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

Association of Nonacute Opioid Use and Cardiovascular Diseases: A Scoping Review of the Literature

BACKGROUND In this scoping review, we identified and reviewed 23 original articles from the PubMed database that investigated the relationship between nonacute opioid use (NOU) and cardiovascular outcomes. METHODS AND RESULTS We defined NOU to include both long-term opioid therapy and opioid use disorder. We summarized the association between NOU and 5 classes of cardiovascular disease, including infective endocarditis, coronary heart disease (including myocardial infarction), congestive heart failure, cardiac arrythmia (including cardiac arrest), and stroke. The most commonly studied outcomes were coronary heart disease and infective endocarditis. There was generally consistent evidence of a positive association between community prevalence of injection drug use (with opioids being the most commonly injected type of drug) and community prevalence of infective endocarditis, and between (primarily medically indicated) NOU and myocardial infarction. There was less consensus about the relationship between NOU and congestive heart failure, cardiac arrhythmia, and stroke. CONCLUSIONS There is a dearth of high-quality evidence on the relationship between NOU and cardiovascular disease. Innovative approaches to the assessment of opioid exposure over extended periods of time will be required to address this need

Psychosocial services provided by licensed cardiac rehabilitation programs

BackgroundProfessional health organizations recommend that outpatient cardiac rehabilitation programs include activities to optimize the physical, mental, and social well-being of patients. The study objectives were to describe among cardiac rehabilitation programs (1) mental health assessments performed; (2) psychosocial services offered; and (3) leadership's perception of barriers to psychosocial services offerings.MethodsA cross-sectional survey of North Carolina licensed outpatient cardiac rehabilitation programs on their 2018 services was conducted. Descriptive statistics were used to summarize survey responses. Thematic analysis of free text questions related to barriers to programmatic establishment or expansion of psychosocial services was performed by two team members until consensus was reached.ResultsSixty-eight programs (89%) responded to the survey. Forty-eight programs (70%) indicated offering psychosocial services; however, a majority (73%) of programs reported not directly billing for those services. At program enrollment, mental health was assessed in 94% of programs of which 92% repeated the assessment at discharge. Depression was assessed with the 9-item Patient Health Questionnaire by a majority (75%) of programs. Psychosocial services included individual counseling (59%), counseling referrals (49%), and educational classes (29%). Directors reported lack of internal resources (92%) and patient beliefs (45%) as the top barriers to including or expanding psychosocial services at their facilities.ConclusionsCardiac rehabilitation programs routinely assess mental health but lack the resources to establish or expand psychosocial services. Interventions aimed at improving patient education and reducing stigma of mental health are important public health opportunities

Identification of Heart Failure Events in Medicare Claims: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the accuracy of CMS Medicare HF diagnostic codes in the identification of acute decompensated and chronic stable HF (ADHF and CSHF)

Cardiac Biomarkers and Subsequent Risk of Hospitalization With Bleeding in the Community: Atherosclerosis Risk in Communities Study

Background hs-cTnT (high-sensitivity cardiac troponin T), but not NT-proBNP (N-terminal pro-B natriuretic peptide), has been shown to predict bleeding in patients with atrial fibrillation. Whether these biomarkers are independently associated with bleeding in the general population is unknown. Methods and Results We used Cox proportional hazards models to examine the association of hs‐cTnT and NT‐proBNP with incident bleeding (defined by International Classification of Diseases, Ninth Revision [ICD‐9] codes) among 9550 middle‐aged men and women without a history of cardiovascular disease or bleeding. There were 847 hospitalizations with bleeding (92% from gastrointestinal bleeding) during a median follow‐up of 9.0 years. Serum levels of hs‐cTnT were associated with bleeding in a graded fashion, with a hazard ratio of 1.28 (95% CI, 1.06–1.59) for 6 to \u3c 9 ng/L, 1.52 (1.21–1.91) for 9 to \u3c 14, and 2.05 (1.56–2.69) for ≥14 versus \u3c 3 ng/L. For NT‐proBNP, the highest category (≥264 versus \u3c 42 pg/mL) showed a hazard ratio of 2.00 (1.59–2.61), and the remaining 3 categories had hazard ratios ranging from 1.2 to 1.3. Individuals in the highest category of both hs‐cTnT and NT‐proBNP had a hazard ratio of 3.03 (1.97–4.68) compared with those in the lowest categories. Conclusions In a community‐based population, elevated hs‐cTnT and NT‐proBNP were associated with bleeding‐related hospitalizations. These biomarkers may have a high utility in identifying people at high risk for bleeding. There is a need for research on the underlying mechanisms linking subclinical cardiac abnormalities and bleeding

Protrusion of the carotid canal into the sphenoid sinuses: evaluation before endonasal endoscopic sinus surgery

Background: Many reports have previously indicated the vast number of anatomical variations of the sphenoid sinuses, e.g. presence of the recesses. Notwithstanding, there are a few crucial neurovascular structures directly neighbouring with the sinuses. The following research aimed to evaluate frequency prevalence of the carotid canal’s protrusion into the sphenoid sinuses in adult population.Materials and methods: Computed tomography (CT) scans of the paranasal sinuses of 296 patients (147 females, 149 males) were analysed in this retrospective study. The patients did not present any pathology in the sinuses. Spiral CT scanner Siemens Somatom Sensation 16 was used in the standard procedure in the option Siemens CARE Dose 4D.Results: Protrusion of the carotid canal was found in the majority of the patients — 55.74%, more frequently in males (65.1% of the patients) than in females (46.26% of the patients). The said variant — regardless of gender — was noted more often bilaterally (41.55% of the cases: 29.93% females, 53.02% males) than unilaterally (14.19% of the cases: 16.33% females, 12.08% males). In the unilateral type (regardless of gender), the protrusion was more common for the left sphenoid sinus — 10.81% of the patients (12.24% females, 9.4% males) than for the right — 3.38% of the patients (4.08% females, 2.68% males).Conclusions: Complicated structure of the paranasal sinuses, derived from the high prevalence of their anatomical variations, may perplex routine surgical interventions. Henceforth, referral for a CT scan is imperative in order to abate the risks associated with an invasive procedure in the said region

Decline in Lung Function From Mid-to Late-Life With Central Arterial Stiffness: The Atherosclerosis Risk in Communities Study

We investigated the association of lung function at mid-life, later in life, and its 20-year decline, with arterial stiffness later in life. We examined 5720 Atherosclerosis Risk in Communities Study participants who attended Visits 1 (1987-1989) and 5 (2011-2013). Lung function measures were forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), obtained at Visits 1, 2 (1990–1992), and 5. Central artery stiffness (carotid-femoral pulse wave velocity [cfPWV]) was measured at Visit 5. We evaluated associations of lung function with later-life central artery stiffness and cfPWV >75th percentile by multivariable linear and logistic regressions. Lung function at Visit 1 (FEV1 β: −26, 95% Confidence Interval [CI]: −48, −5; FVC β: −14, 95% CI: −32, 5) and Visit 5 (FEV1 β: −22, 95% CI: −46, 2; FVC β: −18, 95% CI: −38, 2) were inversely associated with cfPWV at Visit 5, and with odds of high cfPWV in fully adjusted models. Twenty-year decline in lung function was not associated with continuous or dichotomous measures of arterial stiffness (FEV1 β: 11, 95% CI: −46, 68; FVC β: −4, 95% CI: −52, 43). Lung function at mid-life and late-life was inversely associated with arterial stiffness in later life

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