Journal of Hypertension

Background: Elevated C-Reactive Protein (CRP), interleukin-6 (IL-6) and testosterone deficiency are associated with advanced age and chronic inflammatory diseases; while normal testosterone levels have been shown to decrease inflammation through several mechanisms. Cross-sectional studies have shown an inverse relationship between CRP, IL-6 and total testosterone (TT) levels, yet mixed findings have been reported when individual components of metabolic syndrome are considered. We evaluated the relationship between CRP, IL-6 and TT levels in men from 2004-2018 using the Baltimore Longitudinal Study of Aging to determine if low testosterone status is associated with a high inflammatory profile. Methods: Participants were selected from the Baltimore Longitudinal Study of Aging. Male participants with serum TT level measured during at least three visits were included in our cohort. Common measures of inflammatory disease such as CRP, High-Density Lipoprotein (HDL) and Triglyceride levels were collected via blood specimens. Comorbidity data were documented at each visit. Panel regression was used to analyze the relationship of a series of independent variables collected in pooled cross-sectional observations over time with a dependent variable for modeling. Results: A total of 347 patients were included in this study (median age = 70, IQR = 18, average follow up time = 6.7 +/- 3.2 years). Participants had a median CRP level of 1.0 mg/dL, median IL-6 level of 3.6, a median TT level of 446 ng/dL. On univariable analysis, increasing TT and HDL levels were associated with a decline in CRP, while high Body Mass Index (BMI), congestive heart failure (CHF), Diabetes, and increased serum triglycerides were associated with increased CRP. Age was not associated with CRP. On multivariable analysis, we found that increasing TT level was associated with a decline in CRP levels, independent of comorbidities (p = 0.018; Table 1). As expected, increased BMI was associated with a significant increase in CRP (p = 0.001, Table 1). Age, CHF, Diabetes, HDL, and Triglycerides were not significant predictors of CRP on multivariable analysis. Similarly, on multivariable analysis, increasing TT levels were independently associated with lower IL-6 levels. Higher HDL cholesterol levels were also associated with lower IL-6 levels, whereas increasing age was associated with higher IL-6 levels. BMI, CHF, diabetes, and triglycerides were not significant predictors of IL-6. Conclusions: Lower levels of serum total testosterone are associated with an increase in CRP in older men over time, independent of chronic inflammatory disease. Given the importance of CRP in pathogenesis of chronic disease, we highlight the potential benefits of using total testosterone as a biomarker of chronic inflammatory states.

Background: Familial hypercholesterolemia (FH) is a semi-dominant genetic disorder characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C) and a markedly increased risk of premature atherosclerotic cardiovascular disease (CVD). Despite this elevated risk, some individuals with FH survive beyond 70 years of age without developing clinical CVD. This study aimed to identify genetic variants associated with protection against cardiovascular events and to uncover mechanisms contributing to this resilience phenotype. Methods: Whole-exome sequencing (WES) was performed in 243 French-Canadian heterozygous FH individuals carrying the pathogenic LDLR c.259T>G (p.Trp87Gly) variant. After stratification by age and cardiovascular event (CVE) status, 35 individuals with premature CVE and 20 individuals aged [≥]70 years who remained free of CVE despite spending several decades in the pre-statin era were selected for comparative analysis. Results: Variant annotation and quality-control validation using Firth logistic regression identified 12 genetic variants potentially associated with cardiovascular resilience. Among these, a stop-gain variant resulting from the single-nucleotide polymorphism rs4985556 in IL34 demonstrated the strongest association with event-free survival (allele frequency in CVE- = 0.25 vs. CVE+ = 0.00; {chi}2 = 19.25; P = 1.15 x 10-5). The IL34 stop-gain variant (c.639C>A [p.Tyr213*]) was associated with a markedly increased likelihood of cardiovascular event-free survival (OR = 20.9; 95% CI, 2.7-2841.7; P = 3.45 x 10-4). Conclusion: These findings identify IL34 as a potential cardiovascular resilience gene and highlight novel genetic determinants that may protect against cardiovascular events despite lifelong exposure to elevated LDL-C levels. In addition to IL34, eleven variants showed strong associations with a CVE-free phenotype and warrant further investigation to elucidate their biological mechanisms and potential relevance for cardiovascular disease prevention.

Background: Black individuals have a lower incidence of atrial fibrillation (AF) than White individuals despite a higher burden of many traditional cardiovascular risk factors. Differences in left atrial (LA) structure and function by race could partly explain the observed pattern of AF risk. Methods: This analysis included 4,576 (978 Black and 3,598 White) participants from the Atherosclerosis Risk in Communities (ARIC) study, followed between 2011 and 2021. The association of selected echocardiographic measures of LA structure and function with AF incidence was evaluated with race-specific Cox proportional hazards models with adjustment for sociodemographic and clinical covariates. Additional analyses assessed whether LA measures attenuated the association between race and incident AF. Results: The analysis included 778 AF cases (113 in Black and 665 in White participants, mean age 75 years). Larger LA size and worse LA function were associated with higher AF risk in both Black and White individuals, with most associations of similar magnitude in both groups, except for a slightly stronger association of LA reservoir strain in Black than White participants (Black: hazard ratio (HR) 0.89, 95% CI 0.86-0.92 per 1% increase; White: HR 0.94, 95% CI 0.92-0.95, p for interaction = 0.01). In the overall sample, White participants showed higher AF risk compared to Black participants (HR 1.59, 95% CI 1.24-2.03). Adjustment for most individual LA measures did not attenuate the association between race and AF risk. Conclusion: Larger LA size and worse LA function were associated with incident AF in both Black and White ARIC participants. However, these measures did not explain the lower AF incidence observed among Black participants. LA remodeling appears to be an important predictor of AF risk, but it is not the primary explanation for the Black-White AF paradox.

_ SURPASS-HF: Safety and Utility of Remote Pulmonary Artery Sensor Shared-management in Heart Failure --Background-- Insulin-dependent diabetics self-titrate therapy to self-obtained glucose values as standard of care, yet heart failure (HF) patients with implanted pulmonary artery (PA) pressure sensors never see their own readings; clinicians interpret and execute every dose change - a model that does not scale to a ~200-patient HF panel. To our knowledge, SURPASS-HF is the first prospective feasibility study applying the insulin-titration paradigm to PA-pressure-guided HF care: patients executing a prescribed loop-diuretic sliding scale, supported by ARTHUR, a domain-trained large language model, with clinician confirmation of every adjustment. --Methods-- Non-randomized, prospective, single-arm, single-center 90-day feasibility study (January 14-April 14, 2026; 60.1 patient-months). Twenty-one adults with implanted PA sensors enrolled (intention-to-treat, ITT); 19 completed full follow-up (per-protocol, PP). Regimens and individual PA diastolic (PAD) targets were explicitly prescribed; when daily pressures met published serial-reading thresholds, the software prepared the pre-determined adjustment, the clinician confirmed it, and the patient executed it. ARTHUR reinforced dose ceilings, prompted surveillance labs, and escalated edge cases for review. Pre-specified outcomes: adverse events, escalations, time in optimal PA range (TIR-PAP, +/- 5 mmHg of goal), reading adherence, provider overrides, and paired delta_PAD (first vs last 7-day windows). Confidence intervals are descriptive; the study was not powered for significance. --Results-- Mean age was 69+/-11 years, 52% women, mean baseline PAD 14.8 mmHg. No pre-specified safety event (KDIGO >or=1 AKI, hyperkalemia, hyponatremia, symptomatic hypotension) was detected (0/8 post-adjustment draws in 5/21 patients; exact 95% CI 0-37%); laboratory ascertainment was sparse, so a meaningful harm rate cannot be excluded. Seventeen of 19 PP patients (89%) required no protocol-triggered escalation; 4 escalations occurred in 2 patients. TIR-PAP was 88.4% (ITT)/91.3% (PP); reading adherence 92.1%; 53 provider alerts (0.88/patient-month) all resolved (median 24 h) with no overrides. delta_PAD was -0.89 mmHg (ITT; 95% CI -2.60 to +0.82) in a cohort already at goal at baseline. Two non-cardiac hospitalizations occurred. --Conclusions-- LLM-mediated, clinician-confirmed patient execution of a published deterministic PA-pressure-guided diuretic algorithm was feasible over 90 days, with high time-in-range and adherence and no detected safety events. Findings from this prospective, single arm, non-randomized, small cohort are descriptive. The study was not designed or powered to demonstrate evidence of a treatment effect; a randomized, well powered prospective comparison study against provider-led PA-pressure management is the next ideal step.

Abstract Background: The influence of taurine on biological ageing remains unclear, particularly whether it acts as a causal driver or a functional biomarker. We aimed to disentangle the distinct roles of plasma taurine relative abundance, dietary taurine supply, and genetic metabolic capacity on all-cause mortality and unhealthy ageing. Methods: This prospective study used data from the Korean Genome and Epidemiology Study (2001~2022). A subcohort of 2,321 participants (mean age 56.5 years; 51.4% female) with complete metabolomic, dietary, and genomic data was analyzed. Three independent pathways were evaluated: (1) plasma taurine/total amino acid (AA) ratio, (2) dietary taurine to protein ratio, and (3) a weighted genetic risk score (GRS) from 21 SNPs in taurine biosynthesis and transport genes. Primary outcomes were all-cause mortality and unhealthy ageing (Physiological Healthy Ageing Index [PHAI] score [≤] 25th percentile). Results: A higher plasma taurine/total AA ratio was consistently associated with improved ageing outcomes. Participants in the highest quartile showed 29% lower all-cause mortality (Hazard Ratio [HR], 0.71; 95% Confidence Interval [CI], 0.52-0.98; P for trend = .04) and lower risk of PHAI-based unhealthy ageing (HR, 0.77; 95% CI, 0.59-1.00; P for trend = .04) versus the lowest quartile. Dietary taurine-to-protein ratio was not associated with mortality (P for trend = .70), nor was the GRS (P for trend = .74). Conclusions: The protective association of taurine was linked to its relative abundance within the systemic amino acid pool, rather than dietary intake or genetic predisposition, supporting taurine as a functional biomarker of metabolic efficiency rather than a deterministic causal driver of ageing.

Despite growing research linking ultra-processed food (UPF) consumption to risk of cardiovascular disease (CVD) and hypertension, no study has systematically evaluated the methodological rigor underlying these associations. We systematically searched major databases to identify eligible studies. Data were extracted for dietary assessment methods, UPF classification, covariate selection, confounding control, statistical modelling and effect estimates. Random-effects meta-analysis was conducted to pool effect estimates. Meta-regression and sensitivity analyses were performed to explore sources of heterogeneity. Substantial heterogeneity was observed in the application of the NOVA classification for categorising UPFs across the 46 eligible studies. Only two studies employed a directed acyclic graph to inform confounder selection; 43 used models with suboptimal adjustment, and 42 were overfitted due to adjustment for potential mediators. Pooled analyses indicated that higher consumption of UPFs was associated with a 9% higher risk of CVD and a 16% higher risk of hypertension, with stronger associations observed for coronary heart and cerebrovascular diseases. While higher UPF intake is consistently associated with increased risks of CVD and hypertension, methodological limitations may attenuate the observed associations. Strengthening methodological rigour through harmonised UPF classification and causal frameworks is essential to better elucidate the effect of UPF consumption on cardiometabolic health.

Relatively little is known regarding suicide among older adults in nursing homes. The aim of this study was to compare the incidence of suicide among older nursing home residents (NHR) with community-dwelling older people (CDP) using newly available, national, individual-level register data, and to assess differences with regard to socio-demographic characteristics. We obtained data on all older adults aged 65+ who were living in Austria at the end of October 2018 (n=1,665,450), including 155,020 NHR. Death by suicide was followed until the end of 2023. A total of 114 and 2,136 suicides were observed among NHR and CDP; corresponding to cumulative incidences of 14 and 27 per 100,000, respectively. Among NHR, suicide incidence was higher among males (28.0, 95% CI=22.1, 35.5), those aged 65-74 years (20.2, 95% CI=13.3, 30.6), with tertiary education (23.3, 95% CI=10.6, 50.6), divorced (25.0, 95% CI=16.2, 38.5), and residing in urban nursing homes (22.0, 95% CI=17.0, 28.4). Compared to CDP, more suicides in NHR occurred by poisoning and but few by firearms. In conclusion, we found that suicide incidence was lower among older NHR compared to CDP. More research on and preventive efforts against suicide among older NHR are needed.

Background: Outpatient chronic heart failure (HF) assessment relies on NYHA class and distance-based testing that can obscure physiological heterogeneity. Near-infrared spectroscopy (NIRS) enables tissue oxygenation phenotyping but is underexplored during standardized stressors in outpatient HF. We tested whether wearable NIRS-derived oxygenation kinetics during a vascular occlusion test (VOT) and six-minute walk test (6MWT) differ across NYHA classes. Methods: In this prospective, single-center pilot study, 44 chronic HF outpatients (mean age 70.9 {+/-} 8.7 years, 75% male; NYHA I [n=19], II [n=12], III [n=13]) were monitored with a novel wearable NIRS device (NIRSense Envello Core) during a VOT and 6MWT. Primary endpoints were the post-occlusion net area under the curve (net AUC; VOT) and post-walk recovery net AUC (modified 6MWT). Secondary endpoints included the exertional tissue oxygenation (Oxy) nadir, VOT reperfusion kinetics, gait metrics, and tolerability. Results: Despite NYHA I and II walking identical median distances (420 m), post-walk recovery net AUC was lower in NYHA II (-16.3 a.u.xs) and III (-12.8 a.u.xs) than NYHA I (46.1 a.u.xs, p=0.004). The exertional Oxy nadir did not differ (p=0.722), but NYHA III walked 27% and 38% slower than NYHA II and I (p<0.001). NYHA II had higher VOT net AUC (134.2 a.u.xs) than NYHA I (71.9; p=0.018) and III (61.1; p=0.011). Post-walk recovery net AUC correlated with gait velocity (rs=0.44) and distance (rs=0.39; both p<0.05). VOT net AUC did not correlate with functional metrics, but resting reperfusion kinetics correlated with 6MWT performance (rs=0.41-0.46, p<0.05). The sensor was well tolerated. Conclusions: Wearable NIRS-derived recovery kinetics differentiated NYHA I from NYHA II despite these classes walking identical median distances. Coupled with distinct resting VOT hyperemic differences, these preliminary findings indicate wearable NIRS may capture physiological heterogeneity in outpatient HF not reflected by NYHA class and standard functional metrics.

Background: The saphenous vein (SV) remains the most widely used graft in coronary artery bypass grafting (CABG). However, graft failure over the years has compromised long-term outcomes. Preservation of the vascular endothelium is fundamental for vein graft patency, and hydrogen sulfide (H2S) a protective gasotransmitter, plays a significant role in vascular homeostasis. This study evaluated how different intraoperative preservation solutions modulate H2S-synthesizing enzymes and endothelial integrity. Methods: SV segments from 20 CABG patients were subdivided into five groups: Control (immediate fixation), normal saline (NS; 0.9% NaCl), autologous heparinized arterial blood (AHB), histidine-tryptophan-ketoglutarate (HTK) solution, and a damage group (no solution for 30 minutes). Structural integrity was evaluated by measuring endothelial coverage using light microscopy, and the expression of eNOS, CD31, and H2S pathway enzymes (CSE, CBS, and 3-MPST) was assessed by immunofluorescence (IF) and confocal microscopy to determine mean fluorescence intensity (MFI). Results: LM analysis revealed that AHB (89.66% {+/-} 3.02) and HTK (88.72% {+/-} 3.07) preserved endothelial coverage significantly better than NS (78.06% {+/-} 4.48) and the Damage Group (76.82% {+/-} 4.90; p < 0.001). In IF, all interventions reduced eNOS and CD31 expression compared to the control, but AHB and HTK maintained significantly higher levels than NS (p < 0.001). All three H2S-producing enzymes were detected in the GSV endothelium, with CSE being the most expressed isoform. The use of NS caused a marked depletion of these enzymes, while AHB and HTK showed specific superiority in preserving H2S synthesizing enzymes. Conclusions: The choice of preservation solution significantly affects endothelial integrity and the modulation of enzymatic H2S synthesis. NS proved to be deleterious to the endothelium, whereas AHB and HTK better preserved vascular structure and function, suggesting their clinical superiority for the preparation of venous grafts during CABG.

In 2022, Austria legalised physician-assisted suicide (PAS). Among 1,847,919 older adults, there were 92 PAS and 977 unassisted suicides (UAS) in 2022-2023. Compared to the general population, older adults who died by either PAS or UAS, were older and more likely to live alone. Compared with UAS, older adults who died by PAS were more likely to be female, higher-educated, live in urban areas, and diagnosed with cancer, or diseases of the nervous system, and less likely diagnosed with mental/ behavioural disorders. PAS and UAS among older adults in Austria showed different sociodemographic and comorbidity characteristics.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods: We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results: Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti-volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions: The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting.

Introduction: Multimorbidity clusters have been associated with increased dementia risk. While lifestyle factors may modify dementia risk, their role in multimorbidity clusters remains unclear. Method: Data from UK Biobank was used to identify clusters of chronic conditions using latent class analysis, assess their associations with dementia risk using Cox regression, and potential moderating effects of lifestyle factors. Results: We included 465,175 participants (mean age (SD) = 56.52 (8.01), 53.87 % female). Five clusters were identified and significantly associated with increased dementia risk, with the cardiometabolic (HR = 2.14, p < 0.001) and mental health cluster (HR =1.99, p < 0.001) exhibiting the highest risk. Only moderate physical activity lowered dementia risk in the pain-dominated multimorbidity cluster (HR = 0.77, p = 0.039). Discussion: Lifestyle factors including physical activity may protect against dementia in specific multimorbidity clusters. Future research involving objective and multiple lifestyle measures is needed.

Background Carotid plaque calcification is commonly interpreted as a marker of atherosclerotic burden, but its prognostic meaning may depend on calcification morphology. Whether histologically defined calcification subtypes in carotid plaques identify systemic cardiovascular disease and long-term cardiac risk remains unclear. Methods We studied 479 patients, including 154 women, undergoing carotid endarterectomy in the Helsinki Carotid Endarterectomy Study 2 with 10-year follow-up. Hematoxylin-eosin-stained plaque sections were digitized, and artificial intelligence-based image analysis was used to quantify sheet, nodular, and total calcification as proportions of plaque tissue area. The primary endpoint was cardiac death; secondary endpoints were major coronary events and major adverse limb events (MALE). Associations between calcification tertiles and outcomes were assessed using Fine-Gray regression models adjusted for conventional cardiovascular risk factors, with prespecified sex-stratified analyses. Results Total calcification was associated with baseline coronary artery disease and chronic heart failure but did not predict cardiac mortality. In contrast, nodular calcification was independently associated with cardiac death. Compared with the lowest tertile, the middle and highest tertiles of nodular calcification were associated with increased cardiac mortality in the whole cohort (subdistribution hazard ratio [sHR], 2.87 [95% CI, 1.39-5.91] and 2.55 [95% CI, 1.24-5.27], respectively). Nodular calcification was also associated with baseline peripheral artery disease. High sheet calcification was associated with cardiac death in men (sHR, 2.3 [95% CI, 1.0-5.1]) but not in women. Exploratory sex-stratified analyses suggested that high total calcification was associated with major coronary events and MALE in women, but not in men. Conclusions Carotid plaque calcification morphology, rather than total calcification burden alone, is associated with long-term cardiac mortality after carotid endarterectomy. Nodular calcification emerged as the strongest prognostic phenotype, while exploratory sex-stratified findings suggest that total calcification may reflect coronary and peripheral event risk in women.

Abstract Introduction Chronic kidney disease (CKD) in adult patients with type 2 diabetus mellitus (T2DM) is a serious public health challenge and continues to be a major source of morbidity and mortality in Sub-Saharan Africa (SSA). The burden of CKD among T2DM patients in SSA has been documented in several studies, but the results remain heterogeneous, and there is limited comprehensive data on its overall prevalence and factors associated with the diseases. Therefore, this study aimed to estimate the pooled prevalence of CKD and assess its associated factors among adult patients with T2DM in SSA. Methods This systematic review and meta-analysis was conducted and reported according to PRISMA 2020 guidelines, and the study protocol was registered in PROSPERO (CRD420261411707). A comprehensive search of relevant studies was conducted from PubMed, Google Scholar, Scopus, Cochrane Library, and EMBASE published between January 2000 and December 2025 in SSA. Data were analyzed using Stata version 17. A random-effects model was used to estimate the pooled prevalence of CKD among adults with T2DM patients. Heterogeneity was assessed using Cochranes Q and I{superscript 2} statistics with visual inspection through forest and Galbraith plots. Publication bias was evaluated using a funnel plot and Eggers test. Subgroup and sensitivity analyses were also performed. Results Out of the 3702 study participants from 16 included studies, the estimated pooled prevalence of CKD among adult T2DM patients in SSA was 35.8% (95% CI: 27.1-44.4), indicating significant heterogeneity (I{superscript 2}=97.25%, p<0.001) across the studies. Subgroup analyses on the pooled prevalence of CKD on the basis of different diagnostic criteria were conducted. Modification of diet in renal disease (MDRD) reported a prevalence of 34% (26, 43), the chronic kidney diseases epidemiology collaboration (CKD-EPI) reported a prevalence of 39% (21, 57), and the Cockcroft-Gault (CG) method reported a prevalence of 34% (12, 56). In addition, older age (OR = 2.27, 95% CI: 1.19-4.33) and longer diabetes duration (OR = 1.90, 95% CI: 1.07-3.40) were factors significantly associated with the prevalence of CKD. Conclusion The prevalence of CKD in SSA was high, affecting nearly one in three adults with T2DM patients. In addition, factors such as older age and longer diabetes duration significantly contributed to the association with CKD. To lessen this issue, focused public health actions are strongly advised, such as screening, education, and awareness campaigns. Systematic review registrations PROSPERO (2026: CRD420261411707).

Study Objectives To develop and initially validate the Circadian Disruption Index (CDI), a self-report measure of circadian disruption, and obtain preliminary evidence of its responsiveness to circadian health education. Methods In Study 1, 244 participants completed a 22-item CDI version and external measures. The sample was randomly divided for exploratory and confirmatory factor analyses. Internal consistency, external associations, and discrimination of poor sleep quality were examined. In Study 2, 72 postgraduate students completed the CDI before and 1 week after a 16-hour circadian health education program in an uncontrolled pre-post design. Results Analyses yielded a 15-item, three-factor structure comprising rhythm stability and light exposure, behavioral habits and diet, and sleep quality and subjective complaints. Total-score internal consistency was acceptable (Cronbach's = 0.871). Confirmatory factor analysis showed a comparative fit index of 0.902 and a root mean square error of approximation of 0.072, although the Tucker-Lewis index was 0.882. CDI scores correlated with sleep quality, chronotype, corrected midsleep on free days, depression, and anxiety, but not social jetlag. The area under the curve for poor sleep quality was 0.807 (95% confidence interval, 0.753-0.862), with an exploratory cutoff of [&le;] 23. In Study 2, CDI scores decreased from 22.26 to 19.88 (p = 0.002; Cohen's dz = 0.36). Conclusions The CDI demonstrated satisfactory internal consistency, a meaningful multidimensional structure, and responsiveness to short-term changes following circadian health education, supporting its potential utility for assessing circadian disruption and monitoring circadian-related behavioral changes.

Background: Hypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain. Objective: To compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension. Methods: We conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1/1/2000-12/31/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach. Results: Among 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death. Discussion: Among US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings. Key words: antihypertensive medication, dementia, natural language processing, target trial emulation, Veteran

Older adults in residential care are usually described as a group at high risk of undernutrition, yet data on the nutritional and cardiometabolic status of institutionalised older adults in Central Asia are scarce. We aimed to characterise the anthropometric, dietary and biochemical profile of older residents of a state social-care institution in Kazakhstan and to examine whether overnutrition, micronutrient inadequacy and cardiometabolic risk coexist. In this cross-sectional study, 62 adults aged 60 years and over from the "Sharapat" centre in Astana underwent anthropometry, bioelectrical impedance body-composition analysis, blood-pressure measurement, dietary assessment (specialized nutrition questionnaires, a 24-hour dietary recall and food diaries) with calculation of nutrient intakes, and venous blood and urine testing; serum 25-hydroxyvitamin D and trace elements were measured in 29 participants. Laboratory analyses and data processing were performed at the Research Institute of Preventive Medicine named after E.D. Dalenov, Astana Medical University. The sample (61.3% men; mean age 74.0 years) showed a high cardiometabolic burden, with arterial hypertension in 63%, total cholesterol of at least 5.0 mmol/L in 60%, LDL-cholesterol of at least 3.0 mmol/L in 71%, and overweight or obesity in 58%, whereas only 5% were underweight. Habitual diets were high in sodium (71% above 2000 mg/day) and low in potassium (92% below 3500 mg/day), calcium (85% below 1000 mg/day) and fibre (90% below 25 g/day). Among those tested, 79% had vitamin D deficiency, and overweight or obesity coexisted with vitamin D deficiency in 16 of 29 participants. None of 56 exploratory diet-risk correlations survived correction for multiple testing. Rather than the undernutrition typical of residential care, these residents displayed a double burden of malnutrition-excess adiposity and cardiometabolic risk alongside micronutrient-poor diets and widespread vitamin D deficiency-identifying concrete targets for institutional catering, supplementation and cardiometabolic screening.

Background & Aims The adoption of plant-based diets in the United Kingdom (UK) is increasing, which has potential health benefits, but may increase risk of inadequate intakes of some nutrients. We aimed to assess differences in biomarkers of nutritional status and disease across diet groups in UK adults. Methods This cross-sectional analysis included 124 omnivores, 131 flexitarians, 71 pescatarians, 124 vegetarians, and 183 vegans from the Feeding the Future (FEED) follow-up study (2024-2025). Capillary blood samples were collected and analysed for: haemoglobin; lipid measures (low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), non-HDL-C, total cholesterol, and triglycerides); vitamins B12 and D. We estimated age- and sex-adjusted arithmetic or geometric mean concentrations and 95% confidence intervals of these biomarkers across diet groups. Participants taking lipid-lowering medications were excluded for analysis of lipid markers (n = 85). Results We observed differences in concentrations of cholesterol, triglycerides, and vitamin B12 across diet groups (P heterogeneity for all [&le;] 0.03). Cholesterol markers (mmol/L) were lower with greater exclusion of animal foods (omnivores vs vegans, total cholesterol = -0.8; LDL-C = -0.7; HDL-C = -0.2). Triglyceride concentrations (mmol/L) were similar across groups, with slightly higher values in vegetarians (+0.2) and vegans (+0.1) compared with omnivores. Vitamin B12 concentrations (pmol/L) were highest in vegans and lowest in vegetarians compared to omnivores. Supplement users had higher vitamin B12 and D concentrations in all groups (P heterogeneity between strata = <0.001), while non-supplementing vegetarians and vegans had lower, but not deficient, vitamin B12 concentrations compared to omnivores (P heterogeneity between diet groups = <0.001). Conclusions In this contemporary UK cohort, those following plant-based diets had more favourable blood lipid profiles, with little evidence of vitamin B12 or D deficiency, or anaemia. Supplement use was associated with higher vitamin B12 and D concentrations, particularly among vegetarians and vegans.

Importance: Adverse drug events in older adults are a substantial public health burden, yet spontaneous reporting systems detect them poorly owing to underreporting and the lack of a defined population. These limitations are of particular concern for older adults, who are underrepresented in pre-approval trials yet at elevated risk owing to polypharmacy, multimorbidity, and age-related changes in drug metabolism. Objective: To develop and apply an active, claims-based pharmacovigilance framework using sequential target trial emulation to detect adverse drug event signals in older adults, with atorvastatin as the initial application. Methods: Using Medicare fee-for-service claims (2017-2019), we studied statin-naive beneficiaries aged 65 years or older following myocardial or cerebral infarction. We emulated up to 14 daily sequential trials from the discharge date, classifying patients as initiating atorvastatin (A1), initiating a different medication (A2), or no new medication (A0); the primary contrast was A1 versus A2. For each trial, incident outcomes were ascertained and classified into 552 outcomes based on the Clinical Classifications Software Refined categories. Per-protocol effects were estimated over a 6-month follow-up period using Fine-Gray regression models weighted by the inverse probability of treatment and censoring, treating death as a competing risk, with the false discovery rate controlled via the Benjamini-Hochberg procedure. A signal was declared when the q-value was 0.10 or lower and the subdistribution hazard ratio (sHR) was 1.20 or greater in any prespecified analytic stratum (sensitivity analyses used thresholds of q 0.20 or lower and sHR 1.20 or greater). Results: Of 70,130 eligible patients, 39,948 initiated atorvastatin (A1) and 19,182 initiated another new medication (A2); after weighting, baseline characteristics were closely balanced. After excluding outcomes with sparse cell counts, 295 outcomes were analyzed; five met the primary signal detection criteria: valve disorders (sHR 1.71, 1.20 to 2.43); sprains and strains (sHR 1.79, 1.26 to 2.54); general sensation/perception symptoms (sHR 1.23, 95 percent CI 1.11 to 1.36); abnormal findings without diagnosis (sHR 1.55, 1.18 to 2.05); and prediabetes (sHR 1.71, 1.24 to 2.36). In the sensitivity analysis, we additionally detected posthemorrhagic anemia, hemorrhagic stroke, varicose veins, and other circulatory and skin conditions. Conclusions: An active, claims-based framework using sequential target trial emulation detected both expected and previously unrecognized adverse drug event signals following atorvastatin initiation in older adults, offering a systematic alternative to passive surveillance that can be extended to other commonly prescribed medications.

Background: Depressive and anxiety symptoms are prevalent among older adults and associated with increased dementia risk. In healthy older adults, higher step counts are associated with fewer depressive and anxiety symptoms; whether this holds in individuals with cognitive concerns (subjective cognitive decline [SCD] or mild cognitive impairment [MCI]) is unknown. In a randomised controlled trial, the 12-month APPLE-Tree group psychosocial lifestyle intervention produced small cognitive improvements but no change in step count. Objective: To test whether step count was associated with depressive and anxiety symptoms (cross-sectionally and over 24 months), and whether APPLE-Tree increased step count in participants with clinical anxiety or depression. Methods: We examined cross-sectional and longitudinal (12- and 24-month) associations between step count (two-week average from wrist-worn wearables) and depressive and anxiety symptoms (Hospital Anxiety and Depression Scale) using adjusted linear regressions, with a mediation analysis of self-perceived mobility. We also tested whether the intervention increased step count in those with baseline clinical anxiety or depression. Findings: We included 629 of 746 trial participants at baseline, of whom 376 contributed 12-month and 215 24-month data. At baseline, higher step counts were associated with fewer depressive symptoms ({beta} = -0.11, 95% CI -0.17 to -0.05, p < 0.001) but, counter to our hypothesis, more anxiety symptoms ({beta} = 0.12, 95% CI 0.06 to 0.19, p = 0.003). Over two years, change in step count was not associated with change in depressive or anxiety symptoms (all p [&ge;] 0.12). Self-perceived mobility problems mediated the association between step count and depressive but not anxiety symptoms. The intervention did not change step count in those with clinical anxiety or depression. Conclusions: This provides the first evidence in older adults with cognitive concerns that higher step counts are associated with fewer depressive but more anxiety symptoms. This may reflect heterogeneity of a population that includes those with prodromal dementia and cognitive health anxiety. Step count did not predict symptoms over time. Clinical implication: Step count may help distinguish anxiety and depressive symptoms in people presenting with cognitive concerns, or underlying reasons for cognitive concerns among those with functional cognitive disorders.