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Supplementary Appendix for manuscript titled: "Asthma in Youth and Early-Onset Type 2 Diabetes: A Nationwide Study of 1.72 Million Israeli Adolescents"

Importance: Current guidelines advocate the use of marine-derived omega-3 fatty acids supplements for the prevention of coronary heart disease and major vascular events in people with prior coronary heart disease, but large trials of omega-3 fatty acids have produced conflicting results.Objective: To conduct a meta-analysis of all large trials assessing the associations of omega-3 fatty acid supplements with the risk of fatal and nonfatal coronary heart disease and major vascular events in the full study population and prespecified subgroups.Data Sources and Study Selection: This meta-analysis included randomized trials that involved at least 500 participants and a treatment duration of at least 1 year and that assessed associations of omega-3 fatty acids with the risk of vascular events.Data Extraction and Synthesis: Aggregated study-level data were obtained from 10 large randomized clinical trials. Rate ratios for each trial were synthesized using observed minus expected statistics and variances. Summary rate ratios were estimated by a fixed-effects meta-analysis using 95% confidence intervals for major diseases and 99% confidence intervals for all subgroups.Main Outcomes and Measures: The main outcomes included fatal coronary heart disease, nonfatal myocardial infarction, stroke, major vascular events, and all-cause mortality, as well as major vascular events in study population subgroups.Results: Of the 77 917 high-risk individuals participating in the 10 trials, 47 803 (61.4%) were men, and the mean age at entry was 64.0 years; the trials lasted a mean of 4.4 years. The associations of treatment with outcomes were assessed on 6273 coronary heart disease events (2695 coronary heart disease deaths and 2276 nonfatal myocardial infarctions) and 12 001 major vascular events. Randomization to omega-3 fatty acid supplementation (eicosapentaenoic acid dose range, 226-1800 mg/d) had no significant associations with coronary heart disease death (rate ratio [RR], 0.93; 99% CI, 0.83-1.03; P = .05), nonfatal myocardial infarction (RR, 0.97; 99% CI, 0.87-1.08; P = .43) or any coronary heart disease events (RR, 0.96; 95% CI, 0.90-1.01; P = .12). Neither did randomization to omega-3 fatty acid supplementation have any significant associations with major vascular events (RR, 0.97; 95% CI, 0.93-1.01; P = .10), overall or in any subgroups, including subgroups composed of persons with prior coronary heart disease, diabetes, lipid levels greater than a given cutoff level, or statin use.Conclusions and Relevance: This meta-analysis demonstrated that omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events. It provides no support for current recommendations for the use of such supplements in people with a history of coronary heart disease.

acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013;310:2533–43. [5] GheorghiadeM, Follath F, Ponikowski P, et al. Assessing and grading congestion in acute heart failure: a scientific statement from the AcuteHeart Failure Committee of theHeart Failure Association of the European Society of Cardiology andendorsed by the European Society of Intensive Care Medicine. Eur J Heart Fail 2010;12:423–33. [6] Nunez J, Nunez E, Sanchis J, et al. Antigen carbohydrate 125 and brain natriuretic peptide serial measurements for risk stratification following an episode of acute heart failure. Int J Cardiol 2012;159:21–8. [7] Givertz MM, Postmus D, Hillege HL, et al. Renal function trajectories and clinical outcomes in acute heart failure. Circ Heart Fail 2014;7:59–67. [8] MetraM, Davison B, Bettari L, et al. Is worsening renal function an ominous prognostic sign inpatientswith acute heart failure? The role of congestion and its interactionwith renal function. Circ Heart Fail 2012;5:54–62. [9] Rogers JK, Pocock SJ, McMurray JJ, et al. Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to CHARM-Preserved. Eur J Heart Fail 2014;16:33–40.

Current evidence suggests that both prediabetes and diabetes can reverse to normoglycemia; however, predictors of remission of these conditions are poorly understood. We performed analyses on 1,209 people with impaired fasting glucose and/or impaired glucose tolerance treated with placebo rosiglitazone and placebo ramipril in the DREAM trial. Normoglycemia was defined as a fasting plasma glucose The effects of baseline ALT and waist to hip ratio (WHR) on regression of prediabetes to normoglycemia 2 years later were found to be interdependent (p-value for interaction 0.01). Adjusted odds ratios ORs (95% CI) of regression to normoglycemia per 10 U/L increase in ALT were 0.79 (0.66-0.94) when WHR was at the mean minus 1 standard deviation (SD), 0.90 (0.80-1.02) when WHR was at the mean of 0.91, and 1.03 (0.90-1.18) when WHR was at the mean plus 1 SD. Adjusted ORs of regression to normoglycemia per 0.1 unit increase in WHR were 0.75 (0.60-0.95) when ALT was at the mean minus 1 SD, 0.91 (0.76-1.08) when ALT was at the mean of 25 U/L, and 1.09 (0.89-1.35) when ALT was at the mean plus 1 SD. Similarly, the effects of baseline ALT and WHR on AUCglucose0-120 min obtained from the OGTT were found to be interdependent (p-value for interaction 0.056). A 10 U/L increase in ALT was associated with an adjusted AUCglucose0-120 min increase of 19.5 (95% CI 5.3 to 33.7) min*mmol/L when WHR was at the mean minus 1 SD, 11.0 (1.4 to 20.6) min*mmol/L when WHR was at the mean of 0.91, and 2.5 (-9.2 to 14.1) min*mmol/L when WHR was at the mean plus 1 SD. A 0.1 unit increase in WHR was associated with an adjusted AUCglucose0-120 min increase of 30.3 (10.2 to 50.3) min*mmol/L when ALT was at the mean minus 1 SD, 18.3 (3.8-32.9) min*mmol/L when ALT was at the mean of 25 U/L, and 6.4 (-11.5 to 24.3) min*mmol/L when ALT was at the mean plus 1 SD. In conclusion, high baseline ALT and WHR predict a lower likelihood of regression of prediabetes to normoglycemia and an increase in AUCglucose0-120 min 2 years later; however, the effects of ALT and WHR on these outcomes are interdependent. Master of Science (MSc)

This thesis describes some of the prominent issues facing primary care practitioners regarding diabetes care. Type 2 diabetes (T2DM) is a common metabolic disturbance among Canadians, now reaching worldwide epidemic proportions. Alarmingly, diabetes prevalence is expected to increase significantly in future years. This increase in diabetes will lead to corresponding increases in the rates of complications, which place a burden on the health care system. However, interventions could prevent or delay T2DM and thus decrease morbidity and mortality associated with its complications if individuals at risk of developing diabetes are detected early. The first paper describes a systematic review to determine the effectiveness of T2DM screening methods using community or family practice-based systematic screening approaches compared to opportunistic family practice-based approaches. The second paper describes a novel community health initiative, the Community Health Awareness of Diabetes (CHAD) Program. It reports participant characteristics and satisfaction with the community-wide diabetes awareness demonstration project. The third paper examines whether the CHAD program was effective in increasing detection of diabetes. As routine diabetes care remains largely a family practice activity, and something that all family doctors participate in, the fourth paper reports on the current state of diabetes care in 96 Ontario family practices.. The final paper reports the findings of a qualitative study examining family physicians’ approach to insulin prescribing in older patients. Current prevalence figures estimate that 16% of people over 65 years have diabetes and family practitioners look after these individuals and their diabetes. Finally, recommendations are made as to how screening and care for diabetes in primary care could be improved. In summary, policies supporting community initiatives partnering with primary healthcare should be promoted in an effort to share the burden of screening for diabetes, and also to target appropriate screening to populations that need it the most. Doctor of Philosophy (PhD)