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
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.
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
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.
Genetic Loci associated with atrial fibrillation: relation to left atrial structure in the Framingham Heart Study
BACKGROUND: Atrial fibrillation (AF) results in significant morbidity and mortality. Genome-wide association studies (GWAS) have identified genetic variants associated with AF. Whether genetic variants associated with AF are also associated with atrial structure, an intermediate phenotype for AF, has had limited investigation. We sought to investigate associations between single nucleotide polymorphisms (SNPs) and atrial structure obtained by cardiovascular imaging in the Framingham Heart Study.
METHODS AND RESULTS: We selected 11 SNPs that have been associated with AF in GWAS. We examined the SNPs' relations to cross-sectional left atrial (LA) dimensions (determined by transthoracic echocardiography) and LA volume (determined by cardiovascular magnetic resonance [CMR]) employing linear regression. The total sample included 1555 participants with CMR LA volume (age 60+/-9 years, 53% women) and 6861 participants with echocardiographic LA diameter (age 48+/-13 years, 52% women) measured. We employed a significance threshold of P < 0.0023 to account for multiple testing of the 11 SNPs and 2 LA measures. In a primary analysis, no SNPs were significantly related to the LA measures. Likewise, in secondary analyses excluding individuals with prevalent AF (n=77, CMR sample; n=105, echocardiography sample) no SNPs were related to LA volume or diameter.
CONCLUSION: In a community-based cohort, we did not identify a statistically significant association between selected SNPs associated with AF and measures of LA anatomy. Further investigations with larger longitudinally assessed samples and a broader array of SNPs may be necessary to determine the relation between genetic loci associated with AF and atrial structure.
The modified Hospital Elder Life Program: adapting a complex intervention for feasibility and scalability in a surgical setting
The purpose of this article is to provide the rationale and methods for adapting the Hospital Elder Life Program (HELP). The HELP is a complex intervention that has been shown to reduce rates of delirium and functional decline. However, modification of the program may be required to meet local circumstances and specialized populations. We selected three key elements based on our prior work and the concept of shared risk factors and modified the HELP to include only three shared risk factors (functional, nutritional, and cognitive status) that were targeted by three nursing protocols: early mobilization, oral and nutritional assistance, and orienting communication. These protocols were adapted, refined, and pilot-tested for feasibility and efficacy. We hope by reporting the rationale and protocols for the modified HELP, we will advance the field for others adapting evidence-based, complex nursing interventions.
Decade-long trends in the characteristics, management and hospital outcomes of diabetic patients with ST-segment elevation myocardial infarction
PURPOSE: Our objectives were to describe recent trends in the characteristics and in-hospital outcomes in diabetic as compared with non-diabetic patients hospitalized with ST-segment elevation myocardial infarction (STEMI).
METHODS: We reviewed the medical records of 2537 persons with (n = 684) and without (n = 1853) a history of diabetes who were hospitalized for STEMI between 1997 and 2009 at 11 medical centres in Central Massachusetts.
RESULTS: Diabetic patients were more likely to be older, female and to have a higher prevalence of previously diagnosed comorbidities. Diabetic patients were more likely to have developed important in-hospital complications and to have a longer hospital stay compared with non-diabetic patients. Between 1997 and 2009, there was a marked decline in hospital mortality in diabetic (20.0%-5.6%) and non-diabetic (18.6%-7.5%) patients.
CONCLUSION: Despite reduced hospital mortality in patients hospitalized with STEMI, diabetic patients continue to experience significantly more adverse outcomes than non-diabetics.
Critical thinking is essential to a health professional's competence to assess, diagnose, and care for patients. Defined as the ability to apply higher-order cognitive skills (conceptualization, analysis, evaluation) and the disposition to be deliberate about thinking (being open-minded or intellectually honest) that lead to action that is logical and appropriate, critical thinking represents a "meta-competency" that transcends other knowledge, skills, abilities, and behaviors required in health care professions. Despite its importance, the developmental stages of critical thinking have not been delineated for nurses and physicians. As part of a task force of educators who considered different developmental stage theories, the authors have iteratively refined and proposed milestones in critical thinking. The attributes associated with unreflective, beginning, practicing, advanced, accomplished, and challenged critical thinkers are conceived as independent of an individual's level of training. Depending on circumstances and environmental factors, even the most experienced clinician may demonstrate attributes associated with a challenged thinker. The authors use the illustrative case of a patient with abdominal pain to demonstrate how critical thinking may manifest in learners at different stages of development, analyzing how the learner at each stage applies information obtained in the patient interaction to arrive at a differential diagnosis and plan for evaluation. The authors share important considerations and provide this work as a foundation for the development of effective approaches to teaching and promoting critical thinking and to establishing expectations for learners in this essential meta-competency.
Heart disease was an uncommon cause of death in the US at the beginning of the 20th century. By mid-century it had become the commonest cause. After peaking in the mid-1960s, the number of heart disease deaths began a marked decline that has persisted to the present. The increase in heart disease deaths from the early 20th century until the 1960s was due to an increase in the prevalence of coronary atherosclerosis with resultant coronary heart disease, as documented by autopsy studies. This increase was associated with an increase in smoking and dietary changes leading to an increase in serum cholesterol levels. In addition, the ability to diagnose acute myocardial infarction with the aid of the electrocardiogram increased the recognition of coronary heart disease before death. The substantial decrease in coronary heart disease deaths after the mid-1960s is best explained by the decreased incidence, and case fatality rate, of acute myocardial infarction and a decrease in out-of-hospital sudden coronary heart disease deaths. These decreases are very likely explained by a decrease in coronary atherosclerosis due to primary prevention, and a decrease in the progression of nonobstructive coronary atherosclerosis to obstructive coronary heart disease due to efforts of primary and secondary prevention. In addition, more effective treatment of patients hospitalized with acute myocardial infarction has led to a substantial decrease in deaths due to acute myocardial infarction. It is very likely that the 20th century was the only century in which heart disease was the most common cause of death in America.
The American College of Clinical Pharmacy and other stakeholder organizations seek to advance clinical pharmacist practitioners, educators, and researchers. Unfortunately, there remains an inadequate supply of residency-trained clinical specialists to meet the needs of our health care system, and nonspecialists often are called on to fill open specialist positions. The impact of clinical pharmacy specialists on pharmacotherapy outcomes in both acute care and primary care settings demonstrates the value of these specialists. This commentary articulates the need for postgraduate year two (PGY2)-trained clinical specialists within the health care system by discussing various clinical and policy rationales, interprofessional support, economic justifications, and their impact on quality of care and drug safety. The integrated practice model that has grown out of the American Society of Health-System Pharmacists Pharmacy Practice Model Initiative (PPMI) could threaten the growth and development of future clinical specialists. Therefore, the ways in which PGY2-trained clinical pharmacist specialists are deployed in the PPMI require further consideration. PGY2 residencies provide education and training opportunities that cannot be achieved in traditional professional degree programs or postgraduate year one residencies. These specialists are needed to provide direct patient care to complex patient populations and to educate and train pharmacy students and postgraduate residents. Limitations to training and hiring PGY2-trained clinical pharmacy specialists include site capacity limitations and lack of funding. A gap analysis is needed to define the extent of the mismatch between the demand for specialists by health care systems and educational institutions versus the capacity to train clinical pharmacists at the specialty level.
Increasing demand for US critical care resources, including beds, intensivists, and invasive mechanical ventilation (IMV),has placed substantial strain on the critical care system. Since 2000, elderly patients treated in the intensive care unit have received higher intensity care (and have experienced lower mortality rates) than historical cohorts. Yet certain populations of elderly patients exposed to intensive care experience substantial long-term adverse effects, including functional decline and excess mortality. Patients with dementia receiving IMV, for example, are at high risk for delirium, which confers a 3.2-fold increased risk of 6-month mortality. The increasing use of aggressive therapies suggests that demand for IMV in elderly populations will increase in the future, both among patients that are likely to benefit and among those with terminal illness. We examined temporal trends in IMV use by older patients with and without dementia and projected future use.
The challenges managing advanced heart failure (AHF) are mounting, not least by the presence of multiple coexisting comorbidities, the lack of evidence of clinical benefit in many subsets of AHF, but also surrounding the uncertainty of the both short-term and long-term prognosis. Clinicians are highly variable in their interpretation of clinical data and are prone to considerable bias when it comes to treatment recommendations. This manuscript provides a critical appraisal of the uncertainties as it pertains to the natural history of AHF and management decisions. First, clinical examples are explored to illustrate common errors of judgment due to unrecognized biases. Secondly, a tool is provided that promulgates a structured approach to key data elements in an attempt to create a sound platform for decision-making.
BACKGROUND: While the incidence of venous thromboembolism increases with age, little is known about its contemporary management or outcomes in older patients. Our goal was to compare the characteristics, treatment, and outcomes associated with venous thromboembolism, in patients aged 65-69 years, 70-74 years, 75-79 years, and 80+ years.
METHODS/PARTICIPANTS: We prospectively followed 542 subjects aged >/=65 years with venous thromboembolism from January 2008 through August 2011 at 6 sites. In addition, a retrospective study of 681 additional subjects aged >/=65 years with venous thromboembolism diagnosed in 2007 and 2009 was conducted at the same 6 sites.
RESULTS: With advancing age, patients were more likely to suffer provoked venous thromboembolism but less likely to present with pulmonary embolism. Patients with unprovoked, provoked, or malignancy-associated venous thromboembolism received warfarin for a median of 401 days, 203 days, and 529 days, respectively. Age >/=80 years was not associated with an increased risk of recurrent venous thromboembolism, but there was an increased risk of all-cause mortality.
CONCLUSION: With advancing age, patients are more likely to suffer hospital-associated and provoked venous thromboembolism. Many elderly patients with provoked or unprovoked venous thromboembolism were treated for >3 months or >12 months, respectively. Given that advanced age was not associated with increased risk of recurrent venous thromboembolism, but elderly patients in general have a higher risk of bleeding from continued anticoagulant therapy, such practice is potentially harmful. At the same time, such an argument could be used to more vigorously offer prophylaxis in the first place.
BACKGROUND: Knowledge about factors associated with provider ordering of appropriate testing is limited.
OBJECTIVE: To determine physician factors associated with ordering recommended laboratory monitoring tests for high-risk medications.
METHODS: Retrospective cohort study of patients prescribed a high-risk medication requiring laboratory monitoring in a large multispecialty group practice between 1 January 2008 and 31 December 2008. Analyses are based on administrative claims and electronic medical records. The outcome is a physician order for each recommended laboratory test for each prescribed medication. Key predictor variables are physician characteristics, including age, gender, specialty training, years since completing training, and prescribing volume. Additional variables are patient characteristics such as age, gender, comorbidity burden, whether the medication requiring monitoring is new or chronic, and drug-test characteristics such as inclusion in black box warnings. We used multivariable logistic regression, accounting for clustering of drugs within patients and patients within providers.
RESULTS: Physician orders for laboratory testing varied across drug-test pairs and ranged from 9 % (Primidone-Phenobarbital level) to 97 % (Azathioprine-CBC), with half of the drug-test pairs in the 85-91 % ordered range. Test ordering was associated with higher provider prescribing volume for study drugs and specialist status (primary care providers were less likely to order tests than specialists). Patients with higher comorbidity burden and older patients were more likely to have appropriate tests ordered. Drug-test combinations with black box warnings were more likely to have tests ordered.
CONCLUSIONS: Interventions to improve laboratory monitoring should focus on areas with the greatest potential for improvement: providers with lower frequencies of prescribing medications with monitoring recommendations and those prescribing these medications for healthier and younger patients; patients with less interaction with the health care system are at particular risk of not having tests ordered. Black box warnings were associated with higher ordering rates and may be a tool to increase appropriate test ordering.
Hospital-level variation in use of cardiovascular testing for adults with incident heart failure: findings from the cardiovascular research network heart failure study
OBJECTIVES: This study aimed to characterize the use of cardiovascular testing for patients with incident heart failure (HF) hospitalization who participated in the National Heart, Lung, and Blood Institute sponsored Cardiovascular Research Network (CVRN) Heart Failure study.
BACKGROUND: HF is a common cause of hospitalization, and testing and treatment patterns may differ substantially between providers. Testing choices have important implications for the cost and quality of care.
METHODS: Crude and adjusted cardiovascular testing rates were calculated for each participating hospital. Cox proportional hazards regression models were used to examine hospital testing rates after adjustment for hospital-level patient case mix.
RESULTS: Of the 37,099 patients in the CVRN Heart Failure study, 5,878 patients were hospitalized with incident HF between 2005 and 2008. Of these, evidence of cardiovascular testing was available for 4,650 (79.1%) patients between 14 days before the incident HF admission and ending 6 months after the incident discharge. We compared crude and adjusted cardiovascular testing rates at the hospital level because the majority of testing occurred during the incident HF hospitalization. Of patients who underwent testing, 4,085 (87.9%) had an echocardiogram, 4,345 (93.4%) had a systolic function assessment, and 1,714 (36.9%) had a coronary artery disease assessment. Crude and adjusted testing rates varied markedly across the profiled hospitals, for individual testing modalities (e.g., echocardiography, stress echocardiography, nuclear stress testing, and left heart catheterization) and for specific clinical indications (e.g., systolic function assessment and coronary artery disease assessment).
CONCLUSIONS: For patients with newly diagnosed HF, we did not observe widespread overuse of cardiovascular testing in the 6 months following incident HF hospitalization relative to existing HF guidelines. Variations in testing were greatest for assessment of ischemia, in which testing guidelines are less certain. Elsevier Inc. All rights reserved.
BACKGROUND: We evaluated how diabetic patients understand and respond to the presentation of personalized risk information.
METHODS: This was a mixed methods study involving 56 patients with type 2 diabetes and at least 1 additional cardiovascular risk factor. We assessed participants' perceptions of diabetes-related risks; asked them to rank order 6 events (death, heart attack, stroke, blindness, amputation, and kidney failure) by likelihood of occurrence in a specified time frame; presented them with personalized risk estimates; and asked them to re-rank the risks. The final 18 participants were tested to verify understanding before re-ranking risks. Qualitative analysis of interview transcripts identified themes and concepts underlying participants' ways of perceiving and reacting to risk.
RESULTS: While mortality was the most likely outcome for almost all participants, nearly all estimated it to be least likely; only 28% adjusted their mortality rankings to match model predictions. Some did not understand the risk information: only two thirds of those asked could rank risks according to the information presented. Risk perceptions were influenced by factors including "knowing myself," powerful anecdotes, and belief that a "warning shot" would occur before death.
CONCLUSIONS: Personalized risk estimates, particularly about mortality, had limited salience. Some participants could not understand the information, despite presentation in ways suggested by previous research.
Time to standardize and broaden the criteria of acute coronary syndrome symptom presentations in women
Early recognition of the signs and symptoms of acute coronary syndromes (ACS) is essential to improving patient management and associated outcomes. It is widely reported that women might have a different ACS symptom presentation than men. Multiple review articles have examined sex differences in symptom presentation of ACS and these studies have yielded inconclusive results and/or inconsistent recommendations. This is largely because these studies have included diverse study populations, different methods of assessing the chief complaint and associated coronary symptoms, relatively small sample sizes of women and men, and lack of adequate adjustment for age or other potentially confounding differences between the sexes. There is a substantial overlap of ACS symptoms that are not mutually exclusive according to sex, and are generally found in women and men. However, there are apparent differences in the frequency and distribution of ACS symptoms among women and men. Women, on average, are also more likely to have a greater number of ACS-related symptoms contributing to the perception that women have more atypical symptoms than men. In this review, we address issues surrounding whether women should have a different ACS symptom presentation message than men, and provide general recommendations from a public policy perspective. In the future, our goal should be to standardize ACS symptom presentation and to elucidate the full range of ACS and myocardial infarction symptoms considering the substantial overlap of symptoms among women and men rather than use conventional terms such as "typical" and "atypical" angina. All rights reserved.
Incident comorbidities and all-cause mortality among 5-year survivors of Stage I and II breast cancer diagnosed at age 65 or older: a prospective-matched cohort study
Five-year breast cancer survivors, diagnosed after 65 years of age, may develop more incident comorbidities than similar populations free of cancer. We investigated whether older breast cancer survivors have a similar comorbidity burden 6-15 years after cancer diagnosis to matched women free of breast cancer at start of follow-up and whether incident comorbidities are associated with all-cause mortality. In this prospective cohort study, 1,361 older 5-year early-stage breast cancer survivors diagnosed between 1990 and 1994 and 1,361 age- and health system-matched women were followed for 10 years. Adjudicated medical record review captured prevalent and incident comorbidities during follow-up or until death as collected from the National Death Index. Older 5-year breast cancer survivors did not acquire incident comorbidities more often than matched women free of breast cancer in the subsequent 10 years [hazard ratio (HR) 1.0, 95 % confidence interval (95 % CI) 0.93, 1.1]. Adjusted for cohort membership, women with incident comorbidities had a higher mortality rate than those without incident comorbidities (HR 4.8, 95 % CI 4.1, 5.6). A breast cancer history continued to be a hazard for mortality 6-15 years after diagnosis (HR 1.3, 95 % CI 1.1, 1.4). We found that older breast cancer survivors who developed comorbidities had an increased all-cause mortality rate even after adjusting for age and prevalent comorbidity burden. Additionally, survivors acquire comorbidities at a rate similar to older women free of breast cancer. These results highlight the association between comorbidity burden and long-term mortality risk among older breast cancer survivors and their need for appropriate oncology and primary care follow-up.