Atherosclerosis of the ascending aorta is a predictor of renal dysfunction after cardiac operations

AbstractObjectives: Renal dysfunction occurring after cardiac operations has been attributed to various factors, but the importance of an atherosclerotic thoracic aorta has not been previously evaluated. The purpose of this study was to identify predictors of postoperative renal dysfunction (50% or more increase from preoperative values) and to evaluate the importance of atherosclerosis of the ascending aorta as a predictor of this complication. Methods: Nine hundred seventy-eight consecutive patients, 50 years of age and older with normal preoperative renal function (serum creatinine level of 1.5 mg/dL or less), who were scheduled to undergo cardiac surgery were prospectively evaluated. Atherosclerosis of the ascending aorta was assessed during the operation (with epiaortic ultrasound), and patients were divided into 3 groups according to its severity (normal-to-mild, moderate, and severe). Results: Univariate predictors of renal dysfunction at postoperative day 1 were atherosclerosis of the ascending aorta (P < .045) and postoperative low cardiac output (P = .05); at postoperative day 6 they were atherosclerosis of the ascending aorta (P < .0001), postoperative low cardiac output (P < .0001), advanced age (P = .001), decreased preoperative left ventricular function (P = .01), and female gender (P = .03). Multivariate analysis showed that atherosclerosis of the ascending aorta (odds ratio, 3.06; P = .04) was the only independent predictor of postoperative renal dysfunction at day 1 and that postoperative low cardiac output (odds ratio, 4.83; P < .0001), atherosclerosis of the ascending aorta (odds ratio, 2.13; P = .0006), and preoperative left ventricular dysfunction (odds ratio, 1.48; P = .028) were independent predictors of postoperative renal dysfunction at day 6. Conclusions: An atherosclerotic ascending aorta is an important predictor of postoperative renal dysfunction, possibly because atheroembolism to the kidneys occurs in the perioperative period (ie, during surgical manipulation of an atherosclerotic aorta) or because the diseased aorta may be a marker of widespread atherosclerotic disease that may predispose to perioperative renal dysfunction. (J Thorac Cardiovasc Surg 1999;117:111-6

Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from \u3e26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the gold standard for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing

Sex Affects Myocardial Blood Flow and Fatty Acid Substrate Metabolism in Humans with Nonischemic Heart Failure

In animal models of heart failure (HF), myocardial metabolism shifts from the normal preference for high-energy fatty acid (FA) metabolism towards the more efficient fuel, glucose. However, FA (vs. glucose) metabolism generates more ATP/mole; thus FA metabolism may be especially advantageous in HF. Sex modulates myocardial blood flow (MBF) and substrate metabolism in normal humans. Whether sex affects MBF and metabolism in patients with HF is unknown. We studied 19 well-matched men and women with nonischemic HF with similar ejection fractions (all ≤ 35%). MBF and myocardial substrate metabolism were quantified using positron emission tomography. Women had higher MBF (mL/g/min), FA uptake (mL/g/min), utilization (nmol/g/min) (P<0.005, <0.005, <0.05, respectively) and trended towards higher FA oxidation than men (P=0.09). These findings were independent of age, obesity, and insulin resistance. There were no sex-related differences in fasting myocardial glucose uptake or metabolism. In an exploratory analysis of the longitudinal follow-up of these subjects (mean 7 y), we found that 4 men had a major cardiovascular event, while one woman died of non-cardiac causes. Higher MBF related to improved event-free survival (HR=0.31, P=0.02). In sum, in nonischemic HF, women have higher MBF and FA uptake and metabolism than men, and these changes are not due to differences in other variables that can affect myocardial metabolism (e.g., age, obesity, or insulin resistance). Moreover, higher MBF portends a better prognosis. These sex-related differences should be taken into account in the development and targeting of novel agents aimed at modulating in MBF and metabolism in HF

Disseminating and implementing a lifestyle-based healthy weight program for mothers in a national organization: A study protocol for a cluster randomized trial

BACKGROUND: Excessive weight gain among young adult women age 18-45 years is an alarming and overlooked trend that must be addressed to reverse the epidemics of obesity and chronic disease. During this vulnerable period, women tend to gain disproportionally large amounts of weight compared to men and to other life periods. Healthy Eating and Active Living Taught at Home (HEALTH) is a lifestyle modification intervention developed in partnership with Parents as Teachers (PAT), a national home visiting, community-based organization with significant reach in this population. HEALTH prevented weight gain, promoted sustained weight loss, and reduced waist circumference. PAT provides parent-child education and services free of charge to nearly 170,000 families through up to 25 free home visits per year until the child enters kindergarten. METHODS: This study extends effectiveness findings with a pragmatic cluster randomized controlled trial to evaluate dissemination and implementation (D&I) of HEALTH across three levels (mother, parent educator, PAT site). The trial will evaluate the effect of HEALTH and the HEALTH training curriculum (implementation strategy) on weight among mothers with overweight and obesity across the USA (N = 252 HEALTH; N = 252 usual care). Parent educators from 28 existing PAT sites (14 HEALTH, 14 usual care) will receive the HEALTH training curriculum through PAT National Center, using PAT\u27s existing training infrastructure, as a continuing education opportunity. An extensive evaluation, guided by RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance), will determine implementation outcomes (acceptability, adoption, appropriateness, feasibility, fidelity, and adaptation) at the parent educator level. The Conceptual Framework for Implementation Research will characterize determinants that influence HEALTH D&I at three levels: mother, parent educator, and PAT site to enhance external validity (reach and maintenance). DISCUSSION: Embedding intervention content within existing delivery channels can help expand the reach of evidence-based interventions. Interventions, which have been adapted, can still be effective even if the effect is reduced and can still achieve population impact by reaching a broader set of the population. The current study will build on this to test not only the effectiveness of HEALTH in real-world PAT implementation nationwide, but also elements critical to D&I, implementation outcomes, and the context for implementation. TRIAL REGISTRATION: https://ClinicalTrials.gov , NCT03758638 . Registered 29 November 2018

The inorganic NItrate and eXercise performance in Heart Failure (iNIX-HF) phase II clinical trial: Rationale and study design

BACKGROUND: Heart failure (HF) is a debilitating and often fatal disease that affects millions of people worldwide. Diminished nitric oxide synthesis, signaling, and bioavailability are believed to contribute to poor skeletal muscle function and aerobic capacity. The aim of this clinical trial (iNIX-HF) is to determine the acute and longer-term effectiveness of inorganic nitrate supplementation on exercise performance in patients with HF with reduced ejection fraction (HFrEF). METHODS: This clinical trial is a double-blind, placebo-controlled, randomized, parallel-arm design study in which patients with HFrEF (n = 75) are randomized to receive 10 mmol potassium nitrate (KNO DISCUSSION: The iNIX-HF phase II clinical trial will evaluate the effectiveness of inorganic nitrate supplements as a new treatment to ameliorate poor exercise capacity in HFrEF. This study also will provide critical preliminary data for a future \u27pivotal\u27, phase III, multi-center trial of the effectiveness of nitrate supplements not only for improving exercise performance, but also for improving symptoms and decreasing other major cardiovascular endpoints. The potential public health impact of identifying a new, relatively inexpensive, safe, and effective treatment that improves overall exercise performance in patients with HFrEF is significant

Parents, but not their children, demonstrate greater delay discounting with resource scarcity

BACKGROUND: Individuals with obesity tend to discount the future (delay discounting), focusing on immediate gratification. Delay discounting is reliably related to indicators of economic scarcity (i.e., insufficient resources), including lower income and decreased educational attainment in adults. It is unclear whether the impact of these factors experienced by parents also influence child delay discounting between the ages of 8 and 12-years in families with obesity. METHODS: The relationship between indices of family income and delay discounting was studied in 452 families with parents and 6-12-year-old children with obesity. Differences in the relationships between parent economic, educational and Medicaid status, and parent and child delay discounting were tested. RESULTS: Results showed lower parent income (p = 0.019) and Medicaid status (p = 0.021) were differentially related to greater parent but not child delay discounting among systematic responders. CONCLUSIONS: These data suggest differences in how indicators of scarcity influence delay discounting for parents and children, indicating that adults with scarce resources may be shaped to focus on immediate needs instead of long-term goals. It is possible that parents can reduce the impact of economic scarcity on their children during preadolescent years. These findings suggest a need for policy change to alleviate the burden of scarce conditions and intervention to modify delay discounting rate and to improve health-related choices and to address weight disparities

Impaired tumor necrosis factor-α secretion by CD4 T cells during respiratory syncytial virus bronchiolitis associated with recurrent wheeze

BACKGROUND: Infants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro-stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life. METHODS: We obtained peripheral blood from 166 infants hospitalized with their first episode of RSV-confirmed bronchiolitis. Granzyme B (GZB) expression, and interleukin-10, interferon-γ, tumor necrosis factor-α (TNF-α), IL-4, and IL-5 production by in vitro anti-CD3/CD28- and anti-CD3/CD46-activated CD4+ T cells, and percentage of peripheral Treg (CD4+CD25 RESULTS: Sixty-seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25 CONCLUSIONS: We demonstrated lower TNF-α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently developed recurrent wheezing, compared with children with no subsequent wheeze. These findings support the role of CD4+ T cell immunity in the development of subsequent wheezing in these children

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting