Heart failure (HF) is a clinical syndrome characterized by structural or functional impairments in ventricular filling or the ejection of blood from the heart. In the United States, HF represents a growing public health concern, affecting an estimated 6.7 million adults 20 years or older, with prevalence expected to continue rising. Despite advances in guideline-directed medical therapy (GDMT), rates of hospitalization and mortality remain high. Therapeutic options are particularly limited for the most prevalent HF phenotypes-HF with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF)-resulting in substantial unmet clinical need. This supplement reviews the pathophysiology, epidemiology, and staging of HF with an emphasis on HFmrEF and HFpEF, and summarizes current GDMT recommendations, including the evolving roles of SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs). A main focus is on the safety and efficacy of finerenone, a nonsteroidal MRA, as an adjunct to standard therapy in patients with HFmrEF or HFpEF. Persistent barriers to optimal care-including challenges related to diagnostic nomenclature, coding, and access-contribute to a disproportionate economic burden associated with these HF phenotypes. Together, these considerations highlight the need for managed care strategies that facilitate appropriate initiation of therapy and access to emerging treatments to improve outcomes while addressing health care resource utilization.

Optimal clinical decision support system (CDSS) implementation for chronic kidney disease (CKD) management in Chinese primary care remains undefined despite the high disease burden.

To examine whether a CDSS for CKD could improve physician behavior and patient outcomes in primary care.

This cluster randomized clinical trial is being conducted in Chinese primary care centers. The trial spans a 3-year period (January 1, 2023, to December 31, 2026) and is divided into 2 phases; this phase 1 analysis includes data from the initial 6-month follow-up (June 10 to December 10, 2023). Centers were stratified by size and randomized 1:1 to intervention or control. Participants are adults (aged ≥18 years) with CKD who had 2 visits or more during the 1-year screening period, all enrolled before randomization.

Both groups received government-supported, nephrologist-delivered training on CKD management. The intervention group was additionally equipped with a CDSS embedded into the electronic health record.

The primary outcome was a 36-month composite of kidney-related and cardiovascular hospitalizations (phase 2). This phase 1 analysis evaluated 6-month process measures (ie, CKD diagnosis and renin-angiotensin-aldosterone system inhibitor or sodium-dependent glucose transporter 2 inhibitor use) and clinical outcomes (ie, blood pressure, glycated hemoglobin, and low-density lipoprotein cholesterol control).

A total of 3390 patients (mean [SD] age, 72.0 [10.2] years; 1881 [55.5%] female) from 30 primary care centers were included (1912 in the intervention group and 1478 in the control group). Follow-up at 6 months was completed by 3055 patients (90.1%; 1743 [91.2%] in the intervention group and 1312 [88.8%] in the control group). CKD diagnosis rates increased by 21.4 (95% CI, 18.6-24.3) percentage points in the intervention group and by 27.9 (95% CI, 24.4-31.3) percentage points in the control group, with a nonsignificant between-group difference (adjusted odds ratio [AOR], 0.91; 95% CI, 0.72-1.14). Renin-angiotensin-aldosterone system inhibitor use (AOR, 0.96; 95% CI, 0.78-1.19), sodium-dependent glucose transporter 2 inhibitor use (AOR, 1.02; 95% CI, 0.78-1.32), and low-density lipoprotein cholesterol control (AOR, 1.10; 95% CI, 0.83-1.46) showed parallel improvements with no between-group differences. Blood pressure (AOR, 0.88; 95% CI, 0.71-1.09) and glycated hemoglobin (AOR, 1.22; 95% CI, 0.74-2.01) control showed no improvement.

In this cluster randomized trial of a CDSS for CKD in primary care, both the intervention and control groups demonstrated comparable improvements in 6-month outcomes, with no independent effect of the CDSS detected.

Chinese Clinical Trial Registry Identifier: ChiCTR2300070555.

Acute ischemic stroke (AIS) remains a leading cause of disability worldwide, and effective treatments are urgently needed beyond reperfusion therapy. Translating preclinical success to clinical impact has been hindered by variability in animal models and the lack of translational biomarkers that predict outcomes across species. To overcome these barriers, we developed a robust rat AIS model optimized for consistency and severity, enabling rigorous therapeutic testing. Additionally, we tested a panel of common clinical serum biomarkers to improve translation from rodents to humans. We demonstrated that serum neurofilament light chain (NfL) -a biomarker widely used in clinical stroke studies- strongly correlated with functional outcomes, establishing a translational link that has not been previously reported in rats. Notably, NfL's predictive capabilities performed as well as infarct volume while outperforming serum biomarkers intercellular adhesion molecule-1 (ICAM-1) and S100 calcium binding protein (S100B). Using this platform, we evaluated the therapeutic impact of neural stem cell-derived extracellular vesicles (NSC EV), a novel biologic therapy poised for clinical trials, on stroke outcome in our rat AIS model. A three-dose regimen of NSC EV over 48 h confirmed our previous studies and produced the best outcomes in stroked animals evidenced by smaller infarct volume, improved neurologic score, and reduced serum NfL. In addition, single-dose and two-dose regimens of NSC EV were both effective at some endpoints. These findings not only validate NfL as a cross-species biomarker but also provide critical dosing insights for NSC EV therapy, accelerating the path from bench to bedside for AIS treatment.

The objective was to evaluate the clinical efficacy and safety of telitacicept in the treatment of pediatric IgA vasculitis nephritis (IgAVN). A retrospective analysis was conducted on clinical data from patients aged 3-18 years with IgAVN treated with telitacicept at the Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, between August 2023 and August 2024. Laboratory parameters were assessed at baseline and at 1, 3, 6, and 12 months posttreatment to determine therapeutic efficacy and safety. A total of 16 patients were enrolled (7 males [43.75%]; mean age 14.3 years). The median disease duration from diagnosis to telitacicept initiation was 4.25 (2.06-33.00) months, and the mean treatment duration was 8.63 ± 1.89 months. Early clinical improvement was observed as early as 1 month compared with baseline, characterized by substantial reductions in 24-h urinary protein (24 h-UP) and urinary red blood cell counts compared to baseline. At 12 months, mean 24 h-UP decreased further to 0.16 ± 0.15 g (P < 0.001), with 68.75% (11/16) of patients achieving complete remission. Serum IgG, IgM, and IgA levels were significantly reduced (P < 0.05), while serum albumin significantly increased (P < 0.001). No serious adverse events occurred; three patients experienced mild upper respiratory tract infections that resolved with symptomatic treatment.

 Telitacicept effectively reduces proteinuria, improves renal function, and enhances clinical remission rates in pediatric IgAVN, demonstrating a favorable safety profile.

• Telitacicept, a dual BAFF/APRIL inhibitor, has shown potential effi cacy in IgA nephropathy (IgAN) and IgA vasculitisnephritis (IgAVN), particularly in reducing proteinuria and maintaining stable renal function. • Evidence regarding the use of telitacicept in pediatric IgAVN remains limited and is mainly derived from small case series and retrospective studies.

• This study provides real-world data on the use of telitacicept in pediatric IgAVN, showing improvement in proteinuria with stable renal function during follow-up. • Most patients were able to discontinue glucocorticoids and/or immunosuppressive agents within 3-6 months after telitacicept initiation, suggesting a potential steroid- and immunosuppressant-sparing effect.

To determine whether routinely available radiology reports, together with basic clinical data, can identify patients with traumatic intracranial hemorrhage (TICH) who are at low risk of adverse events.

This retrospective cohort study of adults with TICH in Region Jönköping, Sweden (2019-2021). Clinical data, findings from radiology reports and outcomes were extracted from medical records. Hemorrhage size was classified as small (≤ 4 mm or described as minimal/very small/discrete) or larger. Adverse events were defined as neurosurgical intervention or death directly attributable to the TICH. Risk difference (RD), relative risk (RR), and Firth's penalized logistic regression were used to assess associations with adverse events.

Among 527 included patients, 195 (37%) had small TICHs. None of these patients experienced adverse events, compared with 13.6% neurosurgical interventions and 13.0% trauma-related deaths in the group with larger TICHs (RD 24.5% points, 95% CI 18.4-29.6; RR 97.1, 95% CI 6.1-1557.1; p < 0.001). Small TICH size had the strongest association with absence of adverse events. Normal neurological status and GCS 14-15 were also associated with a low risk of adverse events. Anticoagulant or antiplatelet therapy showed no significant association with adverse events.

Routinely available radiology reports, combined with basic clinical data, can identify a low-risk subgroup of patients with small TICHs. Hemorrhage size appears to be a useful factor for risk stratification, but the findings require internal and external prospective validation before implementation in clinical practice.

While the single-point insulin sensitivity estimator (SPISE) shows promise as an insulin resistance biomarker, its association with cardiovascular disease (CVD) in early CKM stages (0-3) remains underexplored.

We analyzed 6480 participants with CKM stage 0-3 from the China Health and Retirement Longitudinal Study. CVD outcomes were assessed relative to SPISE index levels. An ensemble machine learning model was employed to predict CVD risk.

6480 subjects were enrolled, of whom 967 developed CVD. After stratifying participants into SPISE quartiles (Q1-Q4) and adjusting for covariates, higher quartiles were linked to a lower CVD risk. This study developed an LR+GMM (Logistic Regression + Gaussian Mixture Model) ensemble model to predict CVD risk using five strong predictors: SPISE, high-density lipoprotein cholesterol (HDL-c), diastolic blood pressure (DBP), body mass index (BMI), and glycated hemoglobin (HbA1c). The model performed well, achieving an accuracy (ACC) of 0.986 and an area under the receiver operating characteristic curve (AUC) of 0.932.

The SPISE index is a significant inverse predictor of CVD risk in individuals with stage 0-3 CKM syndrome. The LR+GMM ensemble model, incorporating the SPISE index and four clinical metrics, demonstrated outstanding predictive performance.

In the phase 3 study SEQUOIA-HCM (NCT05186818), aficamten, a next-in-class cardiac myosin inhibitor, was safe and efficacious in participants with obstructive hypertrophic cardiomyopathy (oHCM). Using pharmacokinetics/pharmacodynamics (PKPD) modeling, we quantified the relationship between aficamten exposure and cardiodynamic measures of safety (left ventricular ejection fraction [LVEF]) and efficacy (post-Valsalva left ventricular outflow tract gradient [LVOT-G]), and used Clinical Trial Simulations (CTS) to predict cardiodynamics for a flexible dose regimen in a post-approval setting. PKPD relationships between aficamten average concentration over 24 h (C_avg,24) and LVEF or LVOT-G were well quantified. Within-subject variability for LVEF was low (CV = 7.6%), indicating that prior LVEF readings are highly predictive of future readings during stable therapy. A ~2% decrease in LVEF is expected per 100 ng/mL increase in C_avg,24. LVOT-G slope was ~10-fold steeper vs. LVEF, suggesting a relatively large therapeutic window. The commercial regimen allows for individualized flexible echocardiography-based dose titration (every 2-8 weeks) from 5 to 20 mg once daily and flexible maintenance dose monitoring. CTS demonstrated minimal differences in population progression of LVOT-G < 30 mmHg and LVEF < 50% between evaluated dose-titration frequencies (every 2, 4, 6, or 8 weeks) over the first 6 months of treatment, supporting a 2-8 week window for dose titration. With maintenance doses, the probability of maintaining LVOT-G < 30 mmHg (~60%) was high and the probability of occurrences of LVEF < 50% (~3%) was low. Therefore, this regimen should maintain safe and efficacious cardiodynamics while increasing convenience and access for patients with oHCM.

C-reactive protein (CRP) is a marker of inflammation associated with autoimmune, cardiovascular, and neuropsychiatric disorders. However, it remains unclear whether CRP causally affects these traits or if observed associations result from reverse causation or confounding. Mendelian randomization (MR) uses genetic variants as instrumental variables to estimate causal effects and avoid the biases present in observational studies. Prior MR studies have suggested causal effects of CRP on several traits, including low-density lipoprotein (LDL) cholesterol, schizophrenia (SCZ), and knee osteoarthritis (OA). However, MR may produce biased results if traits that confound the exposure and outcome are heritable, resulting in horizontal pleiotropy. This is a major concern for studies of CRP, because CRP levels may increase in response to inflammation caused by a wide range of heritable conditions.

Multivariable Mendelian randomization (MVMR) can be used to eliminate bias from heritable confounding when genome-wide association study (GWAS) summary data are available for confounders. In this study, we used MVMR to estimate the causal effects of CRP on 16 outcomes with prior evidence of a causal or associational link to CRP. We used a novel computational pipeline to identify a broad set of potential heritable confounders between CRP and each outcome trait from studies in the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) OpenGWAS database. We compared MVMR results with computationally selected confounders to univariable MR results and MVMR adjusting only for body mass index.

Univariable MR suggests evidence of potential causal effects of CRP on coronary artery disease, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, triglycerides, type 2 diabetes, glycated hemoglobin (HbA1c), rheumatoid arthritis (RA), SCZ and OA at the nominal P < .05 significance level. However, after adjusting for computationally selected heritable confounders, only effects on HDL cholesterol (negative), HbA1c (positive), RA (risk increasing), and SCZ (risk decreasing) remain nominally significant. Using confounder-adjusted MVMR additionally reveals evidence of a protective effect of CRP on bipolar disorder not observed in the univariable analysis.

These results suggest that univariable MR analyses of CRP may be biased by high levels of heritable confounding, though CRP may indeed play a causal role in development of some diseases, potentially mediated by its role in innate immunity. These results also highlight the potential for automatic confounder selection to improve the robustness of MR analyses.

Mediterranean diet (MeDi) has been linked to lower incidence of cardiovascular and neurodegenerative diseases, and overall mortality, in several prospective studies. There is limited data, however, regarding the relationship between MeDi and stroke subtypes. We hypothesized that MeDi would be associated with lower total, ischemic, and hemorrhagic stroke incidence.

The California Teachers Study is a prospective cohort study that comprises 133,477 women who were educators and administrators enrolled in 1995-1996 and followed since. We identified incident strokes using linked California state hospitalization data and national death records from 1996-2020. The MeDi adherence score (range 0-9, higher score indicating better adherence) was calculated based on participants' response to the Block food frequency questionnaire at study baseline. Multivariable Cox proportional hazard models adjusted for socio-demographic, lifestyle and vascular risk variables were constructed to assess the association (hazard ratios and 95% confidence intervals, HR 95% CI) between MeDi score and risk of stroke and its subtypes.

105,614 participants were eligible and included in the final analytic cohort (mean age 52.5 ± 13.8 years). Over the follow-up period (average follow-up time was 20.5 years), there were 4,083 incident stroke events (3,358 ischemic; 725 hemorrhagic). In fully-adjusted models for all stroke, ischemic and hemorrhagic subtypes, there was a lower risk of stroke among those with MeDi scores of 6-9 compared to those with scores of 0-2 (all stroke HR 0.82, 95% CI 0.74-0.92; ischemic HR 0.84, 95% CI 0.75 - 0.95; hemorrhagic HR 0.75, 95% CI 0.58-0.97).

Adherence to the MeDi is associated with lower risk of total, ischemic, and hemorrhagic stroke incidence among women. Potential study limitations include recall bias, misclassification bias, and residual confounding, which would bias our results to the null.

Epidemiological data and the comorbidity situation of cardiovascular-kidney-metabolic disease (CKM) in ethnic minority regions of southern China are lacking. This study aimed to (1) estimate the prevalence and stage distribution of CKM syndrome and (2) identify factors associated with CKM stages and explore the interrelationships among coexisting chronic conditions in a multi-ethnic population in southern China.

We analyzed data from the 2020-2021 China Cardiovascular Disease and Risk Factors Surveillance project in Guangxi. CKM syndrome was defined as the coexistence of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders. The primary outcome was CKM stage (0-4), and binary CKM variables were used in regression analyses. Prevalence was estimated using data from questionnaires, physical examinations, and laboratory tests. Regression and network analyses were conducted to examine factors associated with CKM and the interrelationships among chronic conditions.

Among 8,552 participants (median age 50 [IQR 36-63]; 41.9% male; 66.6% urban; 42.3% Zhuang), the age- and sex-adjusted prevalence of CKM stages 1-4 was 76.4% (95% CI: 75.5-77.3%), with 17.2% at stage 1, 57.7% at stages 2-3, and 1.4% at stage 4 (all p < 0.001). The prevalence of CKM stages 2-4 was significantly higher among males, older individuals, rural residents, and non-Zhuang populations (p < 0.05). Factors independently associated with CKM (stages 2-4) included male sex, older age, rural residence, lower education level, alcohol consumption, low fruit intake, high red meat intake, and hyperuricemia (all p < 0.05). The prevalence of individual chronic conditions was as follows: hypertension, 39.7%; non-hypertension CVD (other CVD), 1.6%; CKD, 13.8%; obesity, 12.2%; and diabetes, 12.1%. Hypertension was a central condition linking CVD, CKD, hyperuricemia, obesity, and diabetes.

This study reveals a substantial burden of CKM stages 2-3 in Guangxi, China, affecting over half of the population, especially rural elderly men. The findings highlight the need for targeted prevention strategies focusing on modifiable factors associated with CKM in ethnic minority regions.