Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes.

Importance: Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. Objective: To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. Design, Setting, and Participants: In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Exposures: Treatment with GLP-1RA was compared with basal insulin. Main Outcome and Measures: Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. Results: During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. Conclusions and Relevance: In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. Trial Registration: ClinicalTrials.gov Identifier: NCT02072902.

Humoral Immunity of Unvaccinated COVID-19 Recovered vs. Naïve BNT162b2 Vaccinated Individuals: A Prospective Longitudinal Study.

To study the differences in the immune response to SARS-CoV-2 infection compared to the response to vaccination, we characterized the humoral immune kinetics of these situations. In this prospective longitudinal study, we followed unvaccinated COVID-19-recovered individuals (n = 130) and naïve, two-dose BNT162b2-vaccinated individuals (n = 372) who were age- and BMI-matched for six months during the first pandemic year. Anti-RBD-IgG, neutralizing antibodies (NAbs), and avidity were assessed monthly. For recovered patients, data on symptoms and the severity of the disease were collected. Anti-RBD-IgG and NAbs titers at peak were higher after vaccination vs. after infection, but the decline was steeper (peak log IgG: 3.08 vs. 1.81, peak log NAbs: 5.93 vs. 5.04, slopes: -0.54 vs. -0.26). Peak anti-RBD-IgG and NAbs were higher in recovered individuals with BMI > 30 and in older individuals compared to individuals with BMI < 30, younger population. Of the recovered, 42 (36%) experienced long-COVID symptoms. Avidity was initially higher in vaccinated individuals compared with recovered individuals, though with time, it increased in recovered individuals but not among vaccinated individuals. Here, we show that while the initial antibody titers, neutralization, and avidity are lower in SARS-CoV-2-recovered individuals, they persist for a longer duration. These results suggest differential protection against COVID-19 in recovered-unvaccinated vs. naïve-vaccinated individuals.

Reverse causation biases weighted cumulative exposure model estimates, but can be investigated in sensitivity analyses.

OBJECTIVES: To examine the effects of reverse causation on estimates from the weighted cumulative exposure (WCE) model that is used in pharmacoepidemiology to explore drug-health outcome associations, and to identify sensitivity analyses for revealing such effects. STUDY DESIGN AND SETTING: 314,099 patients with diabetes under Clalit Health Services, Israel, were followed over 2002-2012. The association between metformin and pancreatic cancer (PC) was explored using a WCE model within the framework of discrete-time Cox regression. We used computer simulations to explore the effects of reverse causation on estimates of a WCE model and to examine sensitivity analyses for revealing and adjusting for reverse causation. We then applied those sensitivity analyses to our data. RESULTS: Simulation demonstrated bias in the weighted cumulative exposure model and showed that sensitivity analysis could reveal and adjust for these biases. In our data, a positive association was observed (hazard ratio (HR) = 3.24, 95% confidence interval (CI): 2.24-4.73) with metformin exposure in the previous 2 years. After applying sensitivity analysis, assuming reverse causation operated up to 4 years before cancer diagnosis, the association between metformin and PC was no longer apparent. CONCLUSION: Reverse causation can cause substantial bias in the WCE model. When suspected, sensitivity analyses based on causal analysis are advocated.

Longitudinal bidirectional link between socioeconomic position and health: a national panel survey analysis.

BACKGROUND: Health inequities can stem from socioeconomic position (SEP) leading to poor health (social causation) or poor health resulting in lower SEP (health selection). We aimed to examine the longitudinal bidirectional SEP-health associations and identify inequity risk factors. METHODS: Longitudinal Household Israeli Panel survey participants (waves 1-4), age ≥25 years, were included (N=11 461; median follow-up=3 years). Health rated on a 4-point scale was dichotomised as excellent/good and fair/poor. Predictors included SEP parameters (education, income, employment), immigration, language proficiency and population group. Mixed models accounting for survey method and household ties were used. RESULTS: Examining social causation, male sex (adjusted OR 1.4; 95% CI 1.1 to 1.8), being unmarried, Arab minority (OR 2.4; 95% CI 1.6 to 3.7, vs Jewish), immigration (OR 2.5; 95% CI 1.5 to 4.2, reference=native) and less than complete language proficiency (OR 2.22; 95% CI 1.50 to 3.28) were associated with fair/poor health. Higher education and income were protective, with 60% lower odds of subsequently reporting fair/poor health and 50% lower disability likelihood. Accounting for baseline health, higher education and income were associated with lower likelihood of health deterioration, while Arab minority, immigration and limited language proficiency were associated with higher likelihood. Regarding health selection, longitudinal income was lower among participants reporting poor baseline health (85%; 95% CI 73% to 100%, reference=excellent), disability (94%; 95% CI 88% to 100%), limited language proficiency (86%; 95% CI 81% to 91%, reference=full/excellent), being single (91%; 95% CI 87% to 95%, reference=married), or Arab (88%; 95% CI 83% to 92%, reference=Jews/other). CONCLUSION: Policy aimed at reducing health inequity should address both social causation (language, cultural, economic and social barriers to good health) and health selection (protecting income during illness and disability).

Sex related differences in the characteristics and outcomes of heart failure: A sub analysis of heart failure disease management study.

Aims: This is a sub-analysis of a randomized controlled trial on heart failure (HF) disease management (DM) in which patients with HF (N = 1,360; 27.5% women) were assigned randomly to DM (N = 682) or usual care (UC) (N = 678). Study intervention did not significantly affect the rate of hospital admissions or mortality. This study evaluates sex-related differences in baseline characteristics, clinical manifestations, adherence to treatment and outcomes among the study cohort. Methods: Association between sex and hospital admissions and mortality was tested in multivariable models adjusted for the patients' baseline characteristics. The primary composite outcome of the study included time to first HF hospitalization or all-cause mortality. Secondary composite outcome included number of hospital admissions and days of hospitalization, for HF and all other causes. Results: Compared to males, females recruited in the study were on average 3 years older [median age 72 (62, 78) vs. 75 (65, 82), p = 0.001], with higher prevalence of preserved left ventricular function (LVEF ≥50%) and lower frequency of ischemic heart disease (IHD) (p ≤ 0.001). Females had shorter 6-min walking distance and worse quality of life and depression scores at baseline (p < 0.001). The proportion of patients receiving HF recommended medical treatment was similar among females and males. During a median follow-up of 2.7 years (range: 0-5), there were no significant differences between females and males with respect to the time elapsed until the study primary endpoint and its components in univariate analysis [557 (56.5%) males and 218 (58.3%) females were hospitalized for HF or died for any cause; p > 0.05]. Multivariable analysis showed that females were significantly less likely than males to experience the primary outcome [adjusted hazard ratio (HR) = 0.835, 95% CI: 0.699, 0.998] or to die from any cause [adjusted HR = 0.712; 95%CI: 0.560, 0.901]. The sex-related mortality differences were especially significant among patients with non-preserved EF, with IHD or with recent HF hospitalization. Females also had lower rates of all-cause hospital admissions [adjusted rate ratio = 0.798; 95%CI: 0.705, 0.904] and were more likely to adhere to HF medical therapy compared to males. Conclusion: Females with HF fare better than men. Sex related differences were not explained by baseline and morbidity-related characteristics or adherence to medical treatment.

Metformin Treatment Among Men With Diabetes and the Risk of Prostate Cancer: A Population-Based Historical Cohort Study.

There is conflicting evidence regarding the association between metformin treatment and prostate cancer risk in diabetic men. We investigated this association in a population-based Israeli cohort of 145,617 men aged 21-89 years with incident diabetes who were followed over the period 2002-2012. We implemented a time-dependent covariate Cox model, using weighted cumulative exposure to relate metformin history to prostate cancer risk, adjusting for use of other glucose-lowering medications, age, ethnicity, and socioeconomic status. To adjust for time-varying glucose control variables, we used inverse probability weighting of a marginal structural model. With 666,553 person-years of follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk (per defined daily dose; without adjustment for glucose control, hazard ratio (HR) = 1.53 (95% confidence interval (CI): 1.19, 1.96); with adjustment, HR = 1.42 (95% CI: 1.04, 1.94)). However, exposure during the previous 2-7 years was negatively associated with risk (without adjustment for glucose control, HR = 0.58 (95% CI: 0.37, 0.93); with adjustment, HR = 0.60 (95% CI: 0.33, 1.09)). These positive and negative associations with previous-year and earlier metformin exposure, respectively, need to be confirmed and better understood.

Effect of ethnicity, country of origin and workplace on health behaviors and health perception among nurses: Cross-sectional study.

PURPOSE: The study aimed to (1) examine health behaviors and perceived health among nurses; (2) analyze the effect of nurses' personal and work characteristics on these variables; and (3) explore the relationship between health behaviors and nurses' health perception. DESIGN AND METHODS: A cross-sectional study was conducted among nurses working in health care organizations (HCOs) across Israel. An email with the online questionnaire was sent to nurses working in 19 HCOs across Israel during September-December 2018. FINDINGS: Of 18,120 nurses employed, 3542 completed the survey. Mean age was 44.8 years, 91% were female), 64.6% were hospital nurses and 52.8% were clinical staff nurses. Two-thirds of nurses did not achieve the physical activity (PA) target; the majority reported unfavorable eating habits; 66% slept less than 7 h at night and 15% smoke. Hospital nurses working night shifts reported the least favorable health behaviors. Non-Jewish nurses had less eating habits compared with Jewish nurses. Nurses born in the Former Soviet Union perceived their health as significantly worse than that of the other respondents. Binomial logistic regression demonstrated that, age, Israeli origin, achieving the PA target, having food breaks during work, consuming a Mediterranean diet, sleeping at least 7 h, undergoing screening tests as recommended, and not smoking predicted better health perception among nurses. CONCLUSIONS: Nurses, particularly hospital-based, non-Jewish and immigrants from the Soviet Union, demonstrated unfavorable health behaviors that may negatively affect their wellbeing and health perception. CLINICAL RELEVANCE: Interventions aimed at improving the health promoting mindset of nurses have the potential to improve their health and wellbeing and to enable them to become role models and health educators for patients and their families.

Diabetes associated risk for mortality increases with time among first stroke survivors - Findings from the Israeli National Stroke Registry.

BACKGROUND: Diabetes is a major risk factor for ischemic stroke and may affect post-stroke survival. Previous large scale studies of long-term post-stroke survival are limited and most of them excluded older patients from the study population. OBJECTIVES: To compare the risk factors and sociodemographic characteristics between first ischemic stroke cases with and without diabetes and to assess the mortality risk associated with diabetes. METHODS: Using population-based National Stroke Registry in Israel, all patients hospitalized for a first event of ischemic stroke between the years 2014-2018 were followed for all-cause mortality. Chi-square analysis was used to compare the differences in risk factors, sociodemographic profile and cumulative mortality between patients with and without diabetes. Cox proportional hazards models were used to estimate the hazard ratio for mortality in selected timeframes. RESULTS: Among 41,639 patients with a first event of ischemic stroke, 44.5% were previously diagnosed with diabetes. Diabetic patients were more likely to be males, members of the Arab ethnic group, with lower socioeconomic status and a higher prevalence of cardiovascular comorbidities, anemia, leukocytosis and abnormal kidney function. Diabetes was associated with a higher mortality risk in the first year and long term, but not in the first month following stroke. Diabetes-associated mortality risk interacted with time and age, was higher in younger age and increased with time. CONCLUSIONS: Our findings suggest that diabetes is associated with a higher prevalence of comorbidities among patients with first ischemic stroke and with a higher risk for mortality in the mid and long term, which is more profound in younger age.

Health Service Utilization Patterns Among Adults With Congenital Heart Disease: A Population-Based Study.

Background Several studies have examined hospitalizations among patients with adult congenital heart disease (ACHD). Few investigated other services or utilization patterns. Our aim was to study service utilization patterns and predictors among patients with ACHD. Methods and Results We identified 11 653 patients with ACHD aged ≥18 years (median, 47 years), through electronic records of 2 large Israeli healthcare providers (2007-2011). The association between patient, disease, and sociogeographic characteristics and healthcare resource utilization were modeled as recurrent events accounting for the competing death risk. Patients with ACHD had high healthcare utilization rates compared with the general population. The highest standardized service utilization ratios (SSRs) were found among patients with complex congenital heart disease including primary care visits (SSR, 1.53; 95% CI, 1.47-1.58), cardiology outpatient visits (SSR, 5.17; 95% CI, 4.69-5.64), hospitalizations (SSR, 6.68; 95% CI, 5.82-7.54), and days in hospital (SSR, 15.37; 95% CI, 14.61-16.12). Adjusted resource utilization hazard increased with increasing lesion complexity. Hazard ratios (HRs) for complex versus simple disease were: primary care (HR, 1.14; 95% CI, 1.06-1.23); cardiology outpatient visits (HR, 1.40; 95% CI, 1.24-1.59); emergency department visits (HR, 1.19; 95% CI, 1.02-1.39); and hospitalizations (HR, 1.75; 95% CI, 1.49-2.05). Effects attenuated with age for cardiology outpatient visits and hospitalizations and increased for emergency department visits. Female sex, geographic periphery, and ethnic minority were associated with more primary care visits, and female sex (HR versus men, 0.89 [95% CI, 0.84-0.94]) and periphery (HR, 0.72 [95% CI, 0.58-0.90] for very peripheral versus very central) were associated with fewer cardiology visits. Arab minority patients also had high hospitalization rates compared with the majority group of Jewish or other patients. Conclusions Healthcare utilization rates were high among patients with ACHD. Female sex, geographic periphery, and ethnicity were associated with less optimal service utilization patterns. Further research should examine strategies to optimize service utilization in these groups.

National study: Most elderly patients benefit from earlier hip fracture surgery despite co-morbidity.

OBJECTIVE: To estimate the potential influence of pre-operative patient condition on the benefit of earlier hip fracture surgery for elderly patients. BACKGROUND: Many studies emphasize the benefit of earlier hip fracture surgery for patient survival. However less is known regarding how this relationship is influenced by clinical factors which could serve as potential contra-indicators for earlier surgery. Rushed surgery of patients with contra-indications may even compromise their survival. METHODS: A retrospective study of patients aged 65 and above with an isolated hip fracture following trauma, based on data from 19 hospitals of the national trauma registry available for the years 2015-2016. Registry data was crossed with data on co-morbidities and medication intake from the biggest health insurance agency in the country, serving more than 50% of the country's population. Mediation analysis was performed on a wide list of co-morbidities, medications and clinical test results in order to establish the mediation of their relationship with inhospital mortality by earlier hip fracture surgery. Factors found significant in the mediation analysis were utilized to adjust a logistic regression for predicting inhospital mortality by function of waiting time to surgery and patient's sex and age. RESULTS: Anti-coagulant and anti-platelet intake; test results pointing to decreased kidney function and being diagnosed with diabetes or Ischemic Heart Disease were found to be significantly mediated in their influence on inhospital mortality by hip fracture surgery. Despite anti-platelet intake and kidney function having a significant impact on mortality in the multi-variate analysis, the positive effect of earlier hip surgery on survival remained unchanged after adjustment. CONCLUSIONS: Earlier hip fracture surgery was found to be beneficial for elderly patients even when their co-morbidities and medication intake are taken into account.

Imputing missing time-dependent covariate values for the discrete time Cox model.

We describe a procedure for imputing missing values of time-dependent covariates in a discrete time Cox model using the chained equations method. The procedure multiply imputes the missing values for each time-period in a time-sequential manner, using covariates from the current and previous time-periods as well as the survival outcome. The form of the outcome variable used in the imputation model depends on the functional form of the time-dependent covariate(s) and differs from the case of Cox regression with only baseline covariates. This time-sequential approach provides an approximation to a fully conditional approach. We illustrate the procedure with data on diabetics, evaluating the association of their glucose control with the risk of selected cancers. Using simulations we show that the suggested estimator performed well (in terms of bias and coverage) for completely missing at random, missing at random and moderate non-missing-at-random patterns. However, for very strong non-missing-at-random patterns, the estimator was seriously biased and the coverage was too low. The procedure can be implemented using multiple imputation with the Fully conditional Specification (FCS) method (MI procedure in SAS with FCS statement or similar packages in other software, e.g. MICE in R). For use with event times on a continuous scale, the events would need to be grouped into time-intervals.

Development and Efficacy of an Electronic, Culturally Adapted Lifestyle Counseling Tool for Improving Diabetes-Related Dietary Knowledge: Randomized Controlled Trial Among Ethnic Minority Adults With Type 2 Diabetes Mellitus.

BACKGROUND: Ethnic minority populations exhibit disproportionately high rates of type 2 diabetes mellitus (T2DM). Electronic health tools have the potential to facilitate the cultural adaptation and tailoring of T2DM education to improve the knowledge and management of diabetes mellitus (DM). OBJECTIVE: This study aimed (1) to develop an adaptable Interactive Lifestyle Assessment, Counseling, and Education (I-ACE) software to support dietitian-delivered lifestyle counseling among low-socioeconomic status (SES) ethnic minority patients with T2DM and (2) to evaluate its effect on DM-related dietary knowledge and management compared with standard lifestyle advice (SLA) in a randomized controlled trial (RCT). METHODS: The I-ACE software, developed in consultation with clinical dieticians, incorporates evidence-based dietary and physical activity (PA) recommendations and educational materials. The features and behavioral change techniques include quantitative lifestyle (dietary intake and PA) assessment and simulation, individually tailored education and recommendations, motivational interviewing, and goal setting. For the unblinded pilot RCT, 50 overweight or obese Arab adults (aged 40-62 years) with poorly controlled T2DM were recruited from primary care clinics and randomly assigned to receive 4 in-person, dietician-delivered counseling sessions over 6 months using either (1) the I-ACE tool (experimental arm) or (2) the SLA methods (comparison arm). All outcome assessments were face-to-face. DM-related dietary knowledge (primary outcome) was measured at baseline, 3, 6, and 12 months. Lifestyle and other parameters were measured before, during, and after the intervention. Multiple linear regression and repeated measures linear mixed models were used to compare the changes in study outcomes and explore time trends in between-group and within-group changes. RESULTS: A total of 25 participants were enrolled in each arm, of whom 24 and 21 completed the final assessment of the primary outcome in the I-ACE and SLA arms, respectively. DM-related lifestyle knowledge increased more rapidly in the I-ACE arm than in the SLA arm (P value for study arm×time interaction=.02). Within the I-ACE arm, the mean (SE) differences in added sugar and dietary fiber intakes from baseline to 12 months were -2.6% (SE 1.0%) of total energy (P=.03) and 2.7 (SE 0.0) g/1000 kcal (P=.003), respectively. The odds of engaging in any leisure PA at 12 months tended to be higher in the I-ACE arm versus SLA arm, but did not reach statistical significance (odds ratio 2.8; 95% CI 0.7-11.6; P=.16). Both arms exhibited significant reductions in HbA1c (P value for change over time <.001). CONCLUSIONS: The use of the I-ACE software in a 6-month, 4-session dietician-delivered lifestyle counseling intervention improved the efficiency of lifestyle education, compared with SLA, among low-SES, ethnic minority patients with T2DM. This pilot trial provides justification for conducting a large-scale trial to evaluate its effectiveness and applicability in routine clinical care among ethnically diverse populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT01858506; https://clinicaltrials.gov/ct2/show/NCT01858506.

Metformin Treatment and Cancer Risk: Cox Regression Analysis, With Time-Dependent Covariates, of 320,000 Persons With Incident Diabetes Mellitus.

There is conflicting evidence regarding the association between metformin use and cancer risk in diabetic patients. During 2002-2012, we followed a cohort of 315,890 persons aged 21-87 years with incident diabetes who were insured by the largest health maintenance organization in Israel. We used a discrete form of weighted cumulative metformin exposure to evaluate the association of metformin with cancer incidence. This was implemented in a time-dependent covariate Cox model, adjusting for treatment with other glucose-lowering medications, as well as age, sex, ethnic background, socioeconomic status, smoking (for bladder and lung cancer), and parity (for breast cancer). We excluded from the analysis metformin exposure during the year before cancer diagnosis in order to minimize reverse causation of cancer on changes in medication use. Estimated hazard ratios associated with exposure to 1 defined daily dose of metformin over the previous 2-7 years were 0.98 (95% confidence interval (CI): 0.82, 1.18) for all-sites cancer (excluding prostate and pancreas), 1.05 (95% CI: 0.67, 1.63) for colon cancer, 0.98 (95% CI: 0.49, 1.97) for bladder cancer, 1.02 (95% CI: 0.59, 1.78) for lung cancer, and 0.88 (95% CI: 0.56, 1.39) for female breast cancer. Our results do not support an association between metformin treatment and the incidence of major cancers (excluding prostate and pancreas).

Disease Management plus Recommended Care versus Recommended Care Alone for Ambulatory Patients with Chronic Obstructive Pulmonary Disease.

Rationale: The efficacy of disease management programs in the treatment of patients with chronic obstructive pulmonary disease (COPD) remains uncertain.Objectives: To study the effect of disease management (DM) added to recommended care (RC) in ambulatory patients with COPD.Measurements and Main Results: In this trial, 1,202 patients with COPD (age, ≥40 yr), with moderate to very severe airflow limitation were randomly assigned either to DM plus RC (study intervention) or to RC alone (control intervention). RC included follow-up by pulmonologists, inhaled long-acting bronchodilators and corticosteroids, smoking cessation intervention, nutritional advice and psychosocial support when indicated, and supervised physical activity sessions. DM, delivered by trained nurses during patients' visits to the designated COPD centers and by remote contacts with the patients between these visits, included patient self-care education, monitoring patients' symptoms and adherence to treatment, provision of advice in case of acute disease exacerbation, and coordination of care vis-à-vis other healthcare providers. The primary composite endpoint was first hospital admission for respiratory symptoms or death from any cause. During 3,537 patient-years, 284 patients (47.2%) in the control group and 264 (44.0%) in the study intervention group had a primary endpoint event. The median (range) time elapsed until a primary endpoint event was 1.0 (0-4.0) years among patients assigned to the study intervention and 1.1 (0-4.1) years among patients assigned to the control intervention; adjusted hazard ratio, 0.92 (95% confidence interval, 0.77-1.08).Conclusions: DM added to RC was not superior to RC alone in delaying first hospital admission or death among ambulatory patients with COPD.

Disease management in the treatment of patients with chronic heart failure who have universal access to health care: a randomized controlled trial.

BACKGROUND: The efficacy of disease management programs in improving the outcome of heart failure patients remains uncertain and may vary across health systems. This study explores whether a countrywide disease management program is superior to usual care in reducing adverse health outcomes and improving well-being among community-dwelling adult patients with moderate-to-severe chronic heart failure who have universal access to advanced health-care services and technologies. METHODS: In this multicenter open-label trial, 1,360 patients recruited after hospitalization for heart failure exacerbation (38%) or from the community (62%) were randomly assigned to either disease management or usual care. Disease management, delivered by multi-disciplinary teams, included coordination of care, patient education, monitoring disease symptoms and patient adherence to medication regimen, titration of drug therapy, and home tele-monitoring of body weight, blood pressure and heart rate. Patients assigned to usual care were treated by primary care practitioners and consultant cardiologists. The primary composite endpoint was the time elapsed till first hospital admission for heart failure exacerbation or death from any cause. Secondary endpoints included the number of all hospital admissions, health-related quality of life and depression during follow-up. Intention-to-treat comparisons between treatments were adjusted for baseline patient data and study center. RESULTS: During the follow-up, 388 (56.9%) patients assigned to disease management and 387 (57.1%) assigned to usual care had a primary endpoint event. The median (range) time elapsed until the primary endpoint event or end of study was 2.0 (0-5.0) years among patients assigned to disease management, and 1.8 (0-5.0) years among patients assigned to usual care (adjusted hazard ratio, 0.908; 95% confidence interval, 0.788 to 1.047). Hospital admissions were mostly (70%) unrelated to heart failure. Patients assigned to disease management had a better health-related quality of life and a lower depression score during follow-up. CONCLUSIONS: This comprehensive disease management intervention was not superior to usual care with respect to the primary composite endpoint, but it improved health-related quality of life and depression. A disease-centered approach may not suffice to make a significant impact on hospital admissions and mortality in patients with chronic heart failure who have universal access to health care. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00533013 . Trial registration date: 9 August 2007. Initial protocol release date: 20 September 2007.

Cardiovascular health among two ethnic groups living in the same region: A population-based study.

BACKGROUND: Poor cardiovascular health (CVH) among ethnic/racial minorities, studied primarily in the USA, may reflect lower access to healthcare. We examined factors associated with minority CVH in a setting of universal access to healthcare. METHODS AND RESULTS: CVH behaviors and factors were evaluated in a random population sample (551 Arabs, 553 Jews) stratified by sex, ethnicity and age. More Jews (10%) than Arabs (3%) had 3 ideal health behaviors. Only one participant had all four. Although ideal diet was rare (≤1.5%) across groups, Arabs were more likely to meet intake recommendations for whole grains, but less likely to meet intake recommendations for fruits/vegetables and fish. Arabs had lower odds of attaining ideal levels for body mass index and physical activity. Smoking prevalence was 57% among Arab men and 6% among Arab women. Having four ideal health factors (cholesterol, blood pressure, glucose, smoking) was observed in 2% and 8% of Arab and Jewish men, respectively, and 13% of Arab and Jewish women. Higher prevalence of ideal total-cholesterol corresponded to lower high-density lipoprotein cholesterol among Arabs. No participant met ideal levels for all 7 metrics and only 1.8% presented with 6. Accounting for age and lower socioeconomic status, Arabs were less likely to meet a greater number of metric goals (odds ratio (95% confidence interval): 0.62 (0.42-0.92) for men, and 0.73 (0.48-1.12) for women). CONCLUSIONS: Ideal CVH, rare altogether, was less prevalent among the Arab minority albeit universal access to healthcare. Health behaviors were the main contributors to the CVH disparity.

Body Mass Index, Height and Socioeconomic Position in Adolescence, Their Trajectories into Adulthood, and Cognitive Function in Midlife.

BACKGROUND: Whether life course anthropometric indices relate to cognitive function in midlife remains insufficiently explored. Rarely was socioeconomic position (SEP) adequately accounted for. OBJECTIVE: To examine the association of the cumulative life course burden of high-ranked body mass index (BMI), its trajectory, and stature with cognitive function in midlife. METHODS: Weight and height were measured from age 17 across a 33-year follow-up. 507 individuals completed a NeuroTrax computerized cognitive assessment at ages 48-52. Life course SEP was assessed by multiple methods. Using mixed models we calculated the area under the curve (AUC), representing both the life-course burden of BMI (total AUC) and trends in BMI (incremental AUC) from age 17 to midlife. The associations of BMI and height with global cognition and its five component domains were assessed by multiple regression. RESULTS: Higher BMI in late adolescence and total AUC over the life course were associated with poorer global cognition (Standardized beta (Beta) = -0.111, p = 0.005 and Beta = -0.105, p = 0.018, respectively), adjusted for childhood and adulthood SEP, and demographic characteristics. The associations with higher adolescent and midlife BMI were both restricted to those with low childhood SEP (p < 0.05 for interaction). Short adolescent stature was related to poorer cognition (Beta = 0.115, p = 0.040), whereas late final growth in women was associated with better cognition (Beta = 0.213, p = 0.007). CONCLUSION: An adverse association of higher BMI with cognitive function began in adolescence and was restricted to low childhood SEP. Taller stature in both sexes and late growth in women were associated with better midlife cognitive performance.

Diabetes, prostate cancer screening and risk of low- and high-grade prostate cancer: an 11 year historical population follow-up study of more than 1 million men.

AIMS/HYPOTHESIS: An inverse association has consistently been shown between diabetes and prostate cancer incidence. We investigated whether lower prostate cancer incidence among men with diabetes is attributable to lower detection due to prostate cancer screening patterns. METHODS: We studied a population-based historical cohort of 1,034,074 Israeli men aged 21-90 years, without a previous history of cancer. The cohort was followed-up from 2002 to 2012, according to diabetes morbidity, for frequency of prostate-specific antigen (PSA) testing, mean PSA values and detection of prostate cancer, after adjustment for age, ethnic origin, socioeconomic status and PSA testing. RESULTS: In January 2002, 74,756 men had prevalent diabetes. During the 11 year follow-up, 765,483 (74%) remained diabetes-free and 193,835 developed diabetes. Approximately 10% more PSA screening was performed in men with than without diabetes, but the rate of PSA positivity (>4 µg/l) was 20% lower in men with diabetes. PSA values were already significantly lower in men who developed diabetes than in those who did not, 3 years before diabetes diagnosis. Reduced prostate cancer risk was observed among men with incident diabetes only for low-moderate grade tumours (Gleason score 2-6: adjusted HR 0.83; 95% CI 0.77, 0.89). No association was observed for high-grade tumours (Gleason score 7-10: HR 0.99; 95% CI 0.88, 1.11). CONCLUSIONS/INTERPRETATION: Our findings suggest that diabetes comorbidity is a factor to be considered in prostate cancer screening strategies, and specifically in the interpretation of PSA levels. Furthermore, our demonstration of reduced incidence of low-moderate grade but not high-grade prostate cancer tumours among men with diabetes supports the possibility that low PSA levels, rather than lower tumour risk, explains the observed reduced incidence of prostate cancer in men with diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02072902.

Estimating and testing interactions when explanatory variables are subject to non-classical measurement error.

Assessing interactions in linear regression models when covariates have measurement error (ME) is complex.We previously described regression calibration (RC) methods that yield consistent estimators and standard errors for interaction coefficients of normally distributed covariates having classical ME. Here we extend normal based RC (NBRC) and linear RC (LRC) methods to a non-classical ME model, and describe more efficient versions that combine estimates from the main study and internal sub-study. We apply these methods to data from the Observing Protein and Energy Nutrition (OPEN) study. Using simulations we show that (i) for normally distributed covariates efficient NBRC and LRC were nearly unbiased and performed well with sub-study size ≥200; (ii) efficient NBRC had lower MSE than efficient LRC; (iii) the naïve test for a single interaction had type I error probability close to the nominal significance level, whereas efficient NBRC and LRC were slightly anti-conservative but more powerful; (iv) for markedly non-normal covariates, efficient LRC yielded less biased estimators with smaller variance than efficient NBRC. Our simulations suggest that it is preferable to use: (i) efficient NBRC for estimating and testing interaction effects of normally distributed covariates and (ii) efficient LRC for estimating and testing interactions for markedly non-normal covariates.

Jews and Arabs in the same region in Israel exhibit major differences in dietary patterns.

The Jewish majority and Arab minority populations in Israel exhibit disparities in nutrition-related chronic diseases, but comparative, population-based dietary studies are lacking. We evaluated ethnic differences in dietary patterns in a population-based, cross-sectional study of Arab and Jewish urban adults (n = 1104; age 25-74 y). Dietary intake was assessed with an interviewer-administered, quantified FFQ. We used principal-component analysis to identify 4 major dietary patterns: Ethnic, Healthy, Fish and Meat Dishes, and Middle Eastern Snacks and Fast Food. The Ethnic and Healthy patterns exhibited major ethnic differences. Participants in the top Ethnic intake tertile (97% Arab) had modified Mediterranean-style Arabic dietary habits, whereas those in the bottom Ethnic tertile (98% Jewish) had central/northern European-style dietary habits. The Arab participants with less strongly ethnicity-associated dietary habits were younger [OR for 10-y decrease = 1.42 (95% CI: 1.21-1.68)] and male [OR = 2.23 (95% CI: 1.53-3.25)]. Jews with less strongly ethnicity-associated dietary habits were less recent immigrants [OR = 8.97 (95% CI: 5.05-15.92)], older [OR for 10-y decrease = 0.80 (95% CI: 0.69-0.92)], had post-secondary education [OR = 2.04 (95% CI: 1.06-3.94)], and reported other healthy lifestyle behaviors. In relation to the Healthy pattern, Arabs were less likely than Jews to be in the top intake tertile, but the magnitude of the difference was less in diabetic participants. Participants reporting other healthy lifestyle behaviors were more likely to have a high intake of the Healthy pattern. Substantial differences were found between Arabs and Jews in dietary patterns and suggest a need for culturally congruent dietary interventions to address nutrition-related chronic disease disparities.