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

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)

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

Approaches to Address Premature Death of Patients When Assessing Patterns of Use of Health Care Services after an Index Event

Background: Studies of the use of health care after the onset of disease are important for assessing quality of care, treatment disparities, and guideline compliance. Cohort definition and analysis method are important considerations for the generalizability and validity of study results. We compared different approaches for cohort definition (restriction by survival time vs. comorbidity score) and analysis method [Kaplan-Meier (KM) vs. competing risk] when assessing patterns of guideline adoption in elderly patients. Methods: Medicare beneficiaries aged 65-95 years old who had an acute myocardial infarction (AMI) in 2008 were eligible for this study. Beneficiaries with substantial frailty or an AMI in the prior year were excluded. We compared KM with competing risk estimates of guideline adoption during the first year post-AMI. Results: At 1-year post-AMI, 14.2% [95% confidence interval (CI), 14.0%-14.5%) of beneficiaries overall initiated cardiac rehabilitation when using competing risk analysis and 15.1% (95% CI, 14.8%-15.3%) from the KM analysis. Guideline medication adoption was estimated as 52.3% (95% CI, 52.0%-52.7%) and 53.4% (95% CI, 53.1%-53.8%) for competing risk and KM methods, respectively. Mortality was 17.0% (95%CI, 16.8%-17.3%) at 1 year post-AMI. The difference in cardiac rehabilitation initiation at 1-year post-AMI from the overall population was 0.1%, 1.7%, and 1.9% compared with 30-day survivor, 1-year survivor, and comorbidity-score restricted populations, respectively. Conclusions: In this study, the KM method consistently overestimated the competing risk method. Competing risk approaches avoid unrealistic mortality assumptions and lead to interpretations of estimates that are more meaningful

Role of BMI in the Association of the TCF7L2 rs7903146 Variant with Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI < 25 kg/m2) individuals homozygous for the T allele of the TCF7L2 rs7903146 gene risk variant (hazard ratio 1.42; 95% CI 1.03,1.97; P = .01). No association was found among 3,631 blacks, regardless of BMI status. An attenuated hazard ratio was observed among the nondiabetic ARIC cohort members. This study suggests that body mass modifies the association of the TCF7L2 rs7903146 T allele with CHD risk

Temporal Trends and Prognosis of Physical Examination Findings in Patients with Acute Decompensated Heart Failure: The ARIC Study Community Surveillance

BACKGROUND: Bedside evaluation of congestion is a mainstay of heart failure (HF) management. Whether detected physical examination signs have changed over time as obesity prevalence has increased in HF populations, or if the associated prognosis differs for HF with reduced or preserved ejection fraction (HFrEF or HFpEF) is uncertain. METHODS: From 2005 to 2014, the ARIC study (Atherosclerosis Risk in Communities) conducted adjudicated hospital surveillance of acute decompensated HF. We analyzed trends in physical examination findings, imaging signs, and symptoms related to congestion, both over time and by obesity class, and associated 28-day mortality risks. RESULTS: Of 24 937 weighted hospitalizations for acute decompensated HF (mean age 75 years, 53% women, 32% Black), 47% had HFpEF. The prevalence of obesity increased from 2005 to 2014 for both HF types. With increasing obesity category, detected edema increased, while jugular venous distension decreased, and rales remained stable. Detected edema also increased over time, for both HF types. Associations between 28-day mortality and individual signs and symptoms of congestion were similar for HFpEF and HFrEF; however, the adjusted mortality risk with all 3 (edema, rales, and jugular venous distension) versus <3 physical examination findings was higher for patients with HFpEF (odds ratio, 2.41 [95% CI, 1.53-3.79]) than HFrEF (odds ratio, 1.30 [95% CI, 0.87-1.93]); P for interaction by HF type =0.02. CONCLUSIONS: In patients hospitalized with acute decompensated HF, detected physical examination findings differ both temporally and by obesity. Combined findings from the physical examination are more prognostic of 28-day mortality for patients with HFpEF than HFrEF