Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women's Health Initiative study
BACKGROUND: Antidepressants are commonly prescribed medications, but their effect on cardiovascular morbidity and mortality remains unclear.
METHODS: Prospective cohort study of 136 293 community-dwelling postmenopausal women in the Women's Health Initiative (WHI). Women taking no antidepressants at study entry and who had at least 1 follow-up visit were included. Cardiovascular morbidity and all-cause mortality for women with new antidepressant use at follow-up (n = 5496) were compared with those characteristics for women taking no antidepressants at follow-up (mean follow-up, 5.9 years).
RESULTS: Antidepressant use was not associated with coronary heart disease (CHD). Selective serotonin reuptake inhibitor (SSRI) use was associated with increased stroke risk (hazard ratio [HR],1.45, [95% CI, 1.08-1.97]) and all-cause mortality (HR,1.32 [95% CI, 1.10-1.59]). Annualized rates per 1000 person-years of stroke with no antidepressant use and SSRI use were 2.99 and 4.16, respectively, and death rates were 7.79 and 12.77. Tricyclic antidepressant (TCA) use was associated with increased risk of all-cause mortality (HR,1.67 [95% CI, 1.33-2.09]; annualized rate, 14.14 deaths per 1000 person-years). There were no significant differences between SSRI and TCA use in risk of any outcomes. In analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke (HR, 2.12 [95% CI, 1.10-4.07]) and fatal stroke (HR, 2.10 [95% CI, 1.15-3.81]).
CONCLUSIONS: In postmenopausal women, there were no significant differences between SSRI and TCA use in risk of CHD, stroke, or mortality. Antidepressants were not associated with risk of CHD. Tricyclic antidepressants and SSRIs may be associated with increased risk of mortality, and SSRIs with increased risk of hemorrhagic and fatal stroke, although absolute event risks are low. These findings must be weighed against quality of life and established risks of cardiovascular disease and mortality associated with untreated depression.
OBJECTIVE: To describe the development of measures of worksite descriptive social norms for weight loss, physical activity, and eating behaviors.
METHODS: Three surveys were tested in 844 public high school employees. Factor analysis, Cronbach alpha, and tests of association with other worksite social contextual measures and behaviors were performed.
RESULTS: Each survey demonstrated high internal consistency and was associated with measures of social support and behaviors. Confirmatory factor analysis supported the reliability of the weight-loss and eating-behavior norms surveys, but not the physical-activity norms survey.
CONCLUSIONS: The weight-loss and eating norms surveys are reliable, valid measures.
Roles and strategies of state organizations related to school-based physical education and physical activity policies
School-based physical education (PE) and physical activity (PA) policies can improve PA levels of students and promote health. Studies of policy implementation, communication, monitoring, enforcement, and evaluation are lacking. To describe how states implement, communicate, monitor, enforce, and evaluate key school-based PE and PA policies, researchers interviewed 24 key informants from state-level organizations in 9 states, including representatives from state departments of health and education, state boards of education, and advocacy/professional organizations. These states educate 27% of the US student population. Key informants described their organizations' roles in addressing 14 school-based PE and PA state laws and regulations identified by the Bridging the Gap research program and the National Cancer Institute's Classification of Laws Associated with School Students (C.L.A.S.S.) system. On average, states had 4 of 14 school-based PE and PA laws and regulations, and more than one-half of respondents reported different policies in practice besides the "on the books" laws. Respondents more often reported roles implementing and communicating policies compared with monitoring, enforcing, and evaluating them. Implementation and communication strategies used included training, technical assistance, and written communication of policy to local education agency administrators and teachers. State-level organizations have varying roles in addressing school-based PE and PA policies. Opportunities exist to focus state-level efforts on compliance with existing laws and regulations and evaluation of their impact.
Inhibiting food reward: delay discounting, food reward sensitivity, and palatable food intake in overweight and obese women
Overeating is believed to result when the appetitive motivation to consume palatable food exceeds an individual's capacity for inhibitory control of eating. This hypothesis was supported in recent studies involving predominantly normal weight women, but has not been tested in obese populations. The current study tested the interaction between food reward sensitivity and inhibitory control in predicting palatable food intake among energy-replete overweight and obese women (N = 62). Sensitivity to palatable food reward was measured with the Power of Food Scale. Inhibitory control was assessed with a computerized choice task that captures the tendency to discount large delayed rewards relative to smaller immediate rewards. Participants completed an eating in the absence of hunger protocol in which homeostatic energy needs were eliminated with a bland preload of plain oatmeal, followed by a bogus laboratory taste test of palatable and bland snacks. The interaction between food reward sensitivity and inhibitory control was a significant predictor of palatable food intake in regression analyses controlling for BMI and the amount of preload consumed. Probing this interaction indicated that higher food reward sensitivity predicted greater palatable food intake at low levels of inhibitory control, but was not associated with intake at high levels of inhibitory control. As expected, no associations were found in a similar regression analysis predicting intake of bland foods. Findings support a neurobehavioral model of eating behavior in which sensitivity to palatable food reward drives overeating only when accompanied by insufficient inhibitory control. Strengthening inhibitory control could enhance weight management programs.
Clinical characteristics and outcomes of acute coronary syndrome patients with left anterior hemiblock
OBJECTIVE: We aimed to study the relationships between left anterior hemiblock (LAHB) and the patient characteristics, management, and clinical outcomes in the setting of acute coronary syndromes (ACS).
METHODS: Admission ECGs of patients enrolled in the Global Registry of Acute Coronary Events (GRACE) ECG substudy, and the Canadian ACS Registry I, were analysed independently at a blinded core laboratory. Multivariable logistic regression analysis was performed to assess the independent associations between LAHB on the admission ECG and in-hospital and 6-month mortality.
RESULTS: Of the 11 820 eligible ACS patients, 692 (5.9%) patients had LAHB. The presence of LAHB on admission was associated with older age, male sex, prior myocardial infarction, prior heart failure, worse Killip class, higher creatinine level, and higher GRACE risk score (all p<0.01). Patients with LAHB less frequently underwent cardiac catheterisation, coronary revascularisation or reperfusion therapy (all p<0.05). The LAHB group had higher in-hospital (6.9% vs 3.9%, p<0.001) and 6-month mortality (12.5% vs 7.7%, p<0.001). However, after adjusting for the known predictors of mortality in the GRACE risk models, LAHB was not independently associated with in-hospital death (OR 1.07, 95% CI 0.76 to 1.52, p=0.70), or death at 6 months (OR 1.00, 95% CI 0.75 to 1.34, p=0.99).
CONCLUSIONS: Across the broad spectrum of ACS, LAHB was associated with significant comorbidities, high-risk clinical features on presentation, and worse unadjusted outcomes. However, LAHB was not an independent predictor of in-hospital and 6-month mortality and did not carry incremental prognostic value beyond the known prognosticators in the GRACE risk models.
BACKGROUND: Congestive heart failure (CHF) is a common and preventable complication of acute coronary syndrome (ACS). Nevertheless, ACS risk scores have not been shown to predict CHF risk. We investigated whether the at-discharge Global Registry of Acute Coronary Events (GRACE) score predicts heart failure admission following ACS.
METHODS AND RESULTS: Five-year mortality and hospitalization data were obtained for patients admitted with ACS from June 1999 to September 2009 to a single centre of the GRACE registry. CHF was defined as any admission assigned WHO International Classification of Diseases 10 diagnostic code I50. The hazard ratio (HR) for CHF according to GRACE score was estimated in Cox models adjusting for age, gender and the presence of CHF on index admission. Among 1,956 patients, CHF was recorded on index admission in 141 patients (7%), and 243 (12%) were admitted with CHF over 3.8 median years of follow-up. Compared to the lowest quintile, patients in the highest GRACE score quintile had more CHF admissions (116 vs 17) and a shorter time to first admission (1.2 vs 2.0 years, HR 9.87, 95% CI 5.93-16.43). Per standard deviation increment in GRACE score, the instantaneous risk was more than two-fold higher (HR 2.28; 95% CI 2.02-2.57), including after adjustment for CHF on index admission, age and gender (HR 2.49; 95% CI 2.06-3.02). The C-statistic for CHF admission at 1-year was 0.74 (95% CI 0.70-0.79).
CONCLUSIONS: The GRACE score predicts CHF admission, and may therefore be used to target ACS patients at high risk of CHF with clinical monitoring and therapies.
Patient's views on depression care in obstetric settings: how do they compare to the views of perinatal health care professionals
OBJECTIVES: The objectives were to examine patients' perspectives on patient-, provider- and systems-level barriers and facilitators to addressing perinatal depression in outpatient obstetric settings. We also compare the views of patients and perinatal health care professionals.
METHOD: Four 90-min focus groups were conducted with women 3-36 months after delivery (n=27) who experienced symptoms of perinatal depression, anxiety or emotional distress. Focus groups were transcribed, and resulting data were analyzed using a grounded theory approach.
RESULTS: Barriers to addressing perinatal depression included fear of stigma and loss of parental rights, negative experiences with perinatal health care providers and lack of depression management knowledge/skills among professionals. Facilitators included psychoeducation, peer support and training for professionals.
CONCLUSIONS: Patients perceive many multilevel barriers to treatment that are similar to those found in our previous similar study of perinatal health care professionals' perspectives. However, patients and professionals do differ in their perceptions of one another. Interventions would need to close these gaps and include an empathic screening and referral process that facilitates discussion of mental health concerns. Interventions should leverage strategies identified by both patients and professionals, including empowering both via education, resources and access to varied mental health care options.
INTRODUCTION: Muscle-directed gene therapy is rapidly gaining attention primarily because muscle is an easily accessible target tissue and is also associated with various severe genetic disorders. Localized and systemic delivery of recombinant adeno-associated virus (rAAV) vectors of several serotypes results in very efficient transduction of skeletal and cardiac muscles, which has been achieved in both small and large animals, as well as in humans. Muscle is the target tissue in gene therapy for many muscular dystrophy diseases, and may also be exploited as a biofactory to produce secretory factors for systemic disorders. Current limitations of using rAAVs for muscle gene transfer include vector size restriction, potential safety concerns such as off-target toxicity and the immunological barrier composing of pre-existing neutralizing antibodies and CD8(+) T-cell response against AAV capsid in humans.
AREAS COVERED: In this article, we will discuss basic AAV vector biology and its application in muscle-directed gene delivery, as well as potential strategies to overcome the aforementioned limitations of rAAV for further clinical application.
EXPERT OPINION: Delivering therapeutic genes to large muscle mass in humans is arguably the most urgent unmet demand in treating diseases affecting muscle tissues throughout the whole body. Muscle-directed, rAAV-mediated gene transfer for expressing antibodies is a promising strategy to combat deadly infectious diseases. Developing strategies to circumvent the immune response following rAAV administration in humans will facilitate clinical application.
BACKGROUND: A novel data warehouse based on automated retrieval from an institutional health care information system (HIS) was made available to be compared with a traditional prospectively maintained surgical database.
METHODS: A newly established institutional data warehouse at a single-institution academic medical center autopopulated by HIS was queried for International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes for pancreatic neoplasm. Patients with ICD-9-CM diagnosis codes for pancreatic neoplasm were captured. A parallel query was performed using a prospective database populated by manual entry. Duplicated patients and those unique to either data set were identified. All patients were manually reviewed to determine the accuracy of diagnosis.
RESULTS: A total of 1107 patients were identified from the HIS-linked data set with pancreatic neoplasm from 1999-2009. Of these, 254 (22.9%) patients were also captured by the surgical database, whereas 853 (77.1%) patients were only in the HIS-linked data set. Manual review of the HIS-only group demonstrated that 45.0% of patients were without identifiable pancreatic pathology, suggesting erroneous capture, whereas 36.3% of patients were consistent with pancreatic neoplasm and 18.7% with other pancreatic pathology. Of the 394 patients identified by the surgical database, 254 (64.5%) patients were captured by HIS, whereas 140 (35.5%) patients were not. Manual review of patients only captured by the surgical database demonstrated 85.9% with pancreatic neoplasm and 14.1% with other pancreatic pathology. Finally, review of the 254 patient overlap demonstrated that 80.3% of patients had pancreatic neoplasm and 19.7% had other pancreatic pathology.
CONCLUSIONS: These results suggest that cautious interpretation of administrative data rely only on ICD-9-CM diagnosis codes and clinical correlation through previously validated mechanisms.
We provide an overview of the individual and combined clinical endpoints and patient-reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes.
BACKGROUND: Galectin 3 (Gal-3) is a potential mediator of cardiac fibrosis, and Gal-3 concentrations predict incident heart failure. The same mechanisms that lead to cardiac fibrosis in heart failure may influence development of atrial fibrosis and atrial fibrillation (AF). We examined the association of Gal-3 and incident AF in the community.
METHODS: Plasma Gal-3 concentrations were measured in 3,306 participants of the Framingham Offspring cohort who attended the sixth examination cycle (1995-1998, mean age 58 years, 54% women). Cox proportional hazards regression models were used to assess the association of baseline Gal-3 concentrations and incident AF.
RESULTS: Over a median follow-up period of 10 years, 250 participants developed incident AF. Crude incidence rates of AF by increasing sex-specific Gal-3 quartiles were 3.7%, 5.9%, 9.1%, and 11.5% (log-rank test P < .0001). In age- and sex-adjusted analyses, each 1-SD increase in loge-Gal-3 was associated with a 19% increased hazard of incident AF (hazard ratio 1.19, 95% CI 1.05-1.36, P = .009). This association was not significant after adjustment for traditional clinical AF risk factors (hazard ratio 1.12, 95% CI 0.98-1.28, P = .10).
CONCLUSION: Higher circulating Gal-3 concentrations were associated with increased risk of developing AF over the subsequent 10 years in age- and sex-adjusted analyses but not after accounting for other traditional clinical AF risk factors. Our results do not support a role for Gal-3 in AF risk prediction. Further studies are needed to evaluate whether Gal-3 plays a role in the development of AF substrate similar to HF.
Decade-long trends in the magnitude, treatment, and outcomes of patients aged 30 to 54 years hospitalized with ST-segment elevation and non-ST-segment elevation myocardial infarction
Although acute myocardial infarction (AMI) occurs primarily in the elderly, this disease also affects young adults. Few studies have, however, presented data on relatively young patients hospitalized with AMI. The objectives of this population-based study were to examine recent trends in the magnitude, clinical characteristics, management, and in-hospital and long-term outcomes associated with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) in patients aged 30 to 54 years. We reviewed the medical records of 955 residents of the Worcester (Massachusetts) metropolitan area aged 30 to 54 years who were hospitalized for an initial STEMI or NSTEMI in 6 biennial periods from 1999 to 2009 at 11 greater Worcester medical centers. From 1999 to 2009, the proportion of young adults hospitalized with an STEMI decreased from approximately 2/3 to 2/5 of all patients with an initial AMI. Patients with STEMI were less likely to have a history of heart failure, hypertension, hyperlipidemia, and kidney disease than those with NSTEMI. Both groups received similar effective medical therapies during their acute hospitalization. In-hospital clinical complications and mortality were low and no significant differences in these end points were observed between patients with STEMI and NSTEMI or with regard to 1-year postdischarge death rates (1.9% vs 2.8%). The present results demonstrate recent decreases in the proportion of relatively young patients diagnosed with an initial STEMI. Patients with STEMI and NSTEMI had similar in-hospital outcomes and long-term survival. Trends in these and other important outcomes warrant continued monitoring.
BACKGROUND: The quality of transitional care is associated with important health outcomes such as rehospitalization and costs. The widely used Care Transitions Measure (CTM-15) was developed with a classic test theory approach; its short version (CTM-3) was included in the CAHPS Hospital Survey. We conducted a psychometric evaluation of both measures and explored whether item response theory (IRT) could produce a more precise measure.
METHODS AND RESULTS: As part of the Transitions, Risks, and Actions in Coronary Events Center for Outcomes Research and Education, 1545 participants were interviewed during an acute coronary syndrome hospitalization, providing information on general health status (Short Form-36), CTM-15, health utilization, and care process questions at 1 month postdischarge. We used classic and IRT analyses and compared the measurement precision of CTM-15-, CTM-3-, and CTM-IRT-based score using relative validity. Participants were 79% non-Hispanic white and 67% male, with an average age of 62 years. The CTM-15 had good internal consistency (Cronbach's alpha=0.95) but demonstrated acquiescence bias (8.7% participants responded "Strongly agree" and 19% responded "Agree" to all items) and limited score variability. These problems were more pronounced for the CTM-3. The CTM-15 differentiated between patient groups defined by self-reported health status, health care utilization, and care transition process indicators. Differences between groups were small (2 to 3 points). There was no gain in measurement precision from IRT scoring. The CTM-3 was not significantly lower for patients reporting rehospitalization or emergency department visits.
CONCLUSION: We identified psychometric challenges of the CTM, which may limit its value in research and practice. These results are in line with emerging evidence of gaps in the validity of the measure. Inc., by Wiley Blackwell.
Surgeon volume and elective resection for colon cancer: an analysis of outcomes and use of laparoscopy
BACKGROUND: Surgeon volume may be an important predictor of quality and cost outcomes. We evaluated the association between surgeon volume and quality and cost of surgical care in patients with colon cancer.
STUDY DESIGN: We performed a retrospective study of patients who underwent resection for colon cancer, using data from the University HealthSystem Consortium from 2008 to 2011. Outcomes evaluated included use of laparoscopy, ICU admission, postoperative complications, length of stay, and total direct hospital costs by surgeon volume. Surgeon volume was categorized according to high (HVS), medium (MVS), and low (LVS) average annual volumes.
RESULTS: A total of 17,749 patients were included in this study. The average age of the cohort was 65 years and 51% of patients were female. After adjustment for potential confounders, compared with LVS, HVS and MVS were more likely to use laparoscopy (HVS, odds ratio [OR] 1.27, 95% CI 1.15, 1.39; MVS, OR 1.16 95% CI 1.65, 1.26). Postoperative complications were significantly lower in patients operated on by HVS than LVS (OR 0.77 95% CI 0.76, 0.91). The HVS patients were less likely to require reoperation than those in the LVS group (OR 0.70, 95% CI 0.53, 0.92) Total direct costs were $927 (95% CI -$1,567 to -$287) lower in the HVS group compared with the LVS group.
CONCLUSIONS: Higher quality, lower cost care was achieved by HVS in patients undergoing surgery for colon cancer. An assessment of differences in processes of care by surgeon volume may help further define the mechanism for this observed association. rights reserved.
Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation
Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.
The maytansinoid drug DM1 is 100- to 1000-fold more cytotoxic than anticancer drugs that are currently in clinical use. The immunoconjugate C242-DM1 was prepared by conjugating DM1 to the monoclonal antibody C242, which recognizes a mucin-type glycoprotein expressed to various extents by human colorectal cancers. C242-DM1 was found to be highly cytotoxic toward cultured colon cancer cells in an antigen-specific manner and showed remarkable antitumor efficacy in vivo. C242-DM1 cured mice bearing subcutaneous COLO 205 human colon tumor xenografts (tumor size at time of treatment 65-130 mm3), at doses that showed very little toxicity and were well below the maximum tolerated dose. C242-DM1 could even effect complete regressions or cures in animals with large (260- to 500-mm3) COLO 205 tumor xenografts. Further, C242-DM1 induced complete regressions of subcutaneous LoVo and HT-29 colon tumor xenografts that express the target antigen in a heterogeneous manner. C242-DM1 represents a new generation of immunoconjugates that may yet fulfill the promise of effective cancer therapy through antibody targeting of cytotoxic agents.