Faculty Bibliography

OBJECTIVES/OBJECTIVE:To investigate the association between serum potassium, mortality, and kidney outcomes in the general population and whether potassium-altering medications modify these associations. PATIENTS AND METHODS/METHODS:We studied 15,539 adults in the Atherosclerosis Risk in Communities Study. Cox proportional hazard regression was used to investigate the association of serum potassium at baseline (1987-1989), evaluated categorically (hypokalemia, <3.5 mmol/L; normokalemia, ≥3.5 and <5.5 mmol/L; hyperkalemia, ≥5.5 mmol/L) and continuously using linear spline terms (knots at 3.5 and 5.5 mmol/L), with mortality, sudden cardiac death, incident chronic kidney disease, and end-stage renal disease. The end date of follow-up for all outcomes was December 31, 2012. We also evaluated whether classes of potassium-altering medications modified the association between serum potassium and adverse outcomes. RESULTS:Overall, 413 (2.7%) of the participants had hypokalemia and 321 (2.1%) had hyperkalemia. In a fully adjusted model, hyperkalemia was significantly associated with mortality (hazard ratio, 1.24; 95% CI, 1.04-1.49) but not sudden cardiac death, chronic kidney disease, or end-stage renal disease. Hypokalemia as a categorical variable was not associated with any outcome; however, associations of hypokalemia with all-cause mortality and kidney outcomes were observed among those who were not taking potassium-wasting diuretics (all P for interaction, <.001). CONCLUSIONS:Higher values of serum potassium were associated with a higher risk of mortality in the general population. Lower levels of potassium were associated with adverse kidney outcomes and mortality among participants not taking potassium-wasting diuretics.

Opioid overdose prevention is a pressing public health concern and intranasal naloxone rescue kits are a useful tool in preventing fatal overdose. We evaluated the attitudes, knowledge, and experiences of patients and providers related to overdose and naloxone rescue. Over a six month period, patients and providers within a large community hospital in Staten Island were recruited to complete tailored questionnaires for their respective groupings. 100 patients and 101 providers completed questionnaires between August, 2014 and January, 2015. Patient participants were primarily Caucasian males with a mean age of 37.7 years, of which 65% accurately identified naloxone for opioid overdose, but only 21% knew more specific clinical features. 68% of patients had previously witnessed a drug overdose. Notably, 58% of patients anticipated their behavior would change if provided access to an intranasal naloxone rescue kit, of which 83% predicted an increase in opioid use. Prior overdose was significantly correlated with anticipating no change in subsequent opioid use pattern (p=0.02). 99% of patients reported that their rapport with their health-care provider would be enhanced if offered an intranasal naloxone rescue kit. As for providers, 24% had completed naloxone rescue kit training, and 96% were able to properly identify its clinical application. 50% of providers felt naloxone access would decrease the likelihood of an overdose occurring, and 58% felt it would not contribute to high-risk behavior. Among providers, completion of naloxone training was correlated with increased awareness of where to access kits for patients (p<0.001). This study suggests that patients and providers have distinct beliefs and attitudes toward overdose prevention. Patient-Provider discussion of overdose prevention enhances patients' rapport with providers. However, access to an intranasal naloxone rescue kit may make some patients more vulnerable to high-risk behavior. Future research efforts examining provider and patient beliefs and practices are needed to help develop and implement effective hospital-based opioid overdose prevention strategies.

BACKGROUND: To study the ability of the 30-minute plasma glucose (30 min-PG) during an oral glucose tolerance test (OGTT) to predict the future risk of type 2 diabetes (T2DM), among Asian Indians with impaired glucose tolerance (IGT). METHODS: For the present analyses, we utilized data from 753 participants from two diabetes primary prevention studies, having complete data at the end of the study periods, including 236 from Indian Diabetes Prevention Programme-1 (IDPP-1) and 517 from the 2013 study. Baseline 30-min PG values were divided into tertiles: T1 < 9.1 mmol/l (<163.0 mg/dl); T2 9.2-10.4 mmol/l (164.0-187.0 mg/dl) and T3 > 10.4 mmol/l(>/=188 mg/dl).The predictive values of tertiles of 30-min PG for incident diabetes were assessed using Cox regression analyses RESULTS: At the end of the studies 230 (30.5%) participants developed diabetes. Participants with higher levels of 30-min PG were more likely to have increased fasting, 2hrPG and HbA1c levels, increased prevalence to impaired fasting glucose (IFG), and decreased beta cell function. The progression rate of diabetes increased with increasing tertiles of 30-min PG. Cox's regression analysis showed that 30-min PG was an independent predictor of incident diabetes after adjustment for an array of covariates (HR:1.44 [1.01-2.06]) CONCLUSIONS: This prospective analysis demonstrates, for the first time, an independent association between an elevated 30-min PG level and incident diabetes among Asian Indians with IGT. Predictive utility of glycemic thresholds at various time points other than the traditional fasting and 2 hr PG values should therefore merit further consideration.

AIMS: The present study assessed the longitudinal association of an elevated 1-h plasma glucose [1-h-PG >8.6mmol/l (155mg/dl)] with and without impaired glucose tolerance [IGT; 2-h-PG 7.8-11.0mmol/l (140-199mg/dl)] with cumulative incident of diabetes and prediabetes over 25years in a non-diabetic cohort. METHODS: From 1979 to 1984, 1970 non-diabetic men and women completed an oral glucose tolerance test (OGTT), physical and biochemical measurements as well as a questionnaire related to lifestyle and medical background. During the years 2000-2004, 853 survivors of the original cohort were interviewed and re-examined for glycemic progression. RESULTS: Individuals with 1-h-PG >8.6mmol/l (155mg/dl) but with 2-h-PG <7.8mmol/l (140mg/dl) had a significantly elevated risk, compared to those with both 1-h-PG 8.6mmol/l (155mg/dl) and 2-h-PG <7.8mmol/l (140mg/dl), for both diabetes [OR:4.35 (95%CI: 2.50-7.73)] and prediabetes outcomes [OR:1.87 (95%CI 1.09-3.26)], adjusted for sex and age, smoking, body mass index, blood pressure, fasting blood glucose and insulin. CONCLUSIONS: The risk for diabetes associated with a 1-h level >8.6mmol/l (155mg/dl) is increased and further worsened in the presence of IGT. Identifying individuals at risk with a 1-h-PG glucose level during an OGTT is recommended.

BACKGROUND:Prospective data suggest depressive symptoms worsen insulin resistance and accelerate type 2 diabetes (T2D) onset. PURPOSE:We sought to determine whether reducing depressive symptoms in overweight/obese adolescents at risk for T2D would increase insulin sensitivity and mitigate T2D risk. METHOD:We conducted a parallel-group, randomized controlled trial comparing a 6-week cognitive-behavioral (CB) depression prevention group with a 6-week health education (HE) control group in 119 overweight/obese adolescent girls with mild-to-moderate depressive symptoms (Center for Epidemiological Studies-Depression Scale [CES-D] ≥16) and T2D family history. Primary outcomes were baseline to post-intervention changes in CES-D and whole body insulin sensitivity index (WBISI), derived from 2-h oral glucose tolerance tests. Outcome changes were compared between groups using ANCOVA, adjusting for respective baseline outcome, puberty, race, facilitator, T2D family history degree, baseline age, adiposity, and adiposity change. Multiple imputation was used for missing data. RESULTS:Depressive symptoms decreased (p < 0.001) in CB and HE from baseline to posttreatment, but did not differ between groups (ΔCESD = -12 vs. -11, 95 % CI difference = -4 to +1, p = 0.31). Insulin sensitivity was stable (p > 0.29) in CB and HE (ΔWBISI = 0.1 vs. 0.2, 95 % CI difference = -0.6 to +0.4, p = 0.63). Among all participants, reductions in depressive symptoms were associated with improvements in insulin sensitivity (p = 0.02). CONCLUSIONS:Girls at risk for T2D displayed reduced depressive symptoms following 6 weeks of CB or HE. Decreases in depressive symptoms related to improvements in insulin sensitivity. Longer-term follow-up is needed to determine whether either program causes sustained decreases in depressive symptoms and improvements in insulin sensitivity. TRIAL REGISTRATION NUMBER:The trial was registered with clinicaltrials.gov (NCT01425905).

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. (c) 2016 Wiley Periodicals, Inc.

BACKGROUND:Individuals with chronic kidney disease, particularly those requiring dialysis, are at high risk of sudden cardiac death (SCD). However, comprehensive data for the full spectrum of kidney function and SCD risk in the community are sparse. Furthermore, newly developed equations for estimated glomerular filtration rate (eGFR) and novel filtration markers might add further insight to the role of kidney function in SCD. METHODS:We investigated the associations of baseline eGFRs using serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, and eGFRcr-cys); cystatin C itself; and β2-microglobulin (B2M) with SCD (205 cases through 2001) among 13,070 black and white ARIC participants at baseline during 1990-1992 using Cox regression models accounting for potential confounders. RESULTS:Low eGFR was independently associated with SCD risk: for example, hazard ratio for eGFR <45 versus ≥90mL/(min 1.73m(2)) was 3.71 (95% CI 1.74-7.90) with eGFRcr, 5.40 (2.97-9.83) with eGFRcr-cys, and 5.24 (3.01-9.11) with eGFRcys. When eGFRcr and eGFRcys were included together in a single model, the association was only significant for eGFRcys. When three eGFRs, cystatin C, and B2M were divided into quartiles, B2M demonstrated the strongest association with SCD (hazard ratio for fourth quartile vs first quartile 3.48 (2.03-5.96) vs ≤2.7 for the other kidney markers). CONCLUSIONS:Kidney function was independently and robustly associated with SCD in the community, particularly when cystatin C or B2M was used. These results suggest the potential value of kidney function as a risk factor for SCD and the advantage of novel filtration markers over eGFRcr in this context.

BACKGROUND AND AIMS:Biomarkers and atherosclerosis imaging have been studied individually for association with incident cardiovascular disease (CVD); however, limited data exist on whether the biomarkers are associated with events with a similar magnitude in the presence of atherosclerosis. In this study, we assessed whether the presence of atherosclerosis as measured by carotid intima media thickness (cIMT) affects the association between biomarkers known to be associated with coronary heart disease (CHD) and incident cardiovascular disease (CVD) in a primary prevention cohort. METHODS:8127 participants from the ARIC study (4th visit, 1996-1998) were stratified as having minimal, mild, or substantial atherosclerosis by cIMT. Levels of C-reactive protein, lipoprotein-associated phospholipase A2, cardiac troponin T, N-terminal pro-brain natriuretic peptide, lipoprotein(a), cystatin C, and urine albumin to creatinine ratio were measured in each participant. Hazard ratios were used to determine the relationship between the biomarkers and incident CHD, stroke, and CVD in each category of atherosclerosis. RESULTS:While each of the biomarkers was significantly associated with risk of events overall, we found no significant differences noted in the strength of association of biomarkers with CHD, stroke, and CVD when analyzed by degree of atherosclerosis. CONCLUSIONS:These findings suggest that the level of atherosclerosis does not significantly influence the association between biomarkers and CVD.

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.

BACKGROUND: Pediatric obesity prevalence remains at historically high levels. The objective of this study was to examine secular trends in the proportions of children with overweight/obesity who received notification from a health care professional (HCP) about their unhealthy weight. METHOD: We analyzed data of 25 570 (including 8 639 overweight/obese) children aged 2-18 years collected from seven cross-sectional biennial surveys (National Health and Nutrition Examination Survey, 1999-2014), in which adolescents (16y and older) and caregivers, mostly biological mothers, of children (2-15y) were asked 'Has a doctor or other health professional ever told you that you (or your child) were overweight?' RESULTS: Approximately 90% of overweight/obese children visited HCPs at least once in the past 12 months, but only 22.12% (s.e.=1.92) in 1999 to 34.43% (2.35) in 2014 of the overweight/obese children were notified by HCPs about unhealthy weight. The biennial increase in odds of receipt of notification of unhealthy weight was 1.08 [95%CI=(1.04-1.12)]. Greater likelihood for receipt of notification was associated with being obese [OR=5.03 (4.29-5.89) vs overweight]; black [1.24 (1.06-1.46)] or Hispanic race/ethnicity [1.72 (1.45-2.04) vs white]; female sex [1.22 (1.07-1.11) vs boys]; and child's insurance status [1.31 (1.08-1.59) vs uninsured]. There was an increasing odds of being notified with increasing age: 1.00 (reference), 2.24 (2.06-2.62), 3.22 (2.50-4.13) and 4.87 (3.76-6.32) for children 2-5, 6-11, 12-16 and 16+ year old respectively. The frequency of medical contact was linearly associated with an increased likelihood of being notified. CONCLUSIONS: Notification of child's unhealthy weight by HCPs increased significantly between 1999 and 2014, but the opportunity of clinical intervention remained substantially under-utilized.International Journal of Obesity accepted article preview online, 04 May 2016. doi:10.1038/ijo.2016.85.