta-estradiol, and serum progesterone. Masked outcome analyses are performed using linear mixed-effects models. Results: Recruitment began on 26 March 2026; results will be reported in the Stage 2 manuscript. Discussion: Findings from this trial may help clarify whether menstrual cycle phase constitutes a meaningful source of intra-individual variability in energy metabolism, with implications for the design of metabolic research in premenopausal females.