Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation

To identify rate-limiting steps in T cell-independent type 2 (TI-2) antibody production against polysaccharide antigens, we performed a genome-wide screen by immunizing several hundred pedigrees of C57BL/6 mice segregating ENU-induced mis-sense mutations. Two independent mutations, Tilcara and Untied, were isolated that semi-dominantly diminished antibody against polysaccharide but not protein antigens. Both mutations resulted from single amino acid substitutions within the kinase domain of Protein Kinase C Beta (PKCβ). In Tilcara, a Ser552>Pro mutation occurred in helix G, in close proximity to a docking site for the inhibitory N-terminal pseudosubstrate domain of the enzyme, resulting in almost complete loss of active, autophosphorylated PKCβI whereas the amount of alternatively spliced PKCβII protein was not markedly reduced. Circulating B cell subsets were normal and acute responses to BCR-stimulation such as CD25 induction and initiation of DNA synthesis were only measurably diminished in Tilcara homozygotes, whereas the fraction of cells that had divided multiple times was decreased to an intermediate degree in heterozygotes. These results, coupled with evidence of numerous mis-sense PRKCB mutations in the human genome, identify Prkcb as a genetically sensitive step likely to contribute substantially to population variability in anti-polysaccharide antibody levels

Operationalizing Frailty in the Atherosclerosis Risk in Communities Study Cohort

Background: Factors that may contribute to the development of frailty in late life have not been widely investigated. The Atherosclerosis Risk in Communities (ARIC) Study cohort presents an opportunity to examine relationships of midlife risk factors with frailty in late life. However, we first present findings on the validation of an established frailty phenotype in this predominantly biracial population of older adults. Methods: Among 6,080 participants, we defined frailty based upon the Cardiovascular Health Study (CHS) criteria incorporating measures of weight loss, exhaustion, slow walking speed, low physical activity, and low grip strength. Criterion and predictive validity of the frailty phenotype were estimated from associations between frailty status and participants' physical and mental health status, physiologic markers, and incident clinical outcomes. Results: A total of 393 (6.5%) participants were classified as frail and 50.4% pre-frail, similar to CHS (6.9% frail, 46.6% pre-frail). In age-adjusted analyses, frailty was concurrently associated with depressive symptoms, low self-rated health, low medication adherence, and clinical biomarker levels (ie, cholesterol, hemoglobin A1c, white blood cell count, C-reactive protein, and hemoglobin). During 1-year follow-up, frailty was associated with falls, low physical ability, fatigue, and mortality. Conclusions: These findings support the validity of the CHS frailty phenotype in the ARIC Study cohort. Future studies in ARIC may elucidate early-life exposures that contribute to late-life frailty

Effects of Age and Functional Status on the Relationship of Systolic Blood Pressure With Mortality in Mid and Late Life: The ARIC Study

Impaired functional status attenuates the relationship of systolic blood pressure (SBP) with mortality in older adults but has not been studied in middle-aged populations

The Importance of Mid-to-Late-Life Body Mass Index Trajectories on Late-Life Gait Speed

Background: Prior studies suggest being overweight may be protective against poor functional outcomes in older adults. Methods: Body mass index (BMI, kg/m2) was measured over 25 years across five visits (1987-2011) among Atherosclerosis Risk in Communities Study participants (baseline Visit 1 n = 15,720, aged 45-64 years). Gait speed was measured at Visit 5 ("late-life", aged ≥65 years, n = 6,229). BMI trajectories were examined using clinical cutpoints and continuous mixed models to estimate effects of patterns of BMI change on gait speed, adjusting for demographics and comorbidities. Results: Mid-life BMI (baseline visit; 55% women; 27% black) was associated with late-life gait speed 25 years later; gait speeds were 94.3, 89.6, and 82.1 cm/s for participants with baseline normal BMI (<25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30) (p < .001). In longitudinal analyses, late-life gait speeds were 96.9, 88.8, and 81.3 cm/s for participants who maintained normal, overweight, and obese weight status, respectively, across 25 years (p < .01). Increasing BMI over 25 years was associated with poorer late-life gait speeds; a 1%/year BMI increase for a participant with a baseline BMI of 22.5 (final BMI 28.5) was associated with a 4.6-cm/s (95% confidence interval: -7.0, -1.8) slower late-life gait speed than a participant who maintained a baseline BMI of 22.5. Conclusion: Being overweight in older age was not protective of mobility function. Maintaining a normal BMI in mid- and late-life may help preserve late-life mobility

Cardiovascular Health and Incident Cardiovascular Disease and Cancer

The American Heart Association's “Simple 7” offers a practical public health conceptualization of cardiovascular health (CVH). CVH predicts incident cardiovascular disease (CVD) in younger populations, but has not been studied in a large, diverse population of aging postmenopausal women. The extent to which CVH predicts cancer in postmenopausal women is unknown

Longitudinal Associations between Income Changes and Incident Cardiovascular Disease: The Atherosclerosis Risk in Communities Study

Importance: Higher income is associated with lower incident cardiovascular disease (CVD). However, there is limited research on the association between changes in income and incident CVD. Objective: To examine the association between change in household income and subsequent risk of CVD. Design, Setting, and Participants: The Atherosclerosis Risk In Communities (ARIC) study is an ongoing, prospective cohort of 15792 community-dwelling men and women, of mostly black or white race, from 4 centers in the United States (Jackson, Mississippi; Washington County, Maryland; suburbs of Minneapolis, Minnesota; and Forsyth County, North Carolina), beginning in 1987. For our analysis, participants were followed up until December 31, 2016. Exposures: Participants were categorized based on whether their household income dropped by more than 50% (income drop), remained unchanged/changed less than 50% (income unchanged), or increased by more than 50% (income rise) over a mean (SD) period of approximately 6 (0.3) years between ARIC visit 1 (1987-1989) and visit 3 (1993-1995). Main Outcomes and Measures: Our primary outcome was incidence of CVD after ARIC visit 3, including myocardial infarction (MI), fatal coronary heart disease, heart failure (HF), or stroke during a mean (SD) of 17 (7) years. Analyses were adjusted for sociodemographic variables, health behaviors, and CVD biomarkers. Results: Of the 8989 included participants (mean [SD] age at enrollment was 53 [6] years, 1820 participants were black [20%], and 3835 participants were men [43%]), 900 participants (10%) experienced an income drop, 6284 participants (70%) had incomes that remained relatively unchanged, and 1805 participants (20%) experienced an income rise. After full adjustment, those with an income drop experienced significantly higher risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 1.17; 95% CI, 1.03-1.32). Those with an income rise experienced significantly lower risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 0.86; 95% CI, 0.77-0.96). Conclusions and Relevance: Income drop over 6 years was associated with higher risk of subsequent incident CVD over 17 years, while income rise over 6 years was associated with lower risk of subsequent incident CVD over 17 years. Health professionals should have greater awareness of the influence of income change on the health of their patients

Functional status declines among cancer survivors: Trajectory and contributing factors

This study aimed to quantify functional status (FS) trajectories pre- and post-diagnosis of cancer, FS trajectories among cancer-free individuals, and factors affecting FS

Anger Proneness, Gender, and the Risk of Heart Failure

Evidence concerning the association of anger-proneness with incidence of heart failure is lacking

Trajectory of overall health from self-report and factors contributing to health declines among cancer survivors

This study aims to quantify trajectories of overall health pre- and post-diagnosis of cancer, trajectories of overall health among cancer-free individuals, and factors affecting overall health status

Hospital recruitment for a pragmatic cluster-randomized clinical trial: Lessons learned from the COMPASS study

Abstract Background Pragmatic randomized clinical trials are essential to determine the effectiveness of interventions in “real-world” clinical practice. These trials frequently use a cluster-randomized methodology, with randomization at the site level. Despite policymakers’ increased interest in supporting pragmatic randomized clinical trials, no studies to date have reported on the unique recruitment challenges faced by cluster-randomized pragmatic trials. We investigated key challenges and successful strategies for hospital recruitment in the Comprehensive Post-Acute Stroke Services (COMPASS) study. Methods The COMPASS study is designed to compare the effectiveness of the COMPASS model versus usual care in improving functional outcomes, reducing the numbers of hospital readmissions, and reducing caregiver strain for patients discharged home after stroke or transient ischemic attack. This model integrates early supported discharge planning with transitional care management, including nurse-led follow-up phone calls after 2, 30, and 60 days and an in-person clinic visit at 7–14 days involving a functional assessment and neurological examination. We present descriptive statistics of the characteristics of successfully recruited hospitals compared with all eligible hospitals, reasons for non-participation, and effective recruitment strategies. Results We successfully recruited 41 (43%) of 95 eligible North Carolina hospitals. Leading, non-exclusive reasons for non-participation included: insufficient staff or financial resources (n = 33, 61%), lack of health system support (n = 16, 30%), and lack of support of individual decision-makers (n = 11, 20%). Successful recruitment strategies included: building and nurturing relationships, engaging team members and community partners with a diverse skill mix, identifying gatekeepers, finding mutually beneficial solutions, having a central institutional review board, sharing published pilot data, and integrating contracts and review board administrators. Conclusions Although we incorporated strategies based on the best available evidence at the outset of the study, hospital recruitment required three times as much time and considerably more staff than anticipated. To reach our goal, we tailored strategies to individuals, hospitals, and health systems. Successful recruitment of a sufficient number and representative mix of hospitals requires considerable preparation, planning, and flexibility. Strategies presented here may assist future trial organizers in implementing cluster-randomized pragmatic trials. Trial registration Clinicaltrials.gov, NCT02588664 . Registered on 23 October 2015