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Genome-wide association study of proneness to anger

Fri, 10/17/2014 - 12:48pm

BACKGROUND: Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease.

METHODS: With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger State-Trait Anger Scale in the Atherosclerosis Risk in Communities (ARIC) study (n = 8,747).

RESULTS: Subjects were, on average, 54 (range 45-64) years old at baseline enrollment, 47% (n = 4,117) were male, and all were of European descent by self-report. The mean Angry Temperament and Angry Reaction scores were 5.8 +/- 1.8 and 7.6 +/- 2.2. We observed a nominally significant finding (p = 2.9E-08, lambda = 1.027 - corrected pgc = 2.2E-07, lambda = 1.0015) on chromosome 6q21 in the gene coding for the non-receptor protein-tyrosine kinase, Fyn.

CONCLUSIONS: Fyn interacts with NDMA receptors and inositol-1,4,5-trisphosphate (IP3)-gated channels to regulate calcium influx and intracellular release in the post-synaptic density. These results suggest that signaling pathways regulating intracellular calcium homeostasis, which are relevant to memory, learning, and neuronal survival, may in part underlie the expression of Angry Temperament.

Sex differences in clinical characteristics, hospital management practices, and in-hospital outcomes in patients hospitalized in a vietnamese hospital with a first acute myocardial infarction

Fri, 10/17/2014 - 12:48pm

BACKGROUND: Cardiovascular disease is one of the leading causes of morbidity and mortality in Vietnam. We conducted a pilot study of Hanoi residents hospitalized with acute myocardial infarction (AMI) at the Vietnam National Heart Institute in Hanoi. The objectives of this observational study were to examine sex differences in clinical characteristics, hospital management, in-hospital clinical complications, and mortality in patients hospitalized with an initial AMI.

METHODS: The study population consisted of 302 Hanoi residents hospitalized with a first AMI at the largest tertiary care medical center in Hanoi in 2010.

RESULTS: The average age of study patients was 66 years and one third were women. Women were older (70 vs. 64 years) and were more likely than men to have had hyperlipidemia previously diagnosed (10% vs. 2%). During hospitalization, women were less likely to have undergone percutaneous coronary intervention (PCI) compared with men (57% vs. 74%), and women were more likely to have developed heart failure compared with men (19% vs. 10%). Women experienced higher in-hospital case-fatality rates (CFRs) than men (13% vs. 4%) and these differences were attenuated after adjustment for age and history of hyperlipidemia (OR: 2.64; 95% CI: 1.01, 6.89), and receipt of PCI during hospitalization (OR: 2.09; 95% CI: 0.77, 5.09).

CONCLUSIONS: Our pilot data suggest that among patients hospitalized with a first AMI in Hanoi, women experienced higher in-hospital CFRs than men. Full-scale surveillance of all Hanoi residents hospitalized with AMI at all Hanoi medical centers is needed to confirm these findings. More targeted and timely educational and treatment approaches for women appear warranted.

Whole blood gene expression and atrial fibrillation: the Framingham Heart Study

Fri, 10/17/2014 - 12:48pm

BACKGROUND: Atrial fibrillation (AF) involves substantial electrophysiological, structural and contractile remodeling. We hypothesize that characterizing gene expression might uncover important pathways related to AF.

METHODS AND RESULTS: We performed genome-wide whole blood transcriptomic profiling (Affymetrix Human Exon 1.0 ST Array) of 2446 participants (mean age 66 +/- 9 years, 55% women) from the Offspring cohort of Framingham Heart Study. The study included 177 participants with prevalent AF, 143 with incident AF during up to 7 years follow up, and 2126 participants with no AF. We identified seven genes statistically significantly up-regulated with prevalent AF. The most significant gene, PBX1 (P = 2.8 x 10(-7)), plays an important role in cardiovascular development. We integrated differential gene expression with gene-gene interaction information to identify several signaling pathways possibly involved in AF-related transcriptional regulation. We did not detect any statistically significant transcriptomic associations with incident AF.

CONCLUSION: We examined associations of gene expression with AF in a large community-based cohort. Our study revealed several genes and signaling pathways that are potentially involved in AF-related transcriptional regulation.

RE: Drug risk assessment and data reuse

Fri, 10/17/2014 - 12:48pm

Development and evaluation of a risk communication curriculum for medical students

Fri, 10/17/2014 - 12:48pm

OBJECTIVE: To develop, pilot, and evaluate a curriculum for teaching clinical risk communication skills to medical students.

METHODS: A new experience-based curriculum, "Risk Talk," was developed and piloted over a 1-year period among students at Tufts University School of Medicine. An experimental study of 2nd-year students exposed vs. unexposed to the curriculum was conducted to evaluate the curriculum's efficacy. Primary outcome measures were students' objective (observed) and subjective (self-reported) risk communication competence; the latter was assessed using an Observed Structured Clinical Examination (OSCE) employing new measures.

RESULTS: Twenty-eight 2nd-year students completed the curriculum, and exhibited significantly greater (p < .001) objective and subjective risk communication competence than a convenience sample of 24 unexposed students. New observational measures of objective competence in risk communication showed promising evidence of reliability and validity. The curriculum was resource-intensive.

CONCLUSION: The new experience-based clinical risk communication curriculum was efficacious, although resource-intensive. More work is needed to develop the feasibility of curriculum delivery, and to improve the measurement of competence in clinical risk communication.

PRACTICE IMPLICATIONS: Risk communication is an important advanced communication skill, and the Risk Talk curriculum provides a model educational intervention and new assessment tools to guide future efforts to teach and evaluate this skill.

Venous thromboembolism in patients with prior stroke

Fri, 10/17/2014 - 12:48pm

Patients with prior stroke are susceptible to venous thromboembolism (VTE). We studied patients with stroke in the Worcester VTE study of 2488 consecutive patients hospitalized with VTE. In all, 288 (11.6%) had a clinical history of stroke and 2200 (88.4%) did not. Patients with stroke were more likely to die inhospital (9.2% vs 4%) and within 30 days of VTE diagnosis (16.7% vs 6.9%) compared with patients without stroke (all P < .001). Recent immobilization (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.15-4.09) and inferior vena cava (IVC) filter insertion (adjusted OR 2.1; 95% CI 1.15-3.83) were associated with a doubling of inhospital death. Recent immobilization (adjusted OR 1.84; 95% CI 1.19-2.83) and IVC filter insertion (adjusted OR 1.94; 95% CI 1.2-3.14) were associated with an increased risk of death within 30 days of VTE. In conclusion, patients with VTE and prior stroke were more than twice as likely to die while hospitalized and within 30 days of VTE diagnosis.

Guideline concordance of testing for hyperkalemia and kidney dysfunction during initiation of mineralocorticoid receptor antagonist therapy in patients with heart failure

Fri, 10/17/2014 - 12:48pm

BACKGROUND: Mineralocorticoid receptor antagonists (MRA) reduce morbidity and mortality in heart failure with reduced ejection fraction but can cause hyperkalemia and acute kidney injury. Guidelines recommend measurement of serum potassium (K) and creatinine (Cr) before and serially after MRA initiation, but the extent to which this occurs is unknown.

METHODS AND RESULTS: Using electronic data from 3 health systems 2005 to 2008, we performed a retrospective review of laboratory monitoring among 490 patients hospitalized for heart failure with reduced ejection fraction who were subsequently initiated on MRA therapy. Median age at time of MRA initiation was 73 years, and 37.1% were women. Spironolactone accounted for 99.4% of MRA use. Initial ambulatory MRA dispensing occurred at hospital discharge in 70.0% of cases. In the 30 days before MRA initiation, 94.3% of patients had a K or Cr measurement. Preinitiation K was >5.0 mmol/L in 1.4% and Cr>2.5 mg/dL in 1.7%. In the 7 days after MRA initiation among patients who remained alive and out of the hospital, 46.5% had no evidence of K measurement; by 30 days, 13.6% remained untested. Patient factors explained a small portion of postinitiation K testing (c-statistic, 0.67).

CONCLUSIONS: Although laboratory monitoring before MRA initiation for heart failure with reduced ejection fraction is common, laboratory monitoring after MRA initiation frequently does not meet guideline recommendations, even in patients at higher risk for complications. Quality improvement efforts that encourage the use of MRA should also include mechanisms to address recommended monitoring.

Quality measure attainment in patients with type 2 diabetes mellitus

Fri, 10/17/2014 - 12:48pm

OBJECTIVES: This study examined the demographics, comorbidities, clinical characteristics, and treatments of people with type 2 diabetes mellitus (T2DM) treated with metformin and sulfonylurea as well as an elderly subgroup. Achievement of predefined quality measure goals (glycated hemoglobin [A1C], blood pressure [BP], low-density lipoprotein cholesterol [LDL-C], body mass index [BMI]) and their association with diabetes-related healthcare costs were assessed.

STUDY DESIGN: The study applied a retrospective longitudinal cohort design.

METHODS: Health insurance claims and electronic medical records from 14,532 adults with T2DM (2007- 2011) were used to identify a sample receiving metformin and sulfonylurea (MET+SU) concomitantly. The index date was the first dispensing of MET+SU after 6 months of eligibility. Clinical characteristics were assessed during baseline. Quality measure attainment (A1C < 8%, BP < 140/90 mm Hg, LDL-C level < 100 mg/dL, BMI < 30 kg/m(2)), was evaluated during the 12 months following the index date. Association between attainment and diabetes-related costs was evaluated using non-parametric bootstrap methods adjusting for imbalance in baseline characteristics between cohorts.

RESULTS: Among 2044 patients, including 1283 patients 65 years and older, hyperlipidemia, hypertension, and cardiovascular disease were the most common baseline comorbidities. Quality measure goal attainment was 63.9% for A1C, 33.1% for BP, 68.2% for LDL-C level, and 34.4% for BMI, and was associated with significantly lower diabetes-related costs per patient per year compared with nonattainment (adjusted mean cost differences: -$1445 for A1C; -$1218 for BMI; -$2029 for A1C and BMI; -$2073 for A1C, BMI, and BP; all P < .05).

CONCLUSION: This study highlights the high incidence of comorbidities and potential financial implications of attaining T2DM quality outcomes.

Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials

Fri, 10/17/2014 - 12:48pm

BACKGROUND: Pegloticase is approved in the US for treatment of refractory chronic gout. Since chronic kidney disease (CKD) is common in these patients, we conducted a post-hoc analysis of 2 replicate phase 3 trials and the subsequent open-label extension study to determine the effects of pegloticase on renal function in patients with CKD stages 3 and 4, as well as the effects of renal dysfunction on pegloticase efficacy and safety.

FINDINGS: Patients with renal insufficiency were randomized to pegloticase 8 mg every 2 weeks (n = 42), pegloticase 8 mg every 4 weeks (n = 41), or placebo (n = 20) for 6 months as defined by the study protocols. Renal function was assessed by estimated glomerular filtration rate (eGFR). All patients completing the randomized trials could participate in an open-label extension study for a further 2.5 years. Uric acid response, the primary end point in the trials, was plasma uric acid < 6.0 mg/dl for 80% of months 3 and 6.Mean eGFR in both pegloticase dosing cohorts remained constant over the randomized treatment phase and long-term open-label extension study. The number of patients achieving uric acid response was similar across CKD stages (32% stage 1, 23% stage 2, 35% stage 3, and 39% stage 4, respectively, P = 0.3). There was no difference in the pegloticase safety profile based on CKD stage.

CONCLUSIONS: Pegloticase treatment does not impact eGFR in CKD patients and response to pegloticase is independent of CKD stage.

TRIAL REGISTRATION: Clinical trial identifier: NCT00325195.

Effects of a modified Hospital Elder Life Program on frailty in individuals undergoing major elective abdominal surgery

Fri, 10/17/2014 - 12:48pm

OBJECTIVES: To test the effects of a modified Hospital Elder Life Program (mHELP) on frailty.

DESIGN: Matched and unmatched analyses of data from a before-and-after study.

SETTING: Hospital, inpatient.

PARTICIPANTS: Participants aged 65 and older (n = 189) undergoing major elective abdominal surgery at a medical center in Taiwan.

INTERVENTION: The mHELP included three nursing interventions: early mobilization, oral and nutritional assistance, and orienting communication.

MEASUREMENTS: Frailty rate and transitions between frailty states from hospital discharge to 3 months after discharge using Fried's phenotype criteria categorized as nonfrail (0 or 1 criteria present), prefrail (2 or 3 criteria present), and frail (4 or 5 criteria present).

RESULTS: In matched pairs, participants who received the mHELP interventions were significantly less likely to be frail at discharge (19.2%) than matched controls (65.4%) (adjusted odds ratio (AOR) = 0.10, 95% CI = 0.02-0.39). Transitions to states of greater frailty during hospitalization were more common for participants in the control group. Three months after discharge, participants who received the mHELP intervention during hospitalization were less likely to be frail (17.3%) than matched controls (23.1%) (AOR = 0.73, 95% CI = 0.21-2.56), although this difference did not achieve statistical significance.

CONCLUSION: The mHELP intervention is effective in reducing frailty by hospital discharge, but the benefit is diminished by 3 months after discharge. Thus, the mHELP provides a useful approach to manage in-hospital frailty for older adults undergoing major abdominal surgery. Geriatrics Society.

Antipsychotic use in nursing homes varies by psychiatric consultant

Fri, 10/17/2014 - 12:48pm

BACKGROUND: The relationship between psychiatric consultation and antipsychotic prescribing in nursing homes (NH) is unknown.

OBJECTIVE: To identify the association between psychiatric consultant groups and NH-level antipsychotic prescribing after adjustment for resident case-mix and facility characteristics.

RESEARCH DESIGN AND SUBJECTS: Nested cross-sectional study of 60 NHs in a cluster randomized trial. We linked facility leadership surveys to October 2009-September 2010 Minimum Data Set, Nursing Home Compare, the US Census, and pharmacy dispensing data.

MEASURES: The main exposure is the psychiatric consultant group and the main outcome is NH-level prevalence of atypical antipsychotic use. We calculated annual means and interquartile ranges of NH-level antipsychotic use for each consultant group and arrayed consultant groups from lowest to highest prevalence. Generalized linear models were used to predict antipsychotic prescribing adjusting for resident case-mix and facility characteristics. Observed versus predicted antipsychotic prescribing levels were compared for each consultant group.

RESULTS: Seven psychiatric consultant groups served a range of 3-27 study facilities. Overall mean facility-level antipsychotic prescribing was 19.2%. Mean prevalence of antipsychotic prescribing ranged from 12.2% (SD, 5.8) in the lowest consultant group to 26.4% (SD, 3.6) in the highest group. All facilities served by the highest-ranked consultant group had observed antipsychotic levels exceeding the overall study mean with half exceeding predictions for on-label indications, whereas most facilities served by the lowest-ranked consultant group had observed levels below the overall study and predicted means.

CONCLUSIONS: Preliminary evidence suggests that psychiatric consultant groups affect NH antipsychotic prescribing independent of resident case-mix and facility characteristics.

A tale of two methods: chart and interview methods for identifying delirium

Fri, 10/17/2014 - 12:48pm

OBJECTIVES: To compare chart- and interview-based methods for identification of delirium.

DESIGN: Prospective cohort study.

SETTING: Two academic medical centers.

PARTICIPANTS: Individuals aged 70 and older undergoing major elective surgery (N = 300) (majority orthopedic surgery).

MEASUREMENTS: Participants were interviewed daily during hospitalization for delirium using the Confusion Assessment Method (CAM; interview-based method), and their medical charts were reviewed for delirium using a validated chart-review method (chart-based method). Rate of agreement of the two methods and characteristics of those identified using each approach were examined. Predictive validity for clinical outcomes (length of stay, postoperative complications, discharge disposition) was compared. In the absence of a criterion standard, predictive value could not be calculated.

RESULTS: The cumulative incidence of delirium was 23% (n = 68) according to the interview-based method, 12% (n = 35) according to the chart-based method, and 27% (n = 82) according to the combined approach. Overall agreement was 80%; kappa was 0.30. The methods differed in detection of psychomotor features and time of onset. The chart-based method missed delirium in individuals that the CAM identified who were lacking features of psychomotor agitation or inappropriate behavior. The CAM-based method missed chart-identified cases occurring during the night shift. The combined method had high predictive validity for all clinical outcomes.

CONCLUSIONS: Interview- and chart-based methods have specific strengths for identification of delirium. A combined approach captures the largest number and broadest range of delirium cases. Geriatrics Society.

Colonoscopy--don't want to be sedated

Fri, 10/17/2014 - 12:48pm

Comment on: Mandatory anesthesia. [JAMA Intern Med. 2013]

Delirium in elderly people--authors'reply

Fri, 10/17/2014 - 12:48pm

Systematic review of the use of online questionnaires of older adults

Fri, 10/17/2014 - 12:48pm

OBJECTIVES: To describe methodological approaches to population targeting and sampling and to summarize limitations of Internet-based questionnaires in older adults.

DESIGN: Systematic literature review.

SETTING: Studies using online questionnaires in older adult populations.

PARTICIPANTS: English-language articles using search terms for geriatric, age 65 and over, Internet survey, online survey, Internet questionnaire, and online questionnaire in PubMed and EBSCO host between 1984 and July 2012. Inclusion criteria were study population mean age 65 and older and use of an online questionnaire for research. Review of 336 abstracts yielded 14 articles for full review by two investigators; 11 articles met inclusion criteria.

MEASUREMENTS: Articles were extracted for study design and setting, participant characteristics, recruitment strategy, country, and study limitations.

RESULTS: Eleven articles were published after 2001. Studies had populations with a mean age of 65 to 78, included descriptive and analytical designs, and were conducted in the United States, Australia, and Japan. Recruiting methods varied widely from paper fliers and personal e-mails to use of consumer marketing panels. Investigator-reported study limitations included the use of small convenience samples and limited generalizability.

CONCLUSION: Online questionnaires are a feasible method of surveying older adults in some geographic regions and for some subsets of older adults, but limited Internet access constrains recruiting methods and often limits study generalizability. Geriatrics Society.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

Fri, 10/17/2014 - 12:48pm

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity. Elsevier Inc. All rights reserved.

Relations between circulating microRNAs and atrial fibrillation: data from the Framingham Offspring Study

Fri, 10/17/2014 - 12:48pm

BACKGROUND: MicroRNA (miRNA) expression in atrial tissue has been implicated in pathologic susceptibility to atrial fibrillation (AF). Nevertheless, data on how circulating levels relate to AF are limited.

OBJECTIVE: The purpose of this study was to test the hypothesis that circulating miRNAs are associated with AF.

METHODS: Among 2445 Framingham Heart Study Offspring participants, we measured the expression of 385 circulating whole blood miRNAs by high-throughput quantitative reverse transcriptase polymerase chain reaction. We related miRNA levels with prevalent and new-onset AF. RESULTS: Mean age of the cohort was 66.3 +/- 8.9 years, and 56% were women; 153 participants had clinically apparent AF at baseline, and 107 developed AF during median follow-up of 5.4 years. miRNA-328 (miR-328) expression was lower among participants with prevalent AF (8.76 cycle threshold) compared to individuals with no AF (7.75 cycle threshold, P < .001). The association between miR-328 and prevalent AF persisted after adjustment for age, sex, and technical covariates (odds ratio 1.21, P = 1.8 x 10(-4)) but was attenuated in analyses adjusting for clinical AF risk factors (odds ratio 1.14, P = .017). In contrast to the associations between miR-328 and prevalent AF, none of the circulating miRNAs were associated with incident AF.

CONCLUSION: Circulating levels of miR-328, a miRNA known to promote atrial electrical remodeling by reducing L-type Ca(2+) channel density, were associated with prevalent AF. Adjustment for risk factors that promote atrial remodeling, including hypertension, attenuated the association between miR-328 and AF, potentially implicating miR-328 as a potential mediator of atrial remodeling and AF vulnerability. reserved.

Comprehensive evaluation of the incidence of late effects in 5-year survivors of breast cancer

Fri, 10/17/2014 - 12:48pm

Late effects of breast cancer affect the quality of survivorship. Using administrative data, we compared the occurrence of almost all ICD9 codes among older breast cancer survivors to that among a matched comparison cohort to generate new hypotheses. Breast cancer patients 65 years or older diagnosed 1990-1994 in 6 integrated care settings and who survived at least 5 years were matched with a cohort of women without a history of breast cancer on care setting, age, and calendar time. We collected data on the occurrence of incident ICD9 codes beginning 6 years after the breast cancer diagnosis date and continuing to year 15, and comparable data for the matched woman. We calculated hazard ratios (HRs) and 95 % confidence intervals associating breast cancer survivorship with incidence of each ICD9 code. We used semi-Bayes methods to address multiple comparisons. Older breast cancer survivors had about the same occurrence of diseases and conditions 6-15 years after breast cancer diagnosis as comparable women. The median of 564 adjusted HRs equaled 1.06, with interquartile range 0.92-1.3. The distribution of HRs pertaining to cancer-related ICD codes was shifted toward positive associations, and the distribution pertaining to cardiovascular-related ICD codes was shifted toward negative associations. In this hypothesis-scanning study, we observed little difference in the occurrence of non-breast cancer-related diseases and conditions among older, long-term breast cancer survivors, and comparable women without a history of breast cancer.

30-year trends in patient characteristics, treatment practices, and long-term outcomes of adults aged 35 to 54 years hospitalized with acute myocardial infarction

Fri, 10/17/2014 - 12:48pm

Much of our knowledge about the characteristics, clinical management, and postdischarge outcomes of acute myocardial infarction (AMI) is derived from clinical studies in middle-aged and older subjects with little contemporary information available about the descriptive epidemiology of AMI in relatively young men and women. The objectives of our population-based study were to describe >3-decade-long trends in the clinical features, treatment practices, and long-term outcomes of young adults aged 35 to 54 years discharged from the hospital after AMI. The study population consisted of 2,142 residents of the Worcester (Massachusetts) metropolitan area who were hospitalized with AMI at all central Massachusetts medical centers during 16 annual periods from 1975 to 2007. Our primarily male study population had an average age of 47 years. Patients hospitalized during the most recent decade (1997 to 2007) under study were more likely to have a history of hypertension and heart failure than those hospitalized during earlier study years. Patients were less likely to have developed heart failure or stroke during their hospitalization in the most recent compared with the initial decade under study (heart failure 13.7% and stroke 0.7% vs 20.9% and 2.0%, respectively). One- and 2-year postdischarge death rates also decreased significantly between 1975 to 1986 (6.2% and 9.0%, respectively) and 1988 to 1995 (2.6% and 4.9%). These trends were concomitant with the increasing use of effective cardiac therapies and coronary interventions during hospitalization. The present results provide insights into the changing characteristics, management, and improving long-term outcomes of relatively young patients hospitalized with AMI.