Ruzan Udumyan

Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes.

Understanding and improving the prognosis of a disease or health condition is a priority in clinical research and practice. In this article, the authors introduce a framework of four interrelated themes in prognosis research, describe the importance of the first of these themes (understanding future outcomes in relation to current diagnostic and treatment practices), and introduce recommendations for the field of prognosis research

Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients

Aims The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD. Methods and results Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan–Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13–16 life years or 15–18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation. Conclusion These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.

Resveratrol Promotes Foot Ulcer Size Reduction in Type 2 Diabetes Patients

Objective. The effect of a proprietary formulation of trans-resveratrol (t-RSV) on manifestations of diabetic foot syndrome (DFS) was studied in type 2 diabetic patients with newly diagnosed diabetic foot ulcers. Method. Placebo-controlled, examiner-blinded, parallel-group randomized controlled pilot clinical trial (ACTRN Clinical Trial Registry number 12610000629033) involving 24 patients with DFS (15 males and 9 females, average age of 56.4 ± 9.1 years) divided into the placebo and RSV-treatment groups was performed. 50 mg of t-RSV or placebo capsules was given to each patient twice a day over a 60-day time period. Results. Reduction in the parameters reflecting diabetic ulcer size was more profound in the RSV group as compared to placebo. RSV-treated patients also had a marginally improved performance in the foot pressure test. A statistically significant decline in the plasma fibrinogen level, but not CRP, was also found in the RSV-treated patients. Some improvement in the plasma lipid profile and fasting glucose levels were not related to RSV-treatment, since they have been seen on both the RSV and placebo groups, revealing the effectiveness of medical supervision and education in the newly diagnosed patients with DFS. Conclusion. t-RSV supplementation promotes reduction of the foot ulcer size and reduces plasma fibrinogen level in type 2 diabetic patients.

Stable Incidence of Collagenous Colitis and Lymphocytic Colitis in Orebro, Sweden, 1999-2008 : A Continuous Epidemiologic Study

Background:The incidence of microscopic colitis (MC) has increased in several centers, but long-term epidemiologic data are missing. We report an epidemiologic study of collagenous colitis (CC) and lymphocytic colitis (LC) during 1999–2008, as a follow-up of our previous studies 1984–1998. Methods:Population-based study of residents of the catchment area of the hospital, with a new diagnosis of MC between 1999 and 2008. Patients were identified by diagnosis registers of the Departments of Medicine and Pathology. Medical files were reviewed, and colonic biopsies were reevaluated. Results:Collagenous colitis was diagnosed in 96 patients (75 females) and LC in 90 patients (74 females). The mean annual age-standardized incidence (per 100,000 inhabitants) was MC 10.2 (95% confidence interval: 8.7–11.7), CC 5.2 (4.2–6.3), and LC 5.0 (4.0–6.0). Age-specific incidence showed a peak in females older than 70 years. Prevalence (per 100,000 inhabitants) on December 31, 2008, was MC 123 (107.6–140.0), CC 67.7 (56.4–80.6), and LC 55.3 (45.2–67.1). A comparison of current study period with 1993–1998 showed unchanged mean incidence of MC, but a 2-fold increase in women older than 60 years with LC (standardized rate ratios 2.2, [1.2–3.7]) and increased female to male ratio (4.6:1 versus 2.1:1; P = 0.02) in LC. Conclusions:After an initial rise during 1980s and early 1990s, annual incidence of CC and LC has been stable during the last 15 years around 5/100,000 inhabitants for each disorder. The increasing incidence in older women with LC may be related to an increasing proportion of older individuals in the background population and increased colonoscopy frequency in elderly.

Depression as a Risk Factor for the Initial Presentation of Twelve Cardiac, Cerebrovascular, and Peripheral Arterial Diseases: Data Linkage Study of 1.9 Million Women and Men

Background Depression is associated with coronary heart disease and stroke, but associations with a range of pathologically diverse cardiovascular diseases are not well understood. We examine the risk of 12 cardiovascular diseases according to depression status (history or new onset). Methods Cohort study of 1,937,360 adult men and women, free from cardiovascular disease at baseline, using linked UK electronic health records between 1997 and 2010. The exposures were new-onset depression (a new GP diagnosis of depression and/or prescription for antidepressants during a one-year baseline), and history of GP-diagnosed depression before baseline. The primary endpoint was initial presentation of 12 cardiovascular diseases after baseline. We used disease-specific Cox proportional hazards models with multiple imputation adjusting for cardiovascular risk factors (age, sex, socioeconomic status, smoking, blood pressure, diabetes, cholesterol). Results Over a median [IQR] 6.9 [2.1–10.5] years of follow-up, 18.9% had a history of depression and 94,432 incident cardiovascular events occurred. After adjustment for cardiovascular risk factors, history of depression was associated with: stable angina (Hazard Ratio = 1.38, 95%CI 1.32–1.45), unstable angina (1.70, 1.60–1.82), myocardial infarction (1.21, 1.16–1.27), unheralded coronary death (1.23, 1.14–1.32), heart failure (1.18, 1.13–1.24), cardiac arrest (1.14, 1.03–1.26), transient ischemic attack (1.31, 1.25–1.38), ischemic stroke (1.26, 1.18–1.34), subarachnoid haemorrhage (1.17, 1.01–1.35), intracerebral haemorrhage (1.30, 1.17–1.45), peripheral arterial disease (1.24, 1.18–1.30), and abdominal aortic aneurysm (1.12,1.01–1.24). New onset depression developed in 2.9% of people, among whom 63,761 cardiovascular events occurred. New onset depression was similarly associated with each of the 12 diseases, with no evidence of stronger associations compared to history of depression. The strength of association between depression and these cardiovascular diseases did not differ between women and men. Conclusion Depression was prospectively associated with cardiac, cerebrovascular, and peripheral diseases, with no evidence of disease specificity. Further research is needed in understanding the specific pathophysiology of heart and vascular disease triggered by depression in healthy populations.

Stress resilience in male adolescents and subsequent stroke risk : cohort study

Objective Exposure to psychosocial stress has been identified as a possible stroke risk, but the role of stress resilience which may be relevant to chronic exposure is uncertain. We investigated the association of stress resilience in adolescence with subsequent stroke risk. Methods Register-based cohort study. Some 237 879 males born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Cox regression estimated the association of stress resilience with stroke, after adjustment for established stroke risk factors. Results Some 3411 diagnoses of first stroke were identified. Lowest stress resilience (21.8%) compared with the highest (23.7%) was associated with increased stroke risk, producing unadjusted HR (with 95% CIs) of 1.54 (1.40 to 1.70). The association attenuated slightly to 1.48 (1.34 to 1.63) after adjustment for markers of socioeconomic circumstances in childhood; and after further adjustment for markers of development and disease in adolescence (blood pressure, cognitive function and pre-existing cardiovascular disease) to 1.30 (1.18 to 1.45). The greatest reduction followed further adjustment for markers of physical fitness (BMI and physical working capacity) in adolescence to 1.16 (1.04 to 1.29). The results were consistent when stroke was subdivided into fatal, ischaemic and haemorrhagic, with higher magnitude associations for fatal rather than non-fatal, and for haemorrhagic rather than ischaemic stroke. Conclusions Stress susceptibility and, therefore, psychosocial stress may be implicated in the aetiology of stroke. This association may be explained, in part, by poorer physical fitness. Effective prevention might focus on behaviour/lifestyle and psychosocial stress.

Evaluation of a novel nutrition education intervention for medical students from across England

Objectives Problems such as hospital malnutrition (∼40% prevalence in the UK) may be managed better by improving the nutrition education of ‘tomorrows doctors’. The Need for Nutrition Education Programme aimed to measure the effectiveness and acceptability of an educational intervention on nutrition for medical students in the clinical phase of their training. Design An educational needs analysis was followed by a consultative process to gain consensus on a suitable educational intervention. This was followed by two identical 2-day educational interventions with before and after analyses of Knowledge, Attitudes and Practices (KAP). The 2-day training incorporated six key learning outcomes. Setting Two constituent colleges of Cambridge University used to deliver the above educational interventions. Participants An intervention group of 100 clinical medical students from 15 medical schools across England were recruited to attend one of two identical intensive weekend workshops. Primary and secondary outcome measures The primary outcome measure consisted of change in KAP scores following intervention using a clinical nutrition questionnaire. Secondary outcome measures included change in KAP scores 3 months after the intervention as well as a student-led semiqualitative evaluation of the educational intervention. Results Statistically significant changes in KAP scores were seen immediately after the intervention, and this was sustained for 3 months. Mean differences and 95% CIs after intervention were Knowledge 0.86 (0.43 to 1.28); Attitude 1.68 (1.47 to 1.89); Practice 1.76 (1.11 to 2.40); KAP 4.28 (3.49 to 5.06). Ninety-seven per cent of the participants rated the overall intervention and its delivery as ‘very good to excellent’, reporting that they would recommend this educational intervention to colleagues. Conclusion Need for Nutrition Education Programme has highlighted the need for curricular innovation in the area of clinical health nutrition in medical schools. This project also demonstrates the effectiveness and acceptability of such a curriculum intervention for ‘tomorrows doctors’. Doctors, dietitians and nutritionists worked well in an effective interdisciplinary partnership when teaching medical students, providing a good model for further work in a healthcare setting.

Stress resilience and physical fitness in adolescence and risk of coronary heart disease in middle age

Objective Psychosocial stress is a suggested risk for coronary heart disease (CHD). The relationship of stress resilience in adolescence with subsequent CHD risk is underinvestigated, so our objective was to assess this and investigate the possible mediating role of physical fitness. Methods In this register-based study, 237 980 men born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semistructured interview with a psychologist. Some 10 581 diagnoses of CHD were identified. Cox regression estimated the association of stress resilience with CHD, with adjustment for established cardiovascular risk factors. Results Low-stress resilience was associated with increased CHD risk. The association remained after adjustment for physical fitness and other potential confounding and mediating factors, with adjusted HRs (and 95% CIs) of 1.17 (1.10 to 1.25), with some evidence of mediation by physical fitness. CHD incidence rates per 1000 person-years (and 95% CIs) for low-stress, medium-stress and high-stress resilience were 2.61 (2.52 to 2.70), 1.97 (1.92 to 2.03) and 1.59 (1.53 to 1.67) respectively. Higher physical fitness was inversely associated with CHD risk; however, this was attenuated by low-stress resilience, shown by interaction testing (p<0.001). Conclusions Low-stress resilience in adolescence was associated with increased risk of CHD in middle age and may diminish the benefit of physical fitness. This represents new evidence of the role of stress resilience in determining risk of CHD and its interrelationship with physical fitness.

Mortality following unemployment during an economic downturn: Swedish register-based cohort study

Objective To investigate if unemployment during an economic downturn is associated with mortality, even among men with markers of better health (higher cognitive function scores and qualifications), and to assess whether the associations vary by age at unemployment. Design Longitudinal register-based cohort study. Setting Study entry was in 1990 and 2001 when Sweden was entering periods of significant economic contraction. Participants A representative sample of men from the general population (n=234 782) born between 1952 and 1956 who participated in military conscription examinations. Men in receipt of disability or sickness benefit at study entry were excluded. Main outcome measure All-cause mortality. Results Unemployment compared with employment in 1991 (ages 34–38 years) produced adjusted HRs (with 95% CIs) for all-cause mortality (3651 deaths) during follow-up to 2001 and after stratification by education of 2.35 (1.99 to 2.76) for compulsory education, 2.25 (1.97 to 2.58) for up to 3 years postcompulsory education and 1.90 (1.40 to 2.57) for more than 3 years postcompulsory education. When unemployment was compared with employment in 2001 (ages 45–49 years) with follow-up to 2010, the pattern of mortality risk (4271 deaths) stratified by education was reversed, producing adjusted HRs of 2.81 (2.47 to 3.21) for compulsory education, 2.87 (2.58 to 3.19) for up to 3 years postcompulsory education and 3.44 (2.78 to 4.25) for more than 3 years postcompulsory education. Interaction testing confirmed effect modification by age/period (p=0.003). The degree of gradient reversal was slightly less pronounced after stratification by cognitive function but produced a similar pattern of results (p=0.004). Conclusions Unemployment at older ages is associated with greater mortality risk than at younger ages, with the greatest relative increase in risk among men with markers of better health, suggesting the greater vulnerability of all older workers to unemployment-associated exposures.

Adolescent body mass index and erythrocyte sedimentation rate in relation to colorectal cancer risk

Objective Adult obesity and inflammation have been associated with risk of colorectal cancer (CRC); however, less is known about how adolescent body mass index (BMI) and inflammation, as measured by erythrocyte sedimentation rate (ESR), relate to CRC risk. We sought to evaluate these associations in a cohort of 239 658 Swedish men who underwent compulsory military enlistment examinations in late adolescence (ages 16–20 years). Design At the time of the conscription assessment (1969–1976), height and weight were measured and ESR was assayed. By linkage to the national cancer registry, these conscripts were followed for CRC through 1 January 2010. Over an average of 35 years of follow-up, 885 cases of CRC occurred, including 501 colon cancers and 384 rectal cancers. Cox regression was used to estimate adjusted HRs and corresponding 95% CIs. Results Compared with normal weight (BMI 18.5 to <25 kg/m2) in late adolescence, upper overweight (BMI 27.5 to <30 kg/m2) was associated with a 2.08-fold higher risk of CRC (95% CI 1.40 to 3.07) and obesity (BMI 30+ kg/m2) was associated with a 2.38-fold higher risk of CRC (95% CI 1.51 to 3.76) (p-trend: <0.001). Male adolescents with ESR (15+ mm/h) had a 63% higher risk of CRC (HR 1.63; 95% CI 1.08 to 2.45) than those with low ESR (<10 mm/h) (p-trend: 0.006). Associations did not significantly differ by anatomic site. Conclusions Late-adolescent BMI and inflammation, as measured by ESR, may be independently associated with future CRC risk. Further research is needed to better understand how early-life exposures relate to CRC.