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The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune-related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. HIGHLIGHTS: The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Black adults have a higher risk for heart failure (HF) than others, which may be related to higher cardiovascular risk factors and also inflammatory dietary patterns. The Western diet is associated with inflammation and contributes to HF. Trimethylamine N-oxide is a diet-linked metabolite that contributes to inflammation and is associated with higher tumor necrosis factor-alpha (TNF-α) levels, especially in HF populations. The dietary inflammatory index score measures a diet's inflammatory potential and food's inflammatory effects., Objective: The purpose of this pilot study was to explore associations between the Western diet, dietary inflammatory index, trimethylamine N-oxide, relevant covariates and variables, and TNF-α in Black persons with HF., Methods: Thirty-one Black participants (mean age = 55 years, 68% women) with HF were enrolled. Trimethylamine N-oxide and TNF-α levels were analyzed using immunoassays. A food frequency questionnaire was completed, and dietary inflammatory index scores and food groups were calculated. Analyses included correlations and I-test statistics., Results: Mean dietary inflammatory index score was -0.38, noting an anti-inflammatory diet with slightly higher inflammatory diet scores in men compared to women. The dietary inflammatory index score showed a negative association with dietary choline but not with trimethylamine N-oxide or TNF-α. Trimethylamine N-oxide and age were positively correlated, along with the correlation for TNF-α with a moderate effect size. No relationship was found among dietary inflammatory index, TNF-α, and trimethylamine N-oxide variables., Discussion: A greater understanding of intake of inflammatory foods and relationships with immune factors is warranted to inform intervention development. In Black adults with HF, it is important to consider the intake of inflammatory foods as increased age may affect the retention of dietary metabolites. Metabolites may also increase the levels of inflammation. Knowledge about these relationships could lead to tailored dietary interventions based on diet, age, and culture patterns., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Comorbidities such as Type 2 diabetes mellitus significantly and adversely influence heart failure outcomes, especially in Black adult populations. Likewise, heart failure has a negative effect on diabetes and cardiometabolic outcomes. Dyspnea, a common symptom of heart failure, often correlates with disease severity and prognosis. However, the relationship between comorbid diabetes, dyspnea severity, and cardiometabolic biomarkers in Black adults with heart failure remains understudied., Objectives: The purpose of this pilot study was to examine differences in the distressing heart failure symptom of dyspnea and in cardiometabolic and inflammatory biomarkers in Black adults living with heart failure with and without diabetes., Methods: Black adults with heart failure were enrolled in this cross-sectional pilot study. Cardiometabolic and inflammatory biomarkers were measured via multiplex immunoassay. Univariate general liner models were used to identify group differences between persons with heart failure with comorbid diabetes and those without, controlling for age, sex, and comorbid burden., Results: Participants were mostly female with a mean age of 55 years and mean left ventricular ejection fraction of 33%. Participants with diabetes exhibited higher dyspnea scores compared to those without diabetes, indicating greater symptom burden. Moreover, individuals with comorbid diabetes demonstrated higher levels of cardiometabolic and inflammatory markers., Discussion: Comorbid diabetes was associated with higher dyspnea severity and adverse cardiometabolic profiles in Black adults with heart failure. These findings underscore the importance of targeted interventions addressing diabetes management and cardiometabolic risk factors to improve symptom control and outcomes in this high-risk population. Further research is warranted to elucidate the underlying mechanisms and develop tailored therapeutic strategies for managing comorbidities in persons with heart failure, particularly in minoritized communities., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Alzheimer's disease (AD) research has focused on developing accessible biomarkers that accurately detect disease pathology and progression before symptoms present. Lactoferrin (Lf) is an iron-binding antimicrobial glycoprotein found in all biological fluids, and its concentration in saliva has been correlated with AD symptoms. This pilot project aimed to determine whether salivary lactoferrin (sLF) has potential as a biomarker for AD., Methods: Participants were middle to older-aged non-Hispanic white (NHW) and Black Americans (BA) at risk for AD due to parental history. We collected saliva samples after an 8-hour fast and administered a cognitive battery assessing executive function, memory, visuospatial ability, attention, and verbal fluency. We examined the relationship between sLF and cognitive performance and evaluated protein concentration across races., Results: Seventeen middle-to-older-aged (age = 60.29 ± 9.7 years) BA and NHWs were enrolled. After controlling for age, sex, race, and years of education, we found a significant r between sLF and Digit Span Memory Test (DSMT) scores ( P = 0.013) and a modest correlation with Mental Rotation Test scores ( P = 0.194). We found no difference in average concentration across races., Conclusions: Memory concerns and a worsening in visuospatial ability are early signs of cognitive decline in AD patients, and this pilot suggests a correlation of these symptoms with sLF. Bigger-scale longitudinal studies to examine the relationship between sLF and established AD biomarkers in diverse populations are needed to assess its clinical usefulness as an early biomarker for AD., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors.

Incorporating biomarkers into cardiovascular studies, including nursing research, is a common approach when identifying underlying mechanisms and providing targets for intervention. However, effective utilization of biomarker data demands careful consideration. In the analysis, interpretation, and reporting phase, there are many facets to consider, including non-normality of the data, normalization procedures, and potential confounding influences of other clinical data. Furthermore, as many studies focus on patient-reported outcomes (PROs), it is important that the analysis and interpretation of biomarkers in relation to PROs is rigorous and reproducible. In this article, Part 2 of 2, we provide an overview of considerations for the analysis, interpretation, and reporting phases of biomarker studies. We also provide an example of these steps., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Families of children with medical complexity (CMC) may face challenges related to Social Determinants of Health (SDoH). Although standardized SDoH screening has been implemented in numerous medical settings, there has been limited study of screening among CMC. Our global aim is to improve access to institutional and community resources for families of CMC with identified needs. Here, we aimed to establish SDoH screening for families in our outpatient Complex Care Center and attain a screening rate of 80%., Methods: A multidisciplinary team in our clinic used quality improvement methods to implement and study an expanded SDoH screen, which included 3 questions specific to the needs of CMC (ie, emergency planning, social support, and medical equipment concerns). Interventions, informed and refined by 5 key drivers, were tested over a 12-month period. A statistical process control chart tracked key outcome and process measures over time., Results: SDoH screening sustained a mean of 80% after implementation during the study period. Incorporating registration staff in screen distribution was our most impactful intervention. At least 1 SDoH concern was identified on 56% of screens; concerns specific to CMC and mental health were most frequently reported. A total of 309 responses to positive screens were reported in total., Conclusions: Successful implementation of an expanded, tailored SDoH screen revealed a multitude of social needs specific to families of CMC that otherwise may not have been recognized. Our team continues to develop and distribute resources to address identified needs., (Copyright © 2024 by the American Academy of Pediatrics.)

Cardiovascular studies, including nursing research, frequently integrate biomarkers for diagnostic, prognostic, monitoring, and therapeutic insights. However, effective utilization of biomarker data demands careful consideration. In the study design phase, researchers must select biomarkers that align with study objectives while considering resources and logistical factors. Additionally, a nuanced understanding of disease pathophysiology and biomarker characteristics is needed. During data collection, suitable experimental conditions and assays need to be defined. Whether researchers opt to manage these steps internally or outsource some, a comprehensive understanding of biomarker selection and experiments remains crucial. In this article, part 1 of 2, we provide an overview of considerations for the design to measurement phases of biomarker studies., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose.

Background: Telomere length is reduced in persons with heart failure (HF). Inflammation is a putative mechanism contributing to telomere shortening. Although physical activity is known to increase telomere length, its effects in HF are unknown., Objective: The aim of this study was to examine the effects of exercise on telomere length and its relationship with interleukin (IL)-1β in persons with HF., Methods: This secondary analysis of a 3-month home-based aerobic exercise intervention measured total telomere length and IL-1β levels in persons with HF (69% with reduced ejection fraction)., Results: Total telomere length increased and plasma IL-1β levels decreased in the exercise group from baseline to 3 months. Total telomere length was negatively associated with IL-1β at baseline ( r = -0.441 P = .001)., Conclusions: The association between telomere length and IL-1β suggests a relationship between inflammation and cellular aging. Moderate-intensity exercise may help maintain cellular functions. Further research is needed to examine the effects on outcomes in persons with HF., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants., Methods: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2., Results: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW., Discussion: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships., Highlights: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes., Patients and Methods: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform., Results: In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n = 255) versus aEGFR-: 22.0 months (n = 131); hazard ratio (HR) = 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM + ERL was associated with longer PFS versus PBO + ERL [aEGFR+: median PFS (mPFS) = 15.2 versus 11.1 months, HR = 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS = 22.1 versus 19.2 months, HR = 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM + ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS = 14.1 versus 7.0 months, HR = 0.481, 95% CI 0.33-0.71). RAM + ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%)., Conclusions: Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM + ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules., Competing Interests: Disclosure EBG declares grants from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, EMD Serono, Eli Lilly and Company, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees from AbbVie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly and Company, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio; payment for expert testimony from UCLA relating to motif neoepitopes for cancer immunotherapy; leadership/fiduciary role with LUNGevity and Jonsson Comprehensive Cancer Center at UCLA. JVH declares advisory board/committee membership with Genentech, Mirati Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, DAVA Oncology, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, and Novartis; research support from AstraZeneca, Boehringer-Ingelheim, Spectrum, and Takeda; royalties and licensing fees from Spectrum. MR declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; support for meetings/travel from Amgen, AstraZeneca, Boehringer-Ingelheim, BeiGene, BMS, GSK, Mirati, Merck, MSD, Eli Lilly and Company, Novartis, Pfizer, Roche, Regeneron, and Sanofi; board participation for Daiichi and Sanofi. KN declares grants from Nippon Boehringer-Ingelheim, West Japan Oncology Group, Thoracic Oncology Research Group, North East Japan Study Group, Clinical Research Support Center Kyushu, Nichirei Biosciences Inc., Eli Lilly and Company, Hitachi, Sysmex, and Otsuka Pharmaceutical; consulting fees from SymBio Pharmaceuticals, Solasia Pharma, Eli Lilly and Company, and Otsuka Pharmaceutical; honoraria from Chugai, Pfizer, Eli Lilly and Company, MSD, Novartis Pharma, AstraZeneca, Amgen, Merck Biopharma, Roche Diagnostics, Yakult Honsha, Guardant Health, Takeda Pharmaceuticals, Boehringer-Ingelheim Japan, FUJIREBIO, Bristol-Myers Squibb, Merck Biopharma, Janssen Pharmaceutical Daiichi-Sankyo, and Ono Pharmaceutical. MN declares honoraria from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly and Company, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer-Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. SN declares grants from Eli Lilly and Company; consulting fees from BMS, Eli Lilly and Company, Takeda, Roche, Pfizer, AstraZeneca, BI, MSD, AbbVie, PharmaMar, and BeiGene; support for meetings and/or travel from Eli Lilly and Company, Thermo Fisher, and Takeda; participation on advisory boards for Guardant Health, GSK, Novocure, Amgen, AstraZeneca, Janssen, and Eli Lilly and Company; and declares leadership/fiduciary roles as President of WALCE (Women against Lung Cancer in Europe) Onlus. LPA declares grants from MSD, AstraZeneca, Pfizer, and BMS; consulting fees from Eli Lilly and Company, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Daiichi-Sankyo; honoraria from AstraZeneca, Janssen, Merck, and Mirati; member of the board of directors of Altum Sequencing and Genomica; principal investigator for studies sponsored by Alkermes, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, IO Biotech, Janssen-Cilag, Eli Lilly and Company, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda, and Tesaro. SP declares consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly and Company, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Serono; support for attending meetings and/or travel from Janssen and Roche; unpaid leadership/fiduciary roles in British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP-IBCSG Partners Foundation Board. SPA declares no conflicts of interest. HG was an employee and stockholder of Eli Lilly and Company during the time of study analysis and manuscript preparation; contributions to the manuscript were made as part of the roles at Eli Lilly and Company. BDB and CVG are full-time employees and minor shareholders of Eli Lilly and Company. KN declares grants to institution from AstraZeneca, MSD, Ono Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis, Pfizer Japan Inc., Bristol-Myers Squibb, Eli Lilly and Company, Chugai Pharmaceutical, Daiichi-Sankyo, Merck, Paraxel International Corp., PRA Health Sciences, EPS Corporation, Kissei Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., PPD-SNBL K.K., SymBio Pharmaceuticals Limited, IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co. Ltd., EP-CRSU Co. Ltd., Mebix, Janssen Pharmaceutical K.K., AbbVie Inc., Bayer Yakuhin Ltd., Eisai, Mochida Pharmaceutical Co. Ltd. Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co. Ltd., GlaxoSmithKline, Sanofi, Sysmex Corporation, Medical Research Support, Otsuka Pharmaceutical Co. Ltd., SRL Inc., Pfizer R&D Japan G.K., and Amgen Inc.; consulting fees from Eli Lilly and Company, KYORIN Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., and Pfizer Japan Inc.; honoraria from Ono Pharmaceutical Co. Ltd., Amgen Inc. Nippon Kayaku Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly and Company, MSD, Pfizer Japan Inc., Nippon Boehringer-Ingelheim Co. Ltd., Taiho Pharmaceutical Co. Ltd., Bayer Yakuhin, CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Roche Diagnostics K.K., AbbVie Inc, Merck Biopharma Co. Ltd., Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co. Ltd., 3H Clinical Trial Inc., Care Net Inc., Medical Review Co. Ltd., Medical Mobile Communications Co. Ltd., Yodosha Co. Ltd., Nikkei Business Publications Inc., Japan Clinical Research Operations, CMIC Co. Ltd., Novartis, TAIYO Pharma Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Bristol-Myers Squibb K.K.; patents planned, issued, or pending with Daiichi-Sankyo. Data sharing Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It is well known that vascular factors and specific social determinants of health contribute to dementia risk and that the prevalence of these risk factors differs according to race and sex. In this review, we discuss the intersection of sex and race, particularly female sex and Black American race. Women, particularly Black women, have been underrepresented in Alzheimer's disease clinical trials and research. However, in recent years, the number of women participating in clinical research has steadily increased. A greater prevalence of vascular risk factors such as hypertension and type 2 diabetes, coupled with unique social and environmental pressures, puts Black American women particularly at risk for the development of Alzheimer's disease and related dementias. Female sex hormones and the use of hormonal birth control may offer some protective benefits, but results are mixed, and studies do not consistently report the demographics of their samples. We argue that as a research community, greater efforts should be made to not only recruit this vulnerable population, but also report the demographic makeup of samples in research to better target those at greatest risk for the disease., (© 2023. The American Society for Experimental Neurotherapeutics, Inc.)

Introduction: Chymase is a highly destructive serine protease rapidly neutralized in the circulation by protease inhibitors. Here we test whether pericardial fluid (PCF) chymase activation and other inflammatory biomarkers determine intensive care unit length of stay, and explore mechanisms of chymase delivery by extracellular vesicles to the heart., Methods: PCF was collected from adult patients (17 on-pump; 13 off-pump) 4 h after cardiac surgery. Extracellular vesicles (EVs) containing chymase were injected into Sprague-Dawley rats to test for their ability to deliver chymase to the heart., Results: The mean intensive care unit (ICU) stay and mean total length of stay was 2.17 ± 3.8 days and 6.41 ± 1.3 days respectively. Chymase activity and 32 inflammatory markers did not differ in on-pump vs. off-pump cardiac surgery. Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality Score (STS-PROM), 4-hour post-surgery PCF chymase activity and C-X-C motif chemokine ligand 6 (CXCL6) were all independent predictors of ICU and total hospital length of stay by univariate analysis. Mass spectrometry of baseline PCF shows the presence of serine protease inhibitors that neutralize chymase activity. The compartmentalization of chymase within and on the surface of PCF EVs was visualized by immunogold labeling and transmission electron microscopy. A chymase inhibitor prevented EV chymase activity (0.28 fmol/mg/min vs. 14.14 fmol/mg/min). Intravenous injection of PCF EVs obtained 24 h after surgery into Sprague Dawley rats shows diffuse human chymase uptake in the heart with extensive cardiomyocyte damage 4 h after injection., Discussion: Early postoperative PCF chymase activation underscores its potential role in cardiac damage soon after on- or off-pump cardiac surgery. In addition, chymase in extracellular vesicles provides a protected delivery mechanism from neutralization by circulating serine protease inhibitors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Butts, Goeddel, Zheng, Pat, Powell, Mobley, Ahmad, Steele, Mcgiffin, Davies, George, Melby, Ferrario and Dell'Italia.)

Heart failure (HF) is characterized by high symptom burden including, but not limited to fatigue, dyspnea, and edema. Up to 21.5% of HF patients experience significant depressive symptoms, much higher than 7.1% in adults without HF. Diet, metabolites, and other inflammatory mechanisms have gained notable attention in recent studies for contributions to symptoms in HF. Symptoms for black adults (B/As) with HF are often influenced by lifestyle factors, which may influence their higher mortality rates; few studies address these factors. Distinguishing the links between key elements with diet, inflammation, and symptoms may bring clarity for new dietary strategies in HF clinical care. The purpose of this integrative review is to examine the existing literature regarding relationships among physiologic pathways in HF along with physical and emotional symptoms in the context of inflammation, dietary intake, tumor necrosis factor-alpha (TNF-α), a biomarker of inflammation, and trimethylamine-N-Oxide (TMAO). Based on available evidence, inflammation may be a key link between physical symptoms, diet, depression, TMAO, and TNF-α in persons with HF and warrants further examination to clarify pathological links to solidify evidence for better guidance with dietary modifications. The literature reviewed in this study demonstrates that more work is needed to examine dietary planning, social support, and differences between men and women in the B/A community. Results of this literature review call attention to the essential, personalized care needs related to symptom monitoring and dietary planning which is expected to decrease symptom burden in the HF population., Competing Interests: Conflicts of interest There are no conflicts of interest.

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Objectives: To assess the association between neighborhood socioeconomic deprivation and health care utilization in a cohort of children with medical complexity (CMC)., Methods: Cross-sectional study of children aged <18 years receiving care in our institution's patient-centered medical home (PCMH) for CMC in 2016 to 2017. Home addresses were assigned to census tracts and a tract-level measure of socioeconomic deprivation (Deprivation Index with range 0-1, higher numbers represent greater deprivation). Health care utilization outcomes included emergency department visits, hospitalizations, inpatient bed days, and missed PCMH clinic appointments. To evaluate the independent association between area-level socioeconomic deprivation and utilization outcomes, multivariable Poisson and linear regression models were used to control for demographic and clinical covariates., Results: The 512 included CMC lived in neighborhoods with varying degrees of socioeconomic deprivation (median 0.32, interquartile range 0.26-0.42, full range 0.12-0.82). There was no association between area-level deprivation and emergency department visits (adjusted risk ratio [aRR] 0.98; 95% confidence interval [CI]: 0.93 to 1.04), hospitalizations (aRR 0.97; 95% CI: 0.92 to 1.01), or inpatient bed-days (aRR 1.00, 95% CI: 0.80 to 1.27). However, there was a 13% relative increase in the missed clinic visit rate for every 0.1 unit increase in Deprivation Index (95% CI: 8%-18%)., Conclusions: A child's socioeconomic context is associated with their adherence to PCMH visits. Our PCMH for CMC includes children living in neighborhoods with a range of socioeconomic deprivation and may blunt effects from harmful social determinants. Incorporating knowledge of the socioeconomic context of where CMC and their families live is crucial to ensure equitable health outcomes., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: We previously reported increased plasma XO (xanthine oxidase) activity in patients with resistant hypertension. Increased XO can cause mitochondrial DNA damage and promote release of fragments called mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs). Here, we report racial differences in XO activity and mtDNA DAMPs in Black and White adults with resistant hypertension., Methods: This retrospective study includes 91 resistant hypertension patients (44% Black, 47% female) with blood pressure >140/90 mm Hg on ≥4 medications and 37 normotensive controls (30% Black, 54% female) with plasma XO activity, mtDNA DAMPs, and magnetic resonance imaging of left ventricular morphology and function., Results: Black-resistant hypertension patients were younger (mean age 52±10 versus 59±10 years; P =0.001), with higher XO activity and left ventricular wall thickness, and worse diastolic dysfunction than White resistant hypertension patients. Urinary sodium excretion (mg/24 hour per kg) was positively related to left ventricular end-diastolic volume ( r =0.527, P =0.001) and left ventricular mass ( r =0.394, P =0.02) among Black but not White resistant hypertension patients. Patients with resistant hypertension had increased mtDNA DAMPs versus controls ( P <0.001), with Black mtDNA DAMPS greater than Whites ( P <0.001). Transmission electron microscopy of skeletal muscle biopsies in resistant hypertension patients demonstrates mitochondria cristae lysis, myofibrillar loss, large lipid droplets, and glycogen accumulation., Conclusions: These data warrant a large study to examine the role of XO and mitochondrial mtDNA DAMPs in cardiac remodeling and heart failure in Black adults with resistant hypertension.

Background: When the COVID-19 pandemic hit in 2020, researchers in the P30 Center for the Study of Symptom Science, Metabolomics, and Multiple Chronic Conditions at Emory University's Nell Hodgson Woodruff School of Nursing faced major challenges in recruitment and data collection because of limited access to the clinic and community facilities and the risk of COVID-19 exposure associated with in-person study contact., Objectives: The purpose of this article is to (a) describe how a cadre of pilot/supplement principal investigators adapted their studies to allow for safe and trustworthy data collection during the COVID-19 pandemic (March 2020 through date of publication) and (b) discuss steps that facilitated the technical aspects of remote data collection, especially involving biological specimens., Results: Four pilot studies and two administrative supplements within the center-all at different stages of execution-adopted various alternative remote recruitment, enrollment, and data and specimen collection approaches to continue their research endeavors in a way that maximized the safety of both the research participants and the research teams., Discussion: The article concludes with a discussion on the importance of a participant-centered approach when using remote methods, actions, or steps initiated to facilitate the technical aspects of remote data collection and reflections on the continued use of remote research strategies beyond the COVID-19 pandemic., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This study evaluated a 12-week, home-based combined aerobic exercise (walking) and computerized cognitive training (EX/CCT) program on heart failure (HF) self-care behaviors (Self-care of HF Index [SCHFI]), disease specific quality of life (Kansas City Cardiomyopathy Questionnaire [KCCQ]), and functional capacity (6-minute walk distance) compared to exercise only (EX) or a usual care attention control (AC) stretching and flexibility program. Participants ( N = 69) were older, predominately female (54%) and African American (55%). There was significant improvement in self-care management, F (2, 13) = 5.7, p < .016; KCCQ physical limitation subscale, F (2, 52) = 3.4, p < .039; and functional capacity (336 ± 18 vs 388 ± 20 m, p < .05) among the EX/CCT participants. The underlying mechanisms that EX and CCT targets and the optimal dose that leads to improved outcomes are needed to design effective interventions for this rapidly growing population.

Greater family caregiver exposure to uncontrolled patient symptoms is predictive of greater caregiver psychological and physiological stress in dementia and other chronic illnesses, but these phenomena have not been well-studied in heart failure (HF) - a disease with high symptom burden. The purpose of this study was to test the hypothesis that worse patient functional status (as reflected by increasing HF symptoms) would be associated with elevated psychological and physiological stress for the caregiver. This was a secondary analysis of data from 125 HF caregivers in the Caregiver Opportunities for Optimizing Lifestyle (COOL) study. Psychological stress was measured on four dimensions: care-related strain/burden (Oberst Caregiving Burden Scale), depression (Center for Epidemiological Studies Depression Scale), anxiety (State-Trait Anxiety Index), and general stress (Perceived Stress Scale). Physiological stress was measured by markers of HPA axis function (elevated cortisol awakening response [CAR]), endothelial dysfunction (increased PAI-1), and inflammation (increased IL-6, hsCRP). HF patient functional status was quantified by caregiver assessment of New York Heart Association (NYHA) Class. Generalized linear models were used to test associations between patient NYHA Class and stress (one model per indicator). NYHA Class (ordinal) was backwards difference coded in each model to examine caregiver stress in relation to increasing levels of HF severity. Caregivers were mostly female and in their mid-fifties, with a slight majority of the sample being African American and the patient's spouse. Overall, patient functional status was associated with greater caregiver psychological and physiological stress. In terms of psychological stress, higher NYHA Class was significantly associated with greater caregiver anxiety and general stress, but not with caregiver burden or depression. In terms of physiological stress, higher NYHA Class was associated with elevated markers in all models (elevated CAR and higher IL-6, hsCRP, and PAI-1). Across models, most associations between NYHA Class and stress were present at relatively early stages of functional limitation (i.e. Class II), while others emerged when functional limitations became more severe. To inform timing and mechanisms for much-needed caregiver interventions, research is needed to determine which aspects of HF symptomatology are most stressful for caregivers across the HF trajectory., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Sleepiness in obstructive sleep apnoea is associated with cardiovascular risk; however, the biological mechanisms are not known. This study explored whether those with subjective sleepiness have increased plasma tumour necrosis factor-related protein 1 (C1qTNF1), a novel adipose-derived hormone (adipokine), and 24-h ambulatory blood pressure (ABP) compared to those without sleepiness in newly diagnosed, treatment-naïve participants with obstructive sleep apnoea., Methods: Overall, 94 participants were included in the analysis. Participants completed the Epworth Sleepiness Scale (ESS), 24-h ABP was monitored, and plasma C1qTNF1 was measured. Sleepy participants were defined as ESS≥10 and nonsleepy as ESS<10. Multiple linear regression was used to explore differences in C1qTNF1, and 24-h mean arterial pressure (MAP) between sleepy and nonsleepy participants, adjusting for age, sex, body mass index, apnoea-hypopnoea index, and smoking status., Results: C1qTNF1 was significantly higher in sleepy participants (n=57) compared to nonsleepy participants (n=37) (β=0.41 NPX, 95% CI 0.02, 0.80; p=0.04). The 24-h MAP was significantly higher in sleepy participants compared to nonsleepy participants (β=4.06 mmHg, 95% CI 0.36, 7.77; p=0.03)., Conclusions: Our findings show that sleepiness is associated with inflammation and higher 24-h MAP in sleep apnoea., Competing Interests: Conflict of interest: V.M. Pak has nothing to disclose. Conflict of interest: B. Butts has nothing to disclose. Conflict of interest: V. Hertzberg has nothing to disclose. Conflict of interest: N. Collop has nothing to disclose. Conflict of interest: A.A. Quyyumi has nothing to disclose. Conflict of interest: J. Cox has nothing to disclose. Conflict of interest: A. Rogers has nothing to disclose. Conflict of interest: S.B. Dunbar has nothing to disclose., (Copyright ©ERS 2020.)

Objectives: The transition from hospital to home is a period of risk, particularly for children with medical complexity. Our aim was to identify and address discharge challenges through execution of postdischarge phone calls., Methods: In this prospective study, we designed and executed a postdischarge phone call for patients discharged from an inpatient complex care team between May and November 2018. The call included dichotomous and open-ended questions to identify challenges regarding health status, follow-up appointments, medications, home nursing, medical supplies and/or equipment, and discharge instructions. These were recorded in the electronic health record. Details regarding identified challenges and corrective actions were categorized by 2 reviewers and adjudicated by a third reviewer if disagreement occurred., Results: Descriptive statistics were used to summarize these findings. Sixty-seven phone calls were completed within 1 week of discharge. Two-thirds of calls identified at least 1 challenge, and more than one-third of calls identified 2 or more challenges for a total of 90 challenges. The most common challenges involved health status (26.7%), follow-up appointments (21.1%), and medications (20%). The majority of challenges were addressed by either caregivers or the multidisciplinary team, with the exception of home nursing challenges., Conclusions: Discharge challenges were commonly identified by caregivers of children with medical complexity. The majority of postdischarge challenges were addressed, with some addressed by families themselves. These results can inform health care providers about challenges to anticipate and suggest future interventions to mitigate anticipated challenges for a safe discharge and transition of care for these at-risk patients., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Objective: This randomized controlled trial was conducted to determine whether a 12-week home-based aerobic and resistance exercise program would improve physical function and caregiving perceptions among family caregivers (FCGs) of persons with heart failure. Method: Overall, 127 FCGs were randomized to one of three groups: usual care attention control (UCAC), psychoeducation only (PE), and psychoeducation plus exercise (PE + EX). Physical function measures (6-min walk test, handgrip, and upper and lower strength) and caregiving perceptions (Bakas Caregiving Outcomes Scale) were obtained at baseline and at 6 months. Results: FCGs in the PE + EX showed significant improvement in 6-min walk distance ( p = .012), handgrip, and lower extremity strength compared with the PE and UCAC groups. The combined group had the greatest improvement in caregiver perceptions ( p < .001). Conclusion: FCGs in the PE + EX group improved the most in physical function and caregiver perception outcomes. Directions for future research are provided.

Increasing left atrial (LA) size predicts outcomes in patients with isolated mitral regurgitation (MR). Chymase is plentiful in the human heart and affects extracellular matrix remodeling. Chymase activation correlates to LA fibrosis, LA enlargement, and a decreased total LA emptying fraction in addition to having a potential intracellular role in mediating myofibrillar breakdown in LA myocytes. Because of the unreliability of the left ventricular ejection fraction in predicting outcomes in MR, LA size and the total LA emptying fraction may be more suitable indicators for timing of surgical intervention.

Objective: Mild cognitive impairment, especially memory loss, is prevalent in patients with heart failure (HF) and contributes to poor clinical outcomes and higher mortality., Methods: This study evaluated a combined aerobic exercise and cognitive training (EX/CT) program on memory, executive function, attention, processing speed and reaction time compared to exercise only or a usual care attention control (UCAC) stretching and flexibility program. Participants completed a standardized neurocognitive battery at baseline, 3 months, and 6 months along with demographic, clinical, and functional capacity (6-minute walk test). A linear mixed model analysis was used with comorbidity as a covariate., Results: Sixty-nine participants were enrolled, the mean age was 61 ± 10 years, 54% were women, 55% were African American, and the mean left ventricular ejection fraction percentage was 35 ± 15. A significant group by time interaction for verbal memory was found at 3 months (F [2, 53] = 4.3, p = 0.018) but was not sustained at 6 months in the EX/CT group. Processing speed/attention differed across treatment groups between baseline and 6 months, but improvement occurred among UCAC participants. There were also significant group differences in the 6MWT distance occurring at 3 months (F [2, 52] = 3.5, p = 0.036); however, significant improvement was observed within the EX/CT group only. There were no significant differences in 6MWT in the other groups at 3 or 6 months., Conclusion: An EX/CT intervention was associated with improved memory in persons with HF and warrants further investigation in a larger trial. The relationship between functional capacity and cognitive function also needs further study., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN)., Methods: The study group included persons with RHTN (n = 91), defined as a blood pressure > 140/90 mmHg on ≥ 3 medications at pharmacologically effective doses. Plasma XO activity and 24-h urine were collected, and cardiac magnetic resonance imaging (MRI) was performed to assess LV function and morphology. Sixty-seven normotensive persons on no cardiovascular medications served as controls. A subset of RHTN (n = 19) received spironolactone without salt restriction for six months with follow-up XO activity measurements and MRI analyses., Results: XO activity was increased two-fold in RHTN vs. normal and was positively correlated with LV mass, LV diastolic function, and 24-h urinary sodium. In RHTN patients receiving spironolactone without salt restriction, LV mass decreased, but LV diastolic function and XO activity did not improve. Baseline urinary sodium was positively associated with rate of change of LV mass to volume ratio and the LV E/A ratio., Conclusions: These results demonstrate a potential role of endothelium-derived oxidative stress and excess dietary salt in the pathophysiology of LV hypertrophy and diastolic dysfunction in persons with RHTN unaffected by the addition of spironolactone., (Copyright © 2019. Published by Elsevier Inc.)

Introduction/purpose: Inflammation contributes to heart failure (HF) progression and the interleukin (IL)-1 cytokine IL-1β is implicated in this process. The adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is necessary for inflammasome activation of IL-1β. Lower ASC methylation is associated with worse outcomes in HF. The purpose of this study was to examine the effects of exercise on changes in ASC methylation and activation of the IL-1 family cytokine IL-1β in persons with HF., Methods: Participants (N = 54) were randomized to receive exercise intervention (n = 38) or attention control (n = 16) for 3 months. Percent methylation of the ASC gene, plasma IL-1β, and ASC mRNA and were obtained at baseline, 3 months, and 6 months., Results: ASC methylation was higher in the exercise group as compared to control at 3 months (6.10% ± 0.5% vs 5.80% ± 0.4%; P = 0.04) and 6 months (6.07 ± 0.4 vs 5.82 ± 0.4; P = 0.04). Plasma IL-1β was lower in the exercise group at 3 months (1.43 ± 0.5 pg·mL vs 2.09 ± 1.3 pg·mL; P = 0.02) and 6 months (1.49 ± 0.5 pg·mL vs 2.13 ± 1.4 pg·mL; P = 0.004). ASC mRNA expression was negatively associated with ASC methylation at baseline (r = -0.97, P = 0.001), 3 months (r = -0.90, P = 0.001), and 6 months (r = -0.81, P = 0.001). ASC mRNA was lower than baseline at 3 months (P = 0.004) and 6 months (P = 0.002) among those in the exercise group. ASC methylation was positively associated with 6-min walk test at baseline (r = 0.517, P < 0.001), 3 months (r = 0.464, P = 0.004), and 6 months (r = 497, P = 0.05)., Conclusions: Exercise was related to increased mean percent ASC methylation and decreased IL-1β and ASC mRNA gene expression in HF. Epigenetic regulation of ASC can be a biological mechanism by which exercise can promote better outcomes in HF.

Background and Objective: Since first being published in 2009, the Atlanta Heart Failure Knowledge Test (AHFKT) has proven a reliable and valid instrument and has been used in multiple studies. Given advances in heart failure (HF) self-care, we proposed to reevaluate the psychometric properties of the AHFKTv2 across these recent studies and update the instrument., Methods: Demographic, clinical, and baseline AHFKTv2 data from 4 intervention studies in persons with HF were combined for this analysis (N = 284). The 30 questions of the AHFKT are focused on 5 HF self-care knowledge domains: pathophysiology, nutrition, behavior, medications, and symptoms. Characteristics of the sample were analyzed using descriptive statistics; validity testing with t tests and Mann-Whitney 2-group tests and Pearson r and Spearman ρ correlations; and reliability calculations and factor analysis were performed based on tetrachoric correlations., Results: Participants were 22 to 84 years of age, 66% were African American, 63% were male, and 94% had New York Heart Association class II to III HF. Mean AHFKT score was 80.6% (±11%). Hypotheses that higher levels of knowledge would be associated with higher education level (t = -2.7, P < .01) and less sodium consumption (ρ = -0.22, P = .03) were validated. Factor analysis revealed 1 general knowledge factor with good reliability, Cronbach's α was .87. Item response analysis identified individual questions requiring review and revision., Conclusion: Comprehensive psychometric evaluation of the AHFKTv2 confirmed its internal consistency reliability and validity and provided direction for production of the AHFKTv3 available for use in research and clinical practice.

Background: Aerobic capacity, as measured by peak oxygen uptake (V˙O2), is one of the most powerful predictors of prognosis in heart failure (HF). Inflammation is a key factor contributing to alterations in aerobic capacity, and interleukin (IL)-1 cytokines are implicated in this process. The adaptor protein ASC is necessary for inflammasome activation of IL-1β and IL-18. ASC expression is controlled through epigenetic modification; lower ASC methylation is associated with worse outcomes in HF. The purpose of this study is to examine the relationships between ASC methylation, IL-1β, and IL-18 with V˙O2peak in persons with HF., Methods: This study examined the relationship between ASC methylation, IL-1β, and IL-18 with V˙O2peak in 54 stable outpatients with HF. All participants were NYHA class II or III, not engaged in an exercise program, and physically able to complete an exercise treadmill test., Results: Mean V˙O2peak was 16.68 ± 4.7 mL·kg·min. V˙O2peak was positively associated with mean percent ASC methylation (r = 0.47, P = 0.001) and negatively associated with IL-1β (r = -0.38, P = 0.007). Multiple linear regression models demonstrated that V˙O2peak increased by 2.30 mL·kg·min for every 1% increase in ASC methylation and decreased by 1.91 mL·kg·min for every 1 pg·mL increase in plasma IL-1β., Conclusions: Mean percent ASC methylation and plasma IL-1β levels are associated with clinically meaningful differences in V˙O2peak in persons with HF. Inflammasome activation may play a mechanistic role in determining aerobic capacity. ASC methylation is a potentially modifiable mechanism for reducing the inflammatory response, thereby improving aerobic capacity in HF.

Background: Heart failure (HF) is associated with inflammation characterized by the formation of the inflammasome, which triggers maturation of inflammatory cytokines. Apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), a vital component of the inflammasome, is controlled through epigenetic modification, which may be a candidate pathway for worsening HF. This study examined the inflammasome pathway in HF and the relationships between ASC CpG methylation and outcomes in HF., Methods and Results: Stored samples from 155 HF outpatients (ejection fraction 29.9 ± 14.9%) were analyzed for percentage methylation of 7 CpG sites in the intron region preceding exon 1 of the ASC gene. ASC methylation was inversely related to ASC mRNA (r = -0.33; P < .001) and protein (r = -0.464; P < .001). ASC methylation had a positive linear relationship with ejection fraction (r = 0.85; P < .001), quality of life (r = 0.83; P < .001), and 6-minute walk test (r = 0.59; P = .023) and a negative linear relationship with depression (r = -0.81; P < .001) and anxiety (r = -0.75; P < .001). Higher ASC methylation was associated with a lower risk for clinical events (hazard ratio [HR] 0.16; P = .025), whereas higher protein (HR = 1.78; P = .045) and mRNA expression (HR = 1.18; P = .05) were associated with a greater risk., Conclusions: Increased methylation of CpG sites in the intron region of ASC is associated with improved outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes and may represent a therapeutic target., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Persons with concomitant heart failure (HF) and diabetes mellitus (DM) have complicated, often competing, self-care expectations and treatment regimens that may reduce quality of life (QOL). This randomized controlled trial tested an integrated self-care intervention on outcomes of HF and DM QOL, physical function, and physical activity (PA)., Methods and Results: Participants with HF and DM (n = 134; mean age 57.4 ± 11 years, 66% men, 69% minority) were randomized to usual care (control) or intervention. The control group received standard HF and DM educational brochures with follow-up telephone contact. The intervention group received education and counseling on combined HF and DM self-care (diet, medications, self-monitoring, symptoms, and PA) with follow-up home visit and telephone counseling. Measures included questionnaires for HF- and DM-specific and overall QOL, PA frequency, and physical function (6-min walk test [6MWT]) and were obtained at baseline and 3 and 6 months. Analysis included mixed models with a priori post hoc tests. Adjusting for age, body mass index, and comorbidity, the intervention group improved in HF total (P = .002) and physical (P < .001) QOL scores at 3 months with retention of improvements at 6 months, improved in emotional QOL scores compared with control at 3 months (P = .04), and improved in health status ratings (P = .04) at 6 months compared with baseline. The intervention group improved in 6MWT distance (924 ft to 952 ft; P = .03) whereas the control group declined (834 ft to 775 ft; F1,63 = 6.86; P = .01). The intervention group increased self-reported PA between baseline and 6 months (P = .01)., Conclusions: An integrated HF and DM self-care intervention improved perceived HF and general QOL but not DM QOL. Improved physical functioning and self-reported PA were also observed with the integrated self-care intervention. Further study of the HF and DM integrated self-care intervention on other outcomes, such as hospitalization and cost, is warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Persons with concomitant heart failure (HF) and diabetes mellitus constitute a growing population whose quality of life is encumbered with worse clinical outcomes as well as high health resource use (HRU) and costs., Methods and Results: Extensive data on HRU and costs were collected as part of a prospective cost-effectiveness analysis of a self-care intervention to improve outcomes in persons with both HF and diabetes. HRU costs were assigned from a Medicare reimbursement perspective. Patients (n = 134) randomized to the self-care intervention and those receiving usual care/attention control were followed for 6 months, revealing significant differences in the number of hospitalization days and associated costs between groups. The mean number of inpatient days was 3 with bootstrapped bias-corrected (BCa) confidence intervals (CIs) of 1.8-4.4 d for the intervention group and 7.3 d (BCa CI 4.1-10.9 d) in the control group: P = .044. Total direct HRU costs per participant were an estimated $9,065 (BCa CI $6,496-$11,936) in the intervention and $16,712 (BCa CI 8,200-$26,621) in the control group, for a mean difference of -$7,647 (BCa CI -$17,588 to $809; P = .21) in favor of the intervention, including intervention costs estimated to be $130.67 per patient., Conclusions: The self-care intervention demonstrated dominance in lowering costs without sacrificing quality-adjusted life-years., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Patients with heart failure continue to suffer adverse health consequences despite advances in therapies over the past 2 decades. Identification of novel therapeutic targets that may attenuate disease progression is therefore needed. The inflammasome may play a central role in modulating chronic inflammation and in turn affecting heart failure progression. The inflammasome is a complex of intracellular interaction proteins that trigger maturation of proinflammatory cytokines interleukin-1β and interleukin-18 to initiate the inflammatory response. This response is amplified through production of tumor necrosis factor α and activation of inducible nitric oxide synthase. The purpose of this review is to discuss recent evidence implicating this inflammatory pathway in the pathophysiology of heart failure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To review some of the proposed pathways that increase frailty risk in older persons with heart failure and to discuss tools that may be used to assess for changes in physical and cognitive functioning in this population in order to assist with appropriate and timely intervention., Methods: Review of the literature., Results: Heart failure is the only cardiovascular disease that is increasing by epidemic proportions, largely due to an aging society and therapeutic advances in disease management. Because heart failure is largely a cardiogeriatric syndrome, age-related syndromes such as frailty and cognitive impairment are common in heart failure patients. Compared with age-matched counterparts, older adults with heart failure 4 to 6 times more likely to be frail or cognitively impaired. The reason for the high prevalence of frailty and cognitive impairment in this population is not well known but may likely reflect the synergistic effects of heart failure and aging, which may heighten vulnerability to stressors and accelerate loss of physiologic reserve. Despite the high prevalence of frailty and cognitive impairment in the heart failure population, these conditions are not routinely screened for in clinical practice settings and guidelines on optimal assessment strategies are lacking., Conclusion: Persons with heart failure are at an increased risk for frailty, which may worsen symptoms, impair self-management, and lead to worse heart failure outcomes. Early detection of frailty and cognitive impairment may be an opportunity for intervention and a key strategy for improving clinical outcomes in older adults with heart failure.

Studies show 30% to 47% of people with heart failure (HF) have concomitant diabetes mellitus (DM). Self-care for persons with both of these chronic conditions is conflicting, complex, and often inadequate. This pilot study tested an integrated self-care program for its effects on HF and DM knowledge, self-care efficacy, self-care behaviors, and quality of life (QOL). Hospitalized HF-DM participants (N = 71) were randomized to usual care or intervention using a 1:2 allocation and followed at 30 and 90 days after intervention. Intervention was an integrated education and counseling program focused on HF-DM self-care. Variables included demographic and clinical data, knowledge about HF and DM, HF- and DM-specific self-efficacy, standard HF and DM QOL scales, and HF and DM self-care behaviors. Analysis included descriptive statistics, multilevel longitudinal models for group and time effects, post hoc testing, and effect size calculations. Sidak adjustments were used to control for type 1 error inflation. The integrated HF-DM self-care intervention conferred effects on improved HF knowledge (30 days, p = .05), HF self-care maintenance (30 and 90 days, p < .001), HF self-care management (90 days, p = .05), DM self-efficacy (30 days, p = .03; 90 days, p = .004), general diet (30 days, p = .05), HF physical QOL (p = .04), and emotional QOL scores (p = .05) at 90 days within the intervention group. The participants in the usual care group also reported increased total and physical QOL. Greater percentages of participants in the intervention group improved self reported exercise between 0 and 30 days (p = .005 and moderate effect size ES = .47) and foot care between 0 and 90 days (p = .03, small ES = .36). No group differences or improvements in DM-specific QOL were observed. An integrated HF-DM self-care intervention was effective in improving essential components of self-care and had sustained (90 day) effects on selected self-care behaviors. Future studies testing HF-DM integrated self-care interventions in larger samples with longer follow-up and on other outcomes such as hospitalization and clinical markers are warranted., (Copyright © 2014 Elsevier Inc. All rights reserved.)