Search

INTRODUCTION: Individuals living in rural communities are at heightened risk for Alzheimer's disease and related dementias (ADRD), which parallels other persistent place-based health disparities. Identifying multiple potentially modifiable risk factors specific to rural areas that contribute to ADRD is an essential first step in understanding the complex interplay between various barriers and facilitators. METHODS: An interdisciplinary, international group of ADRD researchers convened to address the overarching question of: “What can be done to begin minimizing the rural health disparities that contribute uniquely to ADRD?” In this state of the science appraisal, we explore what is known about the biological, behavioral, sociocultural, and environmental influences on ADRD disparities in rural settings. RESULTS: A range of individual, interpersonal, and community factors were identified, including strengths of rural residents in facilitating healthy aging lifestyle interventions. DISCUSSION: A location dynamics model and ADRD-focused future directions are offered for guiding rural practitioners, researchers, and policymakers in mitigating rural disparities. HIGHLIGHTS: Rural residents face heightened Alzheimer's disease and related dementia (ADRD) risks and burdens due to health disparities. Defining the unique rural barriers and facilitators to cognitive health yields insight. The strengths and resilience of rural residents can mitigate ADRD-related challenges. A novel “location dynamics” model guides assessment of rural-specific ADRD issues.

IntroductionDementia caregiving is complex and disproportionally burdens caregivers living in rural areas due to fewer resources and formal support systems. There is an immediate need to identify effective, scalable, and accessible online programs to support rural caregivers' well-being. Building Better Caregivers (BBC), a possible solution, is an asynchronous online 6-week, interactive, and skills-building workshop developed for caregivers of persons with dementia. This research aims to assess the effectiveness and implementation of the BBC workshop when delivered among rural dementia caregivers in the United States.MethodsA hybrid effectiveness and implementation trial applying mixed methods will be conducted in collaboration with local, state, and national partnering organizations. Eligible participants live in a rural area of the United States, give care at least 10h a week for a family member or friend with dementia, and have internet access. Evaluation is based on the RE-AIM framework. Effectiveness outcomes are assessed using a randomized control trial. Caregivers are randomly assigned to the BBC workshop (intervention) or attention control group. Implementation outcomes are assessed using surveys and debriefing interviews from partnering organizations and participants. The study protocol including the study design, methods of recruitment and assessment, and outcomes are described.ConclusionThis is the first known study to evaluate both the effectiveness and implementation of a caregiver support intervention under real-world conditions in rural areas. If successful, this online workshop will be a practical and acceptable approach for promoting the health and well-being of geographically isolated rural dementia caregivers.

Background Caregivers of children with primary immunodeficiency disorders (PIDs) experience significant psychological distress during their child's hematopoietic cell transplantation (HCT) process. Objectives This study aims to understand caregiver challenges and identify areas for health care system-level improvements to enhance caregiver well-being. Methods In this mixed-methods study caregivers of children with PIDs were contacted in August to November 2017 through online and electronic mailing lists of rare disease consortiums and foundations. Caregivers were invited to participate in an online survey assessing sociodemographic variables, the child's medical characteristics, psychosocial support use, and the World Health Organization–5 Well-Being Index. Open-ended questions about health care system improvements were included. Descriptive statistics and linear multivariate regression analyses were conducted. A modified content analysis method was used to code responses and identify emergent themes. Results Among the 80 caregiver respondents, caregivers had a median age of 34 years (range, 23-62 years) and were predominantly female, white, and married with male children given a diagnosis of severe combined immune deficiency. In the adjusted regression model lower caregiver well-being was significantly associated with lower household income and medical complications. Challenges during HCT include maintaining relationships with partners and the child's healthy sibling or siblings, managing self-care, and coping with feelings of uncertainty. Caregivers suggested several organizational-level solutions to enhance psychosocial support, including respite services, online connections to other PID caregivers, and bedside mental health services. Conclusions Certain high-risk subpopulations of caregivers might need more targeted psychosocial support to reduce the long-term effect of the HCT experience on their well-being. Caregivers suggested several organizational-level solutions for provision of this support.

Objective The purpose of this study was to examine the relationship between dynapenia and metabolic risk factors in obese and nonobese older adults. Methods A total of 1453 men and women (age ≥70 years) from the Lifestyle Interventions and Independence for Elders (LIFE) Study were categorized as (1) nondynapenic/nonobese (NDYN-NO), (2) dynapenic/nonobese (DYN-NO), (3) nondynapenic/obese (NDYN-O), or (4) dynapenic/obese (DYN-O), based on muscle strength (Foundation for the National Institute of Health criteria) and body mass index. Dependent variables were blood lipids, fasting glucose, blood pressure, presence of at least 3 metabolic syndrome (MetS) criteria, and other chronic conditions. Results A significantly higher likelihood of having abdominal obesity criteria in NDYN-NO compared with DYN-NO groups (55.6 vs 45.1%, P ≤ .01) was observed. Waist circumference also was significantly higher in obese groups (DYN-O = 114.0 ± 12.9 and NDYN-O = 111.2 ± 13.1) than in nonobese (NDYN-NO = 93.1 ± 10.7 and DYN-NO = 92.2 ± 11.2, P ≤ .01); and higher in NDYN-O compared with DYN-O ( P = .008). Additionally, NDYN-O demonstrated higher diastolic blood pressure compared with DYN-O (70.9 ± 10.1 vs 67.7 ± 9.7, P ≤ .001). No significant differences were found across dynapenia and obesity status for all other metabolic components ( P > .05). The odds of having MetS or its individual components were similar in obese and nonobese, combined or not with dynapenia (nonsignificant odds ratio [95% confidence interval]). Conclusion Nonobese dynapenic older adults had fewer metabolic disease risk factors than nonobese and nondynapenic older adults. Moreover, among obese older adults, dynapenia was associated with lower risk of meeting MetS criteria for waist circumference and diastolic blood pressure. Additionally, the presence of dynapenia did not increase cardiometabolic disease risk in either obese or nonobese older adults.

BACKGROUND Although web-based psychoeducational programs may be an efficient, accessible, and scalable option for improving participant well-being, they seldom are sustained beyond trial publication. Implementation evaluations may help optimize program uptake, but few are performed. When the US Department of Veterans Affairs (VA) launched the web-based psychoeducational workshop Building Better Caregivers (BBC) for informal caregivers of veterans nationwide in 2013, the workshop did not enroll as many caregivers as anticipated. OBJECTIVE This study aims to identify the strengths and weaknesses of initial implementation, strategies likely to improve workshop uptake, whether the VA adopted these strategies, and whether workshop enrollment changed. METHODS We used mixed methods and the Promoting Action on Research Implementation in Health Services (PARIHS) implementation evaluation framework. In stage 1, we conducted semistructured interviews with caregivers, local staff, and regional and national VA leaders and surveys with caregivers and staff. We collected and analyzed survey and interview data concurrently and integrated the results to identify implementation strengths and weaknesses, and strategies likely to improve workshop uptake. In stage 2, we reinterviewed national leaders to determine whether the VA adopted recommended strategies and used national data to determine whether workshop enrollment changed over time. RESULTS A total of 54 caregivers (n=32, 59%), staff (n=13, 24%), and regional (n=5, 9%) and national (n=4, 7%) leaders were interviewed. We received survey responses from 72% (23/32) of caregivers and 77% (10/13) of local staff. In stage 1, survey and interview results were consistent across multiple PARIHS constructs. Although participants from low-enrollment centers reported fewer implementation strengths and more weaknesses, qualitative themes were consistent across high- and low-enrollment centers, and across caregiver, staff, and leadership respondent groups. Identified strengths included belief in a positive workshop impact and the use of some successful outreach approaches. Implementation weaknesses included missed opportunities to improve outreach and to better support local staff. From these, we identified and recommended new and enhanced implementation strategies—increased investment in outreach and marketing capabilities; tailoring outreach strategies to multiple stakeholder groups; use of campaigns that are personal, repeated, and detailed, and have diverse delivery options; recurrent training and mentoring for new staff; and comprehensive data management and reporting capabilities. In stage 2, we determined that the VA had adopted several of these strategies in 2016. In the 3 years before and after adoption, cumulative BBC enrollment increased from 2139 (2013-2015) to 4030 (2016-2018) caregivers. CONCLUSIONS This study expands the limited implementation science literature on best practices to use when implementing web-based psychoeducational programs. We found that robust outreach and marketing strategies and support for local staff were critical to the implementation success of the BBC workshop. Other health systems may want to deploy these strategies when implementing their web-based programs.

This survey study evaluates behavioral health risks and burnout among physician mothers who have caregiving responsibilities for persons in addition to their patients and children.

Objective To adapt marketing approaches in a health services environment. Methods Researchers and advertising professionals partnered in developing advertising-style messages designed to activate patients pre-identified as having chronic kidney disease to ask providers about recommended medications. We assessed feasibility of the development process by evaluating partnership structure, costs, and timeframe. We tested messages with patients and providers using preliminary surveys to refine initial messages and subsequent focus groups to identify the most persuasive ones. Results The partnership achieved an efficient structure, $14,550 total costs, and 4-month timeframe. The advertising team developed 11 initial messages. The research team conducted surveys and focus groups with a total of 13 patients and 8 providers to identify three messages as most activating. Focus group themes suggested the general approach of using advertising-style messages was acceptable if it supported patient–provider relationships and had a credible evidence base. Individual messages were more motivating if they elicited personal identification with imagery, particular emotions, active patient role, and message clarity. Conclusion We demonstrated feasibility of a research-advertising partnership and acceptability and likely impact of advertising-style messages on patient medication-seeking behavior. Practice implications Healthcare systems may want to replicate our adaptation of marketing approaches to patients with chronic conditions.

Background Data are sparse regarding the value of physical activity ( PA ) surveillance among older adults—particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. Methods and Results Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home‐based activity data were collected by hip‐worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [ SD ] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84–0.96; P =0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65–0.89 [ P =0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow‐up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85–0.96 [ P =0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63–0.90 [ P =0.002]) were significantly associated with lower cardiovascular event rates. Conclusions Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01072500.

Building Better Caregivers (BBC), a community 6-week, peer-led intervention, targets family caregivers of those with cognitive impairments. BBC was implemented in four geographically scattered areas. Self-report data were collected at baseline, 6 months, and 1 year. Primary outcome were caregiver strain and depression. Secondary outcomes included caregiver burden, stress, fatigue, pain, sleep, self-rated health, exercise, self-efficacy, and caregiver and care partner health care utilization. Paired t tests examined 6 month and 1-year improvements. General linear models examined associations between baseline and 6-month changes in self-efficacy and 12-month primary outcomes. Eighty-three participants (75% of eligible) completed 12-month data. Caregiver strain and depression improved significantly (Effect Sizes = .30 and .41). All secondary outcomes except exercise and caregiver health care utilization improved significantly. Baseline and 6-month improvements in self-efficacy were associated with improvements in caregiver strain and depression. In this pilot pragmatic study, BBC appears to assist caregivers while reducing care partner health care utilization. Self-efficacy appears to moderate these outcomes.

Objectives. To determine the generalizability of crowdsourced, electronic health data from self-selected individuals using a national survey as a reference. Methods. Using the world’s largest crowdsourcing platform in 2015, we collected data on characteristics known to influence cardiovascular disease risk and identified comparable data from the 2013 Behavioral Risk Factor Surveillance System. We used age-stratified logistic regression models to identify differences among groups. Results. Crowdsourced respondents were younger, more likely to be non-Hispanic and White, and had higher educational attainment. Those aged 40 to 59 years were similar to US adults in the rates of smoking, diabetes, hypertension, and hyperlipidemia. Those aged 18 to 39 years were less similar, whereas those aged 60 to 75 years were underrepresented among crowdsourced respondents. Conclusions. Crowdsourced health data might be most generalizable to adults aged 40 to 59 years, but studies of younger or older populations, racial and ethnic minorities, or those with lower educational attainment should approach crowdsourced data with caution. Public Health Implications. Policymakers, the national Precision Medicine Initiative, and others planning to use crowdsourced data should take explicit steps to define and address anticipated underrepresentation by important population subgroups.

Observational studies show a relationship between elevated serum uric acid (UA) and better physical performance and muscle function. The purpose of this paper was to determine whether regular participation in an exercise intervention, known to improve physical functioning, would result in increased serum UA. For this study, 424 older adults at risk for physical disability were randomized to participate in either a 12-mo moderate-intensity physical activity (PA) or a successful aging (SA) health education intervention. UA was measured at baseline, 6, and 12 mo (n = 368, 341, and 332, respectively). Baseline UA levels were 6.03 ± 1.52 mg/dl and 5.94 ± 1.55 mg/dl in the PA and SA groups, respectively. The adjusted mean UA at month 12 was 4.8% (0.24 mg/dl) higher in the PA compared with the SA group (p = .028). Compared with a health education intervention, a 1-yr PA intervention results in a modest increase in systemic concentration of UA in older adults at risk for mobility disability.

Objective To examine weight loss patterns and predictors among participants in a primary care-based translation study of the Diabetes Prevention Program lifestyle intervention. Design and Methods Cluster analysis identified short-term (12-week) weight loss patterns among 72 intervention participants. Analysis of variance assessed cluster differences in weight loss maintenance at 15-month follow-up. Discriminant analysis identified baseline characteristics that best differentiated between clusters. Results Participants had baseline mean (SD) age of 55.0 (10.8) years and BMI of 31.9 (5.2) kg/m2. Cluster analysis identified three short-term weight loss patterns: modest (n = 15; 21%), moderate-and-steady (n = 43; 60%), and substantial-and-early (n = 14; 19%). Only participants with the latter two patterns achieved clinically significant (≥5%) short-term weight loss and maintained it at 15 months. On discriminant analysis, the modest cluster was most differentiated from other clusters by high friend encouragement for dietary change, high obesity-related problems, and low physical well-being. The moderate-and-steady cluster was differentiated by lower physical activity, family encouragement, and depression symptoms. Conclusion Results provided insight into the heterogeneity of response to an effective lifestyle intervention by identifying short-term weight loss patterns and their baseline predictors and relationship to 15-month success. If replicated, results may help tailor strategies for participant subgroups in weight loss programs.

Objective To examine rate differences and explanatory factors for lifestyle counseling to obese Latinos versus non-Hispanic whites (NHWs) in U.S. outpatient settings. Design and Methods The 2009 National Ambulatory Medical Care Survey data assessed the provision of weight-related lifestyle counseling during general medical exam visits (n = 688) by obese Latino and NHW adults. The Blinder-Oaxaca decomposition technique to identify the fraction of the overall ethnic difference in counseling rate explained by a selection of measured variables based on the Anderson-Newman-Aday behavioral model were used. Results Although weight-related lifestyle counseling rates were low in both ethnic groups, the rate among obese Latinos (51.3%) was significantly higher than among NHWs (35.8%) (P = 0.03), with 60% of the difference explained by observed factors. Enabling factors such as provider specialty, metropolitan statistical area, practice type, and provider employment type contributed the most to higher counseling rates among Latinos, whereas geographic region, continuity of care, and health insurance were enabling factors that, along with the predisposing factor of sex, contributed the most in the opposite direction. Conclusions Obese Latinos are more likely to receive weight-related counseling during general medical exams than do NHWs, which is partly explained by physician practice and patient factors.

Obesity is one of the top health priorities in the United States. Primary care physicians are the designated “gatekeepers” for obesity prevention, detection, and treatment. However, they and the current U.S. health care structure and reimbursement systems are often ill-equipped to implement evidence-based obesity care. The Group Lifestyle Balance™ (GLB) program is a group-delivery adaptation of the predominantly one-on-one lifestyle intervention proven efficacious in the Diabetes Prevention Program (DPP) trial. Participant intervention goals are 7% weight loss and sustained moderate physical activity of 150 minutes or more each week. Sequential instruction and coaching encompasses nutrition, behavior modification, and physical activity principles. The E-LITE (Evaluation of Lifestyle Interventions to Treat Elevated Cardiometabolic Risk in Primary Care) trial evaluates the feasibility and potential effectiveness of delivering the GLB program, supplemented with food tasting and supervised physical activity during each of 12 group sessions, and electronic communication for long-term follow up, in a primary care setting. Benefits and potential areas for improvement in three areas of implementation emerged during the 15-month E-LITE trial: (1) delivery of an established lifestyle intervention program by specialized professionals, (2) integration of a lifestyle intervention program into a primary care clinic, and (3) information technology use in a primary care-based lifestyle intervention program. Our experience shows the feasibility of implementing an evidence-based lifestyle intervention program combining group-delivered nutrition and behavioral counseling, physical activity training, and technology-mediated follow-up in a primary care clinic setting, but challenges remain, and we offer possible solutions to overcome them.

Background Because chronic kidney disease (CKD) is associated with muscle wasting, older adults with CKD are likely to have physical function deficits. Physical activity can improve these deficits, but whether CKD attenuates the benefits is unknown. Our objective was to determine if CKD modified the effect of a physical activity intervention in older adults. Methods This is an exploratory analysis of the LIFE-P study, which compared a 12-month physical activity program (PA) to a successful aging education program (SA) in older adults. CKD was defined as a baseline eGFR < 60 mL/min/1.73 m2. We examined the Short Physical Performance Battery (SPPB) at baseline, 6 and 12 months. Secondary outcomes included serious adverse events (SAE) and adherence to intervention frequency. Linear mixed models were adjusted for age, sex, diabetes, hypertension, CKD, intervention, site, visit, baseline SPPB, and interactions of intervention and visit and of intervention, visit, and baseline CKD. Results The sample included 368 participants. CKD was present in 105 (28.5%) participants with a mean eGFR of 49.2 ± 8.1 mL/min/1.73 m2. Mean SPPB was 7.38 ± 1.41 in CKD participants; 7.59 ± 1.44 in those without CKD (p = 0.20). For CKD participants in PA, 12-month SPPBs increased to 8.90 (95% CI 8.32, 9.47), while PA participants without CKD increased to 8.40 (95% CI 8.01, 8.79, p = 0.43). For CKD participants in SA, 12-month SPPBs increased to 7.67 (95% CI 7.07, 8.27), while participants without CKD increased to 8.12 (95% CI 7.72, 8.52, p = 0.86). Interaction between CKD and intervention was non-significant (p = 0.88). Number and type of SAEs were not different between CKD and non-CKD participants (all p > 0.05). In PA, adherence for CKD participants was 65.5 ± 25.4%, while for those without CKD was 74.0 ± 22.2% (p = 0.12). Conclusion Despite lower adherence, older adults with CKD likely derive clinically meaningful benefits from physical activity with no apparent impact on safety, compared to those without CKD.

To evaluate the extent of variability in functional responses in participants in the Lifestyle Interventions and Independence for Elders (LIFE) study and to identify the relative contributions of intervention adherence, physical activity, and demographic and health characteristics to this variability.Secondary analysis.Multicenter institutions.A volunteer sample (N=1635) of sedentary men and women aged 70 to 89 years who were able to walk 400m but had physical limitations, defined as a Short Physical Performance Battery (SPPB) score of ≤9.Moderate-intensity physical activity (n=818) consisting of aerobic, resistance, and flexibility exercises performed both center-based (2times/wk) and home-based (3-4times/wk) sessions or health education program (n=817) consisting of weekly to monthly workshops covering relevant health information.Physical function (gait speed over 400m) and lower extremity function (SPPB score) assessed at baseline and 6, 12, and 24 months.Greater baseline physical function (gait speed, SPPB score) was negatively associated with change in gait speed (regression coefficient β=-.185; P.001) and change in SPPB score (β=-.365; P.001), whereas higher number of steps per day measured by accelerometry was positively associated with change in gait speed (β=.035; P.001) and change in SPPB score (β=.525; P.001). Other baseline factors associated with positive change in gait speed and/or SPPB score include younger age (P.001), lower body mass index (P.001), and higher self-reported physical activity (P=.002).Several demographic and physical activity-related factors were associated with the extent of change in functional outcomes in participants in the LIFE study. These factors should be considered when designing interventions for improving physical function in older adults with limited mobility.

Minimization as proposed by Pocock and Simon for balancing categorical covariates in clinical trials with individual-level, consecutive randomization has been increasingly used. An extension of the method exists that uses the symmetric Kullback-Leibler divergence index to balance both categorical and continuous covariates, albeit for two-arm randomized controlled trials only. To date, the algorithm has not been made widely available to researchers via publicly accessible software. We adapted Endo et al.'s algorithm to randomized trials with two or more arms. In addition, our algorithm incorporates Efron's biased coin method to decrease the predictability of assignment even when a predefined threshold of difference in the numbers of subjects between treatment arms is reached, whereas Endo et al.'s algorithm assigns the next subject to the treatment of smaller size with certainty. We developed code in the free statistical software R to make the algorithm readily available to trialists. While there are no definitive answers regarding the optimal choices for certain statistical parameters that must be defined prior to algorithm application (P(k), D(n), and p_D(n)), we provide guidance on these. We conducted simulations with actual data from a three-arm randomized trial to compare the modified algorithm and R code to another published biased coin minimization method that can accommodate continuous and categorical covariates in multi-arm trials. The three-arm trial used three categorical covariates (sex, race/ethnicity, and online personal health record access) and four continuous covariates (age, fasting blood glucose, body mass index, and waist circumference). All of the continuous and categorical covariates were well balanced, and the results were comparable to the comparison method.

Effective interventions targeting comorbid obesity and depression are critical given the increasing prevalence and worsened outcomes for patients with both conditions. RAINBOW is a type 1 hybrid design randomized controlled trial. The objective is to evaluate the clinical and cost effectiveness and implementation potential of an integrated, technology-enhanced, collaborative care model for treating comorbid obesity and depression in primary care. Obese and depressed adults (n = 404) will be randomized to usual care enhanced with the provision of a pedometer and information about the health system's services for mood or weight management (control) or with the Integrated Coaching for Better Mood and Weight (I-CARE) program (intervention). The 12-month I-CARE program synergistically integrates two proven behavioral interventions: problem-solving therapy with as-needed intensification of pharmacotherapy for depression (PEARLS) and standardized behavioral treatment for obesity (Group Lifestyle Balance(™)). It utilizes traditional (e.g., office visits and phone consults) and emerging care delivery modalities (e.g., patient web portal and mobile applications). Follow-up assessments will occur at 6, 12, 18, and 24 months. We hypothesize that compared with controls, I-CARE participants will have greater improvements in weight and depression severity measured by the 20-item Depression Symptom Checklist at 12 months, which will be sustained at 24 months. We will also assess I-CARE's cost-effectiveness and use mixed methods to examine its potential for reach, adoption, implementation, and maintenance. This study offers the potential to change how obese and depressed adults are treated-through a new model of accessible and integrative lifestyle medicine and mental health expertise-in primary care.

Background Data are sparse regarding the impacts of habitual physical activity (PA) and sedentary behavior on cardiovascular (CV) risk in older adults with mobility limitations. Methods and Results This study examined the baseline, cross‐sectional association between CV risk and objectively measured PA among participants in the Lifestyle Interventions and Independence for Elders (LIFE) study. The relationship between accelerometry measures and predicted 10‐year Hard Coronary Heart Disease (HCHD) risk was modeled by using linear regression, stratified according to CVD history. Participants (n=1170, 79±5 years) spent 642±111 min/day in sedentary behavior (ie, P P >0.05). However, a significant interaction was observed between sex and count frequency ( P =0.036) for those without CVD, as counts per minute was related to HCHD risk in women (β=−0.94, −1.48 to −0.41; P P =0.704). Conclusions Daily time spent being sedentary is positively associated with predicted 10‐year HCHD risk among mobility‐limited older adults. Duration, but not intensity (ie, mean counts/min), of daily PA is inversely associated with HCHD risk score in this population—although the association for intensity may be sex specific among persons without CVD. Clinical Trial Registration URL: www.clinicaltrials.gov Unique identifier: NCT01072500

Introduction: In middle-aged adults, time spent being sedentary is associated with cardiovascular (CV) health risks independent of structured physical activity (PA). However, data are sparse regarding the impact of sedentary behavior on CV risk in older adults. The extent to which the absolute duration or intensity of daily PA reduces CV risk in older adults is also unknown. Objectives: Our objective was to examine the cross-sectional association between objectively-measured sedentary behavior and predicted CV risk among older adults in the Lifestyle Interventions and Independence for Elders (LIFE) study. The secondary objective was to evaluate associations between the duration/intensity of daily PA and predicted CV risk. Methods: LIFE is a randomized clinical trial to determine if regular PA prevents mobility disability among mobility-limited older adults. Activity data were collected by hip-worn accelerometer at baseline prior to participation in study interventions. Only participants with at least three days of accelerometry data (≥ 10 hrs wear time) were included. Unadjusted and adjusted linear regression was used to model the relationship between accelerometry measures and predicted 10-year Framingham risk of Hard Coronary Heart Disease (HCHD; i.e. myocardial infarction or coronary death). Adjusted models included demographic confounders (e.g. education, race, income) and health parameters (e.g. depression, cognition, arthritis) not in the risk score. Accelerometry cut-points were (in counts/min): sedentary behavior: < 100; low-intensity activity: 100-499; higher intensity activity: > 500. Results: Participants (n = 1170; 78.7 ± [SD] 5.3 years; 66.1% female) had a median HCHD risk of 10.3% (25 th -75 th %: 5.7-18.6). Over a mean accelerometer wear time of 8.1 ± 3.2 days, participants spent 77.0 ± 8.2% of their time sedentary. They also spent 16.6 ± 5.0% of their time in low-intensity PA and 6.4 ± 4.4% in higher-intensity PA. For all PA performed (> 100 counts/min), participants achieved a median of 393.4 (337.8-473.5) counts/min. In the unadjusted model, time spent sedentary (β = 2.41; 95% CI : 1.94, 2.89), in low-intensity PA (-2.56; -3.03, -2.08), and in higher-intensity PA (-1.60; -2.09, -1.11) were all associated with HCHD risk (all p’s < 0.001). These associations remained significant after adjustment. The mean intensity of daily PA was not significantly associated with HCHD risk in any model (p > 0.05). Conclusions: Daily time spent being sedentary is positively associated with predicted 10-year HCHD risk among mobility-limited older adults. Duration, but not mean intensity, of daily PA is inversely associated with HCHD risk score in this population.

To date, physical exercise is the only intervention consistently demonstrated to attenuate age-related declines in physical function. However, variability exists in seniors' responsiveness to training. One potential source of variability is the insertion (I allele) or deletion (D allele) of a 287 bp fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. This polymorphism is known to influence a variety of physiological adaptions to exercise. However, evidence is inconclusive regarding the influence of this polymorphism on older adults' functional responses to exercise. This study aimed to evaluate the association of ACE I/D genotypes with changes in physical function among Caucasian older adults ( n = 283) following 12 mo of either structured, multimodal physical activity or health education. Measures of physical function included usual-paced gait speed and performance on the Short Physical Performance Battery (SPPB). After checking Hardy-Weinberg equilibrium, we used using linear regression to evaluate the genotype*treatment interaction for each outcome. Covariates included clinic site, body mass index, age, sex, baseline score, comorbidity, and use of angiotensin receptor blockers or ACE inhibitors. Genotype frequencies [II (19.4%), ID (42.4%), DD (38.2%)] were in Hardy-Weinberg equilibrium ( P > 0.05). The genotype*treatment interaction was statistically significant for both gait speed ( P = 0.002) and SPPB ( P = 0.020). Exercise improved gait speed by 0.06 ± 0.01 m/sec and SPPB score by 0.72 ± 0.16 points among those with at least one D allele (ID/DD carriers), but function was not improved among II carriers. Thus, ACE I/D genotype appears to play a role in modulating functional responses to exercise training in seniors.

Background: Minimization as an adaptive allocation technique has been recommended in the literature for use in randomized clinical trials. However, it remains uncommonly used due in part to a lack of easily accessible implementation tools. Objective: To provide clinical trialists with a robust, flexible, and readily accessible tool for implementing covariate-adaptive biased-coin randomization. Methods: We developed a Web-based random allocation system, MinimRan, that applies Pocock–Simon (for trials with 2 or more arms) and 2-way (currently limited to 2-arm trials) minimization methods for trials using only categorical prognostic factors or the symmetric Kullback–Leibler divergence minimization method for trials (currently limited to 2-arm trials) using continuous prognostic factors with or without categorical factors, in covariate-adaptive biased-coin randomization. Results: In this paper, we describe the system’s essential statistical and computer programming features and provide as an example the randomization results generated by it in a recently completed trial. The system can be used in single- and double-blind trials as well as single-center and multicenter trials. Conclusions: We expect the system to facilitate the translation of the 3 validated random allocation methods into broad, efficient clinical research practice. [J Med Internet Res 2013;15(7):e139]

Objective: To investigate whether the effects on weight loss and cardiometabolic risk factor reduction of two technology-mediated lifestyle interventions for 15 months in a primary care-based translation trial sustained at 24 months (that is, 9 months after the end of intervention). Design: This study analyzed data from an extended follow-up of participants in the original ‘E-LITE' (Evaluation of Lifestyle Interventions to Treat Elevated Cardiometabolic Risk in Primary Care)-randomized controlled trial, which demonstrated the effectiveness of two adapted Diabetes Prevention Program (DPP) lifestyle interventions compared with usual primary care. Subjects: E-LITE randomized 241 overweight or obese participants with pre-diabetes and/or metabolic syndrome to receive usual care alone (n=81) or usual care plus a coach-led (n=79) or self-directed intervention (n=81). The interventions provided coach-led group behavioral weight-loss treatment or a take-home, self-directed DVD using the same 12-week curriculum, followed by 12 additional months of technology-mediated coach contact and self-monitoring support. Participants received no further intervention after month 15. A blinded assessor conducted 24-month visits by following the measurement protocols of the original trial. Measurements include weight and cardiometabolic risk factors (waist circumference, fasting plasma glucose, resting blood pressure, triglycerides, high- and low-density lipoprotein cholesterol, total cholesterol and triglyceride to high-density lipoprotein cholesterol ratio). Results: At month 24, mean±s.e. changes in body mass index (trial primary outcome) and weight (kg) from baseline were –1.9±0.3 (P=0.001) and –5.4±0.9 (P

The Diabetes Prevention Program (DPP) lifestyle intervention reduced the incidence of type 2 diabetes mellitus (DM) among high-risk adults by 58%, with weight loss as the dominant predictor. However, it has not been adequately translated into primary care.We evaluated 2 adapted DPP lifestyle interventions among overweight or obese adults who were recruited from 1 primary care clinic and had pre-DM and/or metabolic syndrome. Participants were randomized to (1) a coach-led group intervention (n = 79), (2) a self-directed DVD intervention (n = 81), or (3) usual care (n = 81). During a 3-month intensive intervention phase, the DPP-based behavioral weight-loss curriculum was delivered by lifestyle coach-led small groups or home-based DVD. During the maintenance phase, participants in both interventions received lifestyle change coaching and support remotely-through secure email within an electronic health record system and the American Heart Association Heart360 website for weight and physical activity goal setting and self-monitoring. The primary outcome was change in body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) from baseline to 15 months.At baseline, participants had a mean (SD) age of 52.9 (10.6) years and a mean BMI of 32.0 (5.4); 47% were female; 78%, non-Hispanic white; and 17%, Asian/Pacific Islander. At month 15, the mean ± SE change in BMI from baseline was -2.2 ± 0.3 in the coach-led group vs -0.9 ± 0.3 in the usual care group (P.001) and -1.6 ± 0.3 in the self-directed group vs usual care (P = .02). The percentages of participants who achieved the 7% DPP-based weight-loss goal were 37.0% (P = .003) and 35.9% (P = .004) in the coach-led and self-directed groups, respectively, vs 14.4% in the usual care group. Both interventions also achieved greater net improvements in waist circumference and fasting plasma glucose level.Proven effective in a primary care setting, the 2 DPP-based lifestyle interventions are readily scalable and exportable with potential for substantial clinical and public health impact.clinicaltrials.gov Identifier: NCT00842426.

To examine rate differences and explanatory factors for lifestyle counseling to obese Latinos versus non-Hispanic whites (NHWs) in U.S. outpatient settings.The 2009 National Ambulatory Medical Care Survey data assessed the provision of weight-related lifestyle counseling during general medical exam visits (n = 688) by obese Latino and NHW adults. The Blinder-Oaxaca decomposition technique to identify the fraction of the overall ethnic difference in counseling rate explained by a selection of measured variables based on the Anderson-Newman-Aday behavioral model were used.Although weight-related lifestyle counseling rates were low in both ethnic groups, the rate among obese Latinos (51.3%) was significantly higher than among NHWs (35.8%) (P = 0.03), with 60% of the difference explained by observed factors. Enabling factors such as provider specialty, metropolitan statistical area, practice type, and provider employment type contributed the most to higher counseling rates among Latinos, whereas geographic region, continuity of care, and health insurance were enabling factors that, along with the predisposing factor of sex, contributed the most in the opposite direction.Obese Latinos are more likely to receive weight-related counseling during general medical exams than do NHWs, which is partly explained by physician practice and patient factors.

Although the Diabetes Prevention Program (DPP) lifestyle intervention reduced type 2 diabetes incidence by 58% among high-risk adults at academic centers, it requires translation into typical primary care settings. Using baseline data from the Evaluation of Lifestyle Interventions to Treat Elevated Cardiometabolic Risk in Primary Care (E-LITE) randomized controlled trial, we evaluated the potential of its two DPP-based interventions to reach their target populations and be adopted into routine use.Overweight/obese adults with increased cardiometabolic risk enrolled from one primary care clinic. Using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) model, we assessed reach with data on patient identification, participation, and representativeness, and adoption with data on intervention feasibility and potential for organizational diffusion.The target population was identified by searching electronic health records. Contact was attempted for 2391 patients who completed initial screening by phone (56% uptake) or online (44%). Most (88%) of those screened ineligible were not within the target population; 12% were excluded because of research requirements. Conservatively estimated participation rate was 44%. Participants (n=241) included 54% men and had a mean (SD) age of 52.9 years (10.6) and body mass index of 32 kg/m(2) (5.4). Regarding adoption, all clinic physicians agreed to participate. The feasibility of intervention implementation and dissemination was enhanced by leveraging existing intervention, training, and primary care resources.E-LITE's lifestyle interventions had fair-to-good potential for primary care reach and adoption. Our trial evidence and structured reporting may inform real-world implementation of translational trials by health networks, physicians, and payers.

Genome-wide association studies (GWAS) have identified more than 1500 disease-associated single nucleotide polymorphisms (SNPs), including many related to atherosclerotic cardiovascular disease (CVD). Associations have been found for most traditional risk factors (TRFs), including lipids,1,2 blood pressure/hypertension,3,4 weight/body mass index,5,6 smoking behavior,7 and diabetes.8–13 GWAS have also identified susceptibility variants for coronary heart disease (CHD). The first and, so far, strongest of these signals was found in the 9p21.3 locus, where common variants in this region increase the relative risk of CVD by 15% to 30% per risk allele in most race/ethnic groups.13–20 Subsequent large-scale GWAS meta-analyses and replication studies in largely white/European populations have led to the reliable identification of an additional 26 loci conferring susceptibility to CHD,2,20–23 all with substantially lower effects sizes compared with the 9p21 locus. Many of these CVD susceptibility loci appear to be conferring risk independent of TRFs and thus cannot currently be assessed by surrogate clinical measures (Table 1). Among the 27 independent loci identified in the most recent large meta-analyses of CVD, 21 were reported not to be associated with any of the TRFs.20,21 View this table: Table 1. SNPs Related to CVD That Are Independent of Traditional Risk Factors Several studies have explored whether initial CVD-related genetic markers can improve risk prediction over standard models restricted to TRFs using a genetic risk score (GRS) constructed on the basis of the number of risk alleles inherited.24–26 Results to date have been mixed. Although all have shown that a GRS is strongly associated with the outcome of interest independent of TRFs, none were able to demonstrate a significant improvement in the c-statistic. Two of the 3 studies showed some modest improvement in …

To evaluate a web-based self-management training for health professionals. Patients spend 99% of their time outside the healthcare system. Thus self-management support from health professionals is central to optimal care. Our objective was to teach health professionals the skills to provide this support.Primary care residents and practicing providers enrolled in six groups. Each group received four web-based interactive training sessions derived from self-efficacy theory. Retrospective-pre/post assessed changes in self-management beliefs and confidence. Wilcoxon signed-rank tests with Bonferroni correction compared responses. Focus groups solicited qualitative feedback.Fifty-seven residents and providers across the United States enrolled. Residents demonstrated positive changes on all belief questions (P 0.001-0.012). Practicing providers had a non-significant positive change on one and significant changes on the remainder (P 0.001-0.018). Both types of participants demonstrated significant increases on confidence questions regarding their ability to support self-management (P0.01 for all). Participants described learned techniques as being useful, reducing burnout, and increasing acceptance of patient involvement in care planning.The web-based self-management support training for health professionals was feasible and changed beliefs and confidence.The program may maximize patient self-management by increasing provider self-efficacy and skill for self-management support.

Objective To examine weight loss patterns and their baseline predictors among participants in a Diabetes Prevention Program-based group lifestyle intervention. Methods Overweight/obese participants in the intensive intervention arm (n=72) of an ongoing 3-arm randomized weight loss trial were weighed at each of 12 weekly classes. Cluster analysis grouped participants with similar patterns of 12-week weight loss. Bivariate analysis identified candidate baseline predictor variables (P Results Participants had a mean age of 55.0 yrs (SD 10.8); 49% were female, 79% Non-Hispanic White, and 97% college educated; and 58% earned >$125,000/yr. Mean Body Mass Index was 31.9 kg/m 2 (SD 5.2), 56% had pre-diabetes, and 90% had metabolic syndrome. Cluster analysis identified three weight loss patterns (Figure): modest & delayed (G1: n=15; 21%); moderate & steady (G2: 43; 60%); and substantial & early (G3: 14; 19%). Only participants in G2 and G3 had significant weight loss. Candidate predictor variables included sex, physical activity, physical function, family/friend encouragement for dietary change, obesity-related problems, depression symptoms, and body image dissatisfaction. On stepwise logistic analysis comparing G2 and G3 vs. G1, greater weight loss patterns were associated with higher physical activity (standardized β=0.62 (95% CI 0.09, 1.14), P=0.01) and physical function (0.47 (-0.04, 0.99), P=0.05), fewer obesity-related problems (-0.48 (-1.03, 0.07), P=0.09), and less friend encouragement for dietary change (-0.79 (-1.37, -0.22), P=0.003). Conclusion We identified 12-week weight loss patterns and baseline variables that may be important predictors of response to an evidence-based group lifestyle intervention. Friend encouragement for dietary change may have a more complex relationship to weight loss than suggested by prior research. Funding(This research has received full or partial funding support from the American Heart Association, National Center)

Abstract 67 Background: Recombinant factor VIIa (rFVIIa) is FDA-approved for treatment of bleeding due to factor VIII or factor IX inhibitors in the setting of congenital or acquired hemophilia or due to congenital factor VII deficiency. When first introduced into clinical practice in 1999, rFVIIa was used predominantly for these labeled indications. Over the years since it became widely available, rFVIIa has been employed extensively for off-label indications. The data to support these uses are sparse or, in some cases, contradictory. Objective: To estimate patterns of off-label rFVIIa use in United States hospitals. Data source: We evaluated data from the Premier Perspectives database of United States hospitals. This representative sample was used to extrapolate national usage patterns of rFVIIa. For each hospitalization at member institutions, the database includes information on patient demographics, primary and secondary diagnoses, medications dispensed, service items used, and disposition at discharge. We examined data encompassing hospitalizations between January 1, 2000 and December 31, 2008. Results: Use of rFVIIa was reported in 235 of 615 hospitals (38%) in the Premier database. 12,644 hospitalizations involving administration of rFVIIa during the study period were identified. Based on statistical weights for each member hospital, this translates to an estimated 73,747 hospitalizations nationwide during which rFVIIa was employed, 18,311 (25%) of which occurred during 2008. Between 2000 and 2008, off-label use of rFVIIa increased more than 140-fold, such that in 2008, 97% of in-hospital indications were off-label. In contrast, in-hospital use for the hemophilias has increased 3.7-fold since 2000 and appears to have plateaued, such that on-label use accounted for only 4.2% of use overall and 2.7% of use in 2008. We found cardiac surgery (29% of use in 2008), trauma (28%), and intracranial hemorrhage (11%) to be the most common off-label indications for rFVIIa use. Consistent with the growth of these and other off-label indications, there has been a significant increase in the mean age of patients receiving rFVIIa from 3 years in 2000 to 59 years in 2008. Conditions with a prominent proportion of use in the elderly (>65 years) included aortic aneurysm (82%), prostatectomy (66%), brain trauma (64%), intracranial hemorrhage (58%), cardiac surgery (57%), and gastrointestinal bleeding (57%). Across all indications, in-hospital mortality has increased substantially over time from 5% in 2000 to 27% in 2008. The highest in-hospital mortality rates were associated with aortic aneurysm (57%), neonatal use (54%), variceal bleeding (51%), other liver disease (49%), liver biopsy (45%), vascular procedures (43%), intracranial hemorrhage (43%), brain trauma (40%), body trauma (36%), and gastrointestinal bleeding (35%). The population receiving rFVIIa for the most common indication, adult cardiac surgery, experienced 24% in-hospital mortality. Amongst all patients treated with rFVIIa in 2008, 43% were discharged to home. Most of the remaining patients were transferred to other facilities, including nursing homes, rehabilitation hospitals, and other acute care facilities. In contrast, hemophilia patients receiving rFVIIa experienced a 3.8% in-hospital mortality rate, while 85% were discharged directly home. Finally, we identified a significant shift in rFVIIa use from academic hospitals (89% in 2000) to non-academic hospitals (67% in 2008). Conclusions: In hospitalized patients, off-label use of rFVIIa far exceeds use for the small number of licensed indications. Cardiac surgery, trauma, and non-traumatic intracranial hemorrhage represent the top indications for in-hospital rFVIIa use in the United States, together accounting for an estimated 12,448 of 18,311 (68%) uses during 2008. Across all off-label indications, in-hospital mortality is high, suggesting a substantial proportion of 'end-stage' use of rFVIIa. Use in such circumstances raises concerns about efficacy, associated adverse events, and allocation of resources. The marked shift in off-label use from academic to non-academic hospitals suggests wide acceptance despite these concerns. These patterns of expanding use are concerning given the absence of strong and consistent evidence to support the off-label application of rFVIIa. Disclosures: Off Label Use: This work characterizes patterns of off-label use of recombinant factor VIIa in United States hospitals..

Objective To determine whether financial ties to one drug company are associated with favourable results or conclusions in meta-analyses on antihypertensive drugs. Design Retrospective cohort study. Setting Meta-analyses published up to December 2004 that were not duplicates and evaluated the effects of antihypertensive drugs compared with any comparator on clinical end points in adults. Financial ties were categorised as one drug company compared with all others. Main outcome measures The main outcomes were the results and conclusions of meta-analyses, with both outcomes separately categorised as being favourable or not favourable towards the study drug. We also collected data on characteristics of meta-analyses that the literature suggested might be associated with favourable results or conclusions. Results 124 meta-analyses were included in the study, 49 (40%) of which had financial ties to one drug company. On univariate logistic regression analyses, meta-analyses of better methodological quality were more likely to have favourable results (odds ratio 1.16, 95% confidence interval 1.07 to 1.27). Although financial ties to one drug company were not associated with favourable results, such ties constituted the only characteristic significantly associated with favourable conclusions (4.09, 1.30 to 12.83). When controlling for other characteristics of meta-analyses in multiple logistic regression analyses, meta-analyses that had financial ties to one drug company remained more likely to report favourable conclusions (5.11, 1.54 to 16.92). Conclusion Meta-analyses on antihypertensive drugs and with financial ties to one drug company are not associated with favourable results but are associated with favourable conclusions.

Background Latino immigrants have high rates of obesity and face barriers to weight loss. Objective To evaluate the effectiveness of a case-management (CM) intervention with and without community health workers (CHWs) for weight loss. Design This was a 2-year, randomized controlled trial comparing two interventions with each other and with usual care (UC). Participants/setting Eligible participants included Latinos with a body mass index of 30 to 60 and one or more heart disease risk factors. The 207 participants recruited during 2009-2010 had a mean age of 47 years and were mostly women (77%). At 24 months, 86% of the sample was assessed. Intervention The CM+CHW (n=82) and CM (n=84) interventions were compared with each other and with UC (n=41). Both included an intensive 12-month phase followed by 12 months of maintenance. The CM+CHW group received home visits. Main outcome measures Weight change at 24 months. Statistical analyses Generalized estimating equations using intent-to-treat. Results At 6 months, mean weight loss in the CM+CHW arm was −2.1 kg (95% CI −2.8 to −1.3) or −2% of baseline weight (95% CI −1% to −2%) compared with −1.6 kg (95% CI −2.4 to −0.7; % weight change, −2%, −1%, and −3%) in CM and −0.9 kg (95% CI −1.8 to 0.1; % weight change, −1%, 0%, and −2%) in UC. By 12 and 24 months, differences narrowed and CM+CHW was no longer statistically distinct. Men achieved greater weight loss than women in all groups at each time point ( P Conclusions This study demonstrated that incorporation of CHWs may help promote initial weight loss, especially among men, but not weight maintenance. Additional strategies to address social and environmental influences may be needed for Latino immigrant populations.

Objectives: To examine the perspectives of journal editors and authors on overlapping and redundant publications in clinical research. Design: Pretested cross-sectional survey, containing both forced choice and open ended questions, administered by mail to the senior editors (N=99) and one randomly selected author (N=99) from all journals in the Abridged Index Medicus (1996) that published clinical research. Main measurements: The views of editors and authors about the extent of redundant publications, why they occur, how to prevent and respond to cases, and when the publication of overlapping manuscripts is justified. Results: Seventy two per cent (N=71) of editors and 65% (N=64) of authors completed the survey. There was consensus between both groups that redundant publications occur because authors feel the pressure to publish and journals do not do enough to publicise, criticise, and punish cases, and that the publication of most types of overlapping articles is unacceptable. Sixty seven per cent of authors but only 31% of editors felt, however, that it was justified to publish an overlapping article in a non-peer reviewed symposium supplement, and 68% of editors but 39% of authors supported imposing restrictions on guilty authors’ future submissions. In written comments, 15% to 30% of both groups emphasised that it was justified to publish overlapping articles when there were different or non-English-speaking audiences, new data, strengthened methods, or disputed findings. Conclusions: Editors, authors, and other academic leaders should together develop explicit guidelines that clarify points of contention and ambiguity regarding overlapping manuscripts.

In April 1997, the Cochrane Collaboration implemented the Criticism Management System for The Cochrane Library, allowing readers to electronically submit criticisms on Cochrane reviews and protocols. As a result of resource constraints and user feedback, the Criticism Management System evolved through three different versions. Major problems have included difficult access to the system, a lack of automation within the system, a low number of submissions (171 criticisms submitted per 1,388 reviews), and a low response rate to these criticisms by authors of reviews (26 criticisms have received published responses). These low figures suggest that users of The Cochrane Library are not commenting on the published reviews or not using the Criticism Management System to make their criticisms known to the authors. An easier-to-use system and better ways of encouraging feedback from readers and responses from reviewers are needed in the future.

A published article is the primary means whereby new work is communicated, priority is established, and academic promotion is determined. Publication depends on trust and requires that authors be held to standards of honesty, completeness, and fairness in their reporting, and to accountability for their statements. The system of authorship, while appropriate for articles with only 1 author, has become inappropriate as the average number of authors of an article has increased; as the work of coauthors has become more specialized and relationships between them have become more complex; and as both credit and, even more, responsibility have become obscured and diluted. Credit and accountability cannot be assessed unless the contributions of those named as authors are disclosed to readers, so the system is flawed. We argue for a radical conceptual and systematic change, to reflect the realities of multiple authorship and to buttress accountability. We propose dropping the outmoded notion of author in favor of the more useful and realistic one of contributor. This requires disclosure to readers of the contributions made to the research and to the manuscript by the contributors, so that they can accept both credit and responsibility. In addition, certain named contributors take on the role of guarantor for the integrity of the entire work. The requirement that all participants be named as contributors will eliminate the artificial distinction between authors and acknowledgees and will enhance the integrity of publication.

Recombinant activated factor VII (rFVIIa) is an expensive and potent procoagulant. Intravenous use of rFVIIa was approved by the U.S. Food and Drug Administration (FDA) in 1999 for patients with Hemophilia A or B and antibody inhibitors against standard factor replacements. Recently its use has expanded beyond these approved indications to encompass a wide range of in-hospital off-label applications. Off-label drug use refers to any application that deviates from FDA approved use. The FDA drug approval process mandates that randomized clinical trials demonstrate efficacy and safety. Once approval is given, however, physicians are free to use the drug for other indications. While off-label use is legal and allows for rapid adoption of some therapies, the available evidence supporting it usually falls short of the rigor that accompanies FDA review. While the resulting uncertainty may be acceptable, concerns increase when off-label use is applied to conditions that are clinically distinct from approved indications or it is frequent, costly, or associated with important side-effects or harms. Increasing off-label use of rFVIIa for hospitalized patients has occurred despite concerns regarding efficacy and safety, including evidence suggesting an increased rate of thromboembolic events (1–5). Our comparative effectiveness review evaluates the benefits and harms of in-hospital off-label rFVIIa use in adults for the selected indications of intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy.

Abstract 1403 Poster Board I-425 Background: Recombinant factor VIIa (rFVIIa) is a potent hemostatic agent licensed for treatment of bleeding in hemophiliac patients with inhibitors but has been increasingly used off-label to treat or prevent bleeding, despite sparse data to support its efficacy and a possible increase in thromboembolic events. While randomized controlled trials (RCTs) provide the best evidence regarding efficacy, they may not identify rare but important adverse events. Observational studies may capture the rate of such events in clinical practice more accurately. Objectives: To compare rates of thromboembolic events associated with off-label use of rFVIIa in RCTs and observational studies. Methods: Studies of off-label application of rFVIIa were identified by review of 10 literature and clinical trial databases through February, 2009. The off-label indications examined were trauma, non-traumatic intracranial hemorrhage (ICH), and adult cardiac surgery. When an appropriate number and quality of studies were available, data from RCTs and higher quality comparative observational studies were combined via meta-analysis using the arc sine statistical method, a method that characterizes uncommon events more accurately than more conventional methods. To describe the absolute rate of thromboembolism for patients treated with rFVIIa in RCTs versus observational studies, we analyzed data from the interventional arms of RCTs and comparative observational studies, as well as data from non-comparative observational studies with 15 or more patients. Results: Included Studies Our search identified 4 RCTs and 4 observational studies of rFVIIa use in ICH. Two RCTs and 5 observational studies were identified for trauma. For cardiac surgery, 2 RCTs, 2 higher quality comparative observational studies (included in the meta-analysis), and 8 additional observational studies were identified. Meta-analyses The meta-analysis of the RCTs investigating use of rFVIIa in ICH showed a trend toward increased thromboembolic risk with rFVIIa (arcsine summary effect size 0.100, 95% CI -0.072-0.272). For trauma, the two RCTs did not provide sufficient data to perform meta-analysis. Individually, they did not demonstrate significantly different incidences of thromboembolic events with rFVIIa compared to placebo but may have been underpowered to detect such differences. For cardiac surgery, the meta-analysis of the 4 studies showed a significant increase in thromboembolic events in the rFVIIa group (arcsine summary effect 0.14; 95% CI 0.038- 0.242). Absolute rates of thromboembolic events in RCTs versus observational studies In ICH, thromboembolic event rates in the treatment arms of the RCTs ranged from 0.07-0.11, while those in the observational studies ranged from 0-0.20. In trauma, thromboembolic event rates in the RCT treatment arms ranged from 0.03-0.06, whereas those in the observational studies ranged from 0.02-0.11. In cardiac surgery, thromboembolic event rates in the RCTs ranged from 0.07-0.22 compared to a range of 0-0.25 in the observational studies. For all three indications, Figure 1 shows that the weighted mean thromboembolic event rates associated with rFVIIa use are higher in the observational studies than in the RCTs. Patients in the observational studies tended to be older and have a worse prognosis than those enrolled in the RCTs. Conclusions: We identified a trend toward significantly higher rates of thromboembolic adverse events with off-label use of rFVIIa compared to placebo in our meta-analyses of ICH and cardiac surgery, but no similar pattern in trauma trials. For each of these indications, we identified a higher rate of thromboembolic adverse events associated with the use of rFVIIa in observational trials compared to RCTs. This finding suggests that patients receiving off-label rFVIIa for these off-label indications in real-world practice may be at higher risk of thromboembolic events than patients enrolled in clinical trials and may caution against widespread use, especially in the absence of convincing data on efficacy. Disclosures: Off Label Use: This study examines the off-label use of rFVIIa in randomized controlled trials and observational studies of intracranial hemorrhage, trauma, and cardiac surgery.

ContextTo determine whether journals have improved their disclosure of ethical protections in clinical trials.MethodsComparison of clinical trials published before and after 1997 (July 1995 to December 1996 and January 1998 to June 1999) in Annals of Internal Medicine, BMJ, JAMA, The Lancet, and The New England Journal of Medicine. Sixty articles per journal per period were randomly selected and assessed for rate of reporting on informed consent and on ethics committee approval.ResultsInformed consent was not described in 79 articles (26%) published before 1997 vs 53 (18%) published after 1997 (P = .01), and ethics committee approval was not mentioned in 93 (31%) before 1997 vs 54 (18%) after 1997 (P

ContextTo determine the prevalence of honorary and ghost authorship in Cochrane reviews, how authorship is assigned, and the ways in which authors and Cochrane editorial teams contribute.MethodsUsing a Web-based, self-administered survey, corresponding authors for 577 reviews published in issues 1 and 2 from 1999 of The Cochrane Library were invited to report on the prevalence of honorary and ghost authors, contributions by authors listed in the byline and members of Cochrane editorial teams, and identification of methods of assigning authorship. Responses were received for 362 reviews (63% response rate), which contained 913 authors.ResultsOne hundred forty-one reviews (39%) had evidence of honorary authors, 32 (9%) had evidence of ghost authors (most commonly a member of the Cochrane editorial team), and 9 (2%) had evidence of both honorary and ghost authors. The editorial teams contributed in a wide variety of ways to 301 reviews (83%). Authorship was decided by the group of authors (31%) or lead author (25%) in most reviews. Authorship order was assigned according to contribution in most reviews (76%). The 3 functions contributed to most by those listed in the byline were assessing the quality of included studies (83%), interpreting data (82%), and abstracting data from included studies (77%).ConclusionsA substantial proportion of reviews had evidence of honorary and ghost authorship. The Cochrane editorial teams contributed to most Cochrane reviews.