Genetic and environmental determinants of bone quality: a cross-sectional analysis of the Hungarian Twin Registry.

There is abundant evidence that bone mineral content is highly heritable, while the heritability of bone quality (i.e. trabecular bone score [TBS] and quantitative ultrasound index [QUI]) is rarely investigated. We aimed to disentangle the role of genetic, shared and unique environmental factors on TBS and QUI among Hungarian twins. Our study includes 82 twin (48 monozygotic, 33 same-sex dizygotic) pairs from the Hungarian Twin Registry. TBS was determined by DXA, QUI by calcaneal bone ultrasound. To estimate the genetic and environmental effects, we utilized ACE-variance decomposition. For the unadjusted model of TBS, an AE model provided the best fit with > 80% additive genetic heritability. Adjustment for age, sex, BMI and smoking status improved model fit with 48.0% of total variance explained by independent variables. Furthermore, there was a strong dominant genetic effect (73.7%). In contrast, unadjusted and adjusted models for QUI showed an AE structure. Adjustments improved model fit and 25.7% of the total variance was explained by independent variables. Altogether 70-90% of the variance in QUI was related to additive genetic influences. We found a strong genetic heritability of bone quality in unadjusted models. Half of the variance of TBS was explained by age, sex and BMI. Furthermore, the adjusted model suggested that the genetic component of TBS could be dominant or an epistasis could be present. In contrast, independent variables explained only a quarter of the variance of QUI and the additive heritability explained more than half of all the variance.

Diagnosis rates, therapeutic characteristics, lifestyle, and cancer screening habits of patients with diabetes mellitus in a highly deprived region in Hungary: a cross-sectional analysis.

Introduction: Low socioeconomic status affects not only diagnosis rates and therapy of patients with diabetes mellitus but also their health behavior. Our primary goal was to examine diagnosis rates and therapy of individuals with diabetes living in Ormánság, one of the most deprived areas in Hungary and Europe. Our secondary goal was to examine the differences in lifestyle factors and cancer screening participation of patients with diagnosed and undiagnosed diabetes compared to healthy participants. Methods: Our study is a cross-sectional analysis using data from the "Ormánság Health Program". The "Ormánság Health Program" was launched to improve the health of individuals in a deprived region of Hungary. Participants in the program were coded as diagnosed diabetes based on diagnosis by a physician as a part of the program, self-reported diabetes status, and self-reported prescription of antidiabetic medication. Undiagnosed diabetes was defined as elevated blood glucose levels without self-reported diabetes and antidiabetic prescription. Diagnosis and therapeutic characteristics were presented descriptively. To examine lifestyle factors and screening participation, patients with diagnosed and undiagnosed diabetes were compared to healthy participants using linear regression or multinomial logistic regression models adjusted for sex and age. Results: Our study population consisted of 246 individuals, and 17.9% had either diagnosed (n=33) or undiagnosed (n=11) diabetes. Metformin was prescribed in 75.8% (n=25) of diagnosed cases and sodium-glucose cotransporter-2 inhibitors (SGLT-2) in 12.1% (n=4) of diagnosed patients. After adjustment, participants with diagnosed diabetes had more comorbidities (adjusted [aOR]: 3.50, 95% confidence interval [95% CI]: 1.34-9.18, p<0.05), consumed vegetables more often (aOR: 2.49, 95% CI: 1.07-5.78, p<0.05), but desserts less often (aOR: 0.33, 95% CI: 0.15-0.75, p<0.01) than healthy individuals. Patients with undiagnosed diabetes were not different in this regard from healthy participants. No significant differences were observed for cancer screening participation between groups. Conclusions: To increase recognition of diabetes, targeted screening tests should be implemented in deprived regions, even among individuals without any comorbidities. Our study also indicates that diagnosis of diabetes is not only important for the timely initiation of therapy, but it can also motivate individuals in deprived areas to lead a healthier lifestyle.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Neutrophil-to-Lymphocyte Ratio Is an Independent Risk Factor for Coronary Artery Disease in Central Obesity.

Several inflammatory biomarkers were found to be associated with an increased risk of cardiovascular disease. Neutrophil-to-lymphocyte ratio (NLR) is a marker of subclinical inflammation that increases with the stress response. Visceral adiposity index (VAI) calculated as a combination of anthropometric and metabolic parameters reflects both the extent and function of visceral adipose tissue. Given the association of subclinical inflammation with both obesity and cardiovascular diseases, it is plausible that the inflammation-CVD association is modulated by the amount and function of adipose tissue. Thus, our aim was to examine the association between NLR and coronary artery calcium score (CACS), an intermediate marker of coronary artery disease in asymptomatic patients across VAI tertiles. Methods: Data from 280 asymptomatic participants of a cardiovascular screening program were analysed. In addition to the collection of lifestyle and medical history, a non-contrast cardiac CT scan and laboratory tests were performed on all participants. Multivariate logistic regression was conducted with CACS > 100 as the outcome and with conventional cardiovascular risk factors and NLR, VAI, and NLR by VAI tertile as predictors. Results: We found an interaction between VAI tertiles and NLR; NLR values were similar in the lower VAI tertiles, while they were higher in the CACS > 100 in the 3rd VAI tertile (CACS ≤ 100: 1.94 ± 0.58 vs. CACS > 100: 2.48 ± 1.1, p = 0.008). According to multivariable logistic regression, the interaction between NLR and VAI tertiles remained: NLR was associated with CACS > 100 in the 3rd VAI tertile (OR = 1.67, 95% CI 1.06-2.62, p = 0.03) but not in the lower tertiles even after adjustment for age, sex, smoking, history of hypertension, hyperlipidaemia, and diabetes mellitus, as well as high-sensitivity C-reactive protein. Our findings draw attention to the independent association between subclinical, chronic, systemic inflammation and subclinical coronary disease in obesity.

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies.

OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted ß -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted ß -0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted ß -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Association of daily composition of physical activity and sedentary behaviour with incidence of cardiovascular disease in older adults.

BACKGROUND: Moderate-to-vigorous physical activity (MVPA) is proposed as key for cardiovascular diseases (CVD) prevention. At older ages, the role of sedentary behaviour (SB) and light intensity physical activity (LIPA) remains unclear. Evidence so far is based on studies examining movement behaviours as independent entities ignoring their co-dependency. This study examines the association between daily composition of objectively-assessed movement behaviours (MVPA, LIPA, SB) and incident CVD in older adults. METHODS: Whitehall II accelerometer sub-study participants free of CVD at baseline (N = 3319, 26.7% women, mean age = 68.9 years in 2012-2013) wore a wrist-accelerometer from which times in SB, LIPA, and MVPA during waking period were extracted over 7 days. Compositional Cox regression was used to estimate the hazard ratio (HR) for incident CVD for daily compositions of movement behaviours characterized by 10 (20 or 30) minutes greater duration in one movement behaviour accompanied by decrease in another behaviour, while keeping the third behaviour constant, compared to reference composition. Analyses were adjusted for sociodemographic, lifestyle, cardiometabolic risk factors and multimorbidity index. RESULTS: Of the 3319 participants, 299 had an incident CVD over a mean (SD) follow-up of 6.2 (1.3) years. Compared to daily movement behaviour composition with MVPA at recommended 21 min per day (150 min/week), composition with additional 10 min of MVPA and 10 min less SB was associated with smaller risk reduction - 8% (HR, 0.92; 95% CI, 0.87-0.99) - than the 14% increase in risk associated with a composition of similarly reduced time in MVPA and more time in SB (HR, 1.14; 95% CI, 1.02-1.27). For a given MVPA duration, the CVD risk did not differ as a function of LIPA and SB durations. CONCLUSIONS: Among older adults, an increase in MVPA duration at the expense of time in either SB or LIPA was found associated with lower incidence of CVD. This study lends support to public health guidelines encouraging increase in MVPA or at least maintain MVPA at current duration.

5-year versus risk-category-specific screening intervals for cardiovascular disease prevention: a cohort study.

BACKGROUND: Clinical guidelines suggest preventive interventions such as statin therapy for individuals with a high estimated 10-year risk of major cardiovascular events. For those with a low or intermediate estimated risk, risk-factor screenings are recommended at 5-year intervals; this interval is based on expert opinion rather than on direct research evidence. Using longitudinal data on the progression of cardiovascular disease risk over time, we compared different screening intervals in terms of timely detection of high-risk individuals, cardiovascular events prevented, and health-care costs. METHODS: We used data from participants in the British Whitehall II study (aged 40-64 years at baseline) who had repeated biomedical screenings at 5-year intervals and linked these data to electronic health records between baseline (Aug 7, 1991, to May 10, 1993) and June 30, 2015. We estimated participants' 10-year risk of a major cardiovascular event (myocardial infarction, cardiac death, and fatal or non-fatal stroke) using the revised Atherosclerotic Cardiovascular Disease (ASCVD) calculator. We used multistate Markov modelling to estimate optimum screening intervals on the basis of progression rates from low-risk and intermediate-risk categories to the high-risk category (ie, ≥7·5% 10-year risk of a major cardiovascular event). Our assessment criteria included person-years spent in a high-risk category before detection, the number of major cardiovascular events prevented and quality-adjusted life-years (QALYs) gained, and screening costs. FINDINGS: Of 6964 participants (mean age 50·0 years [SD 6·0] at baseline) with 152 700 person-years of follow-up (mean follow-up 22·0 years [SD 5·0]), 1686 participants progressed to the high-risk category and 617 had a major cardiovascular event. With the 5-year screening intervals, participants spent 7866 (95% CI 7130-8658) person-years unrecognised in the high-risk group. For individuals in the low, intermediate-low, and intermediate-high risk categories, 21 alternative risk category-based screening intervals outperformed the 5-yearly screening protocol. Screening intervals at 7 years, 4 years, and 1 year for those in the low, intermediate-low, and intermediate-high-risk category would reduce the number of person-years spent unrecognised in the high-risk group by 62% (95% CI 57-66; 4894 person-years), reduce the number of major cardiovascular events by 8% (7-9; 49 events), and raise 44 QALYs (40-49) for the study population. INTERPRETATION: In terms of timely preventive interventions, the 5-year screening intervals were unnecessarily frequent for low-risk individuals and insufficiently frequent for intermediate-risk individuals. Screening intervals based on risk-category-specific progression rates would perform better in terms of preventing major cardiovascular disease events and improving cost-effectiveness. FUNDING: Medical Research Council, British Heart Association, National Institutes on Aging, NordForsk, Academy of Finland.

Neighbourhood socioeconomic disadvantage, risk factors, and diabetes from childhood to middle age in the Young Finns Study: a cohort study.

BACKGROUND: Neighbourhood socioeconomic disadvantage has been linked to increased diabetes risk, but little is known about differences in risk factors in childhood and adulthood in those with high and low neighbourhood socioeconomic disadvantage, or about the association between long-term neighbourhood socioeconomic disadvantage and incidence of diabetes in adulthood. We used data from the prospective, population-based Young Finns Study to address these questions. METHODS: We did a nationwide population-based cohort study in Finland using data from The Young Finns Study, which included 3467 participants aged 6-18 years followed up for over 30 years via eight repeated biomedical examinations and linkage to electronic health records. Participants were also linked to national grid data on neighbourhood disadvantage via their residential address from age 6-48 years. We used these data to examine differences in ten risk factors (dietary habits, physical activity, daily smoking, body-mass index, systolic blood pressure, fasting HDL cholesterol, fasting triglycerides, fasting plasma glucose, fasting serum insulin, and homoeostasis model assessment insulin sensitivity) from childhood (6-21 years) to adulthood (22-48 years) among individuals with high (>0·5 SD above the national mean) and low (≥0·5 SD below the national mean) neighbourhood socioeconomic disadvantage, and the association of cumulative neighbourhood socioeconomic disadvantage with six cardiometabolic risk factors (obesity, high waist circumference, fatty liver, hypertension, carotid plaque, and left ventricle mass index) and diabetes by middle age (22-48 years). We used logistic and linear regression analyses to assess the effects of neighbourhood disadvantage on cardiometabolic and diabetes risk, controlling for potential confounders (age, sex, and individual socioeconomic disadvantage). FINDINGS: We included data for 3002 individuals with risk factor assessment in childhood and adulthood. Of whom, 2048 underwent a clinical examination during the last follow-up at age 33-48 years. Differences in risk factors by neighbourhood socioeconomic disadvantage at the beginning of follow-up were small, but large differences emerged over the follow-up. High neighbourhood socioeconomic disadvantage was characterised by decreased fruit and vegetable intake as early as age 6 years, decreased physical activity, and increased prevalence of daily smoking from adolescence (12 years) onwards, and decreased homoeostasis model assessment insulin sensitivity and increased fasting glucose and insulin concentration from early adulthood (27 years; all p<0·03). Individuals consistently exposed to high neighbourhood socioeconomic disadvantage were more likely to be obese (odds ratio [OR] 1·44, 95% CI 1·01-2·06), hypertensive (1·83, 1·14-2·93), have a fatty liver (1·73, 1·11-2·71), and diabetes (3·71, 1·77-7·75), compared with those who were consistently exposed to low neighbourhood socioeconomic disadvantage. INTERPRETATION: Living in socioeconomically disadvantaged areas can shape health in childhood and adulthood. Neighbourhood socioeconomic disadvantage is associated with differences in health risks across the life course, including detrimental lifestyle factors from childhood and adolescence onwards and worse glucose metabolism from early adulthood. By middle age, cumulative neighbourhood socioeconomic disadvantage is associated with increased cardiometabolic risk factors and increased incidence of diabetes. FUNDING: Academy of Finland, NordForsk, UK Medical Research Council, European Commission, and European Research Council.

Adiponectin, biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study.

BACKGROUND: Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals. METHODS: Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested. RESULTS: Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes. CONCLUSIONS: Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe.

BACKGROUND: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. METHODS: We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0-24·9 kg/m2), overweight (25·0-29·9 kg/m2), class I (mild) obesity (30·0-34·9 kg/m2), and class II and III (severe) obesity (≥35·0 kg/m2). We used an inclusive definition of underweight (<20 kg/m2) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis. FINDINGS: Participants were 120  813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease. INTERPRETATION: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes. FUNDING: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.

Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study.

OBJECTIVE: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. DESIGN AND METHODS: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. RESULTS: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. CONCLUSIONS: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

Independent and combined effects of physical activity and body mass index on the development of Type 2 Diabetes - a meta-analysis of 9 prospective cohort studies.

BACKGROUND: The aim of this harmonized meta-analysis was to examine the independent and combined effects of physical activity and BMI on the incidence of type 2 diabetes. METHODS: Our systematic literature review in 2011 identified 127 potentially relevant prospective studies of which 9 fulfilled the inclusion criteria (total N = 117,878, 56.2 % female, mean age = 50.0 years, range = 25-65 years). Measures of baseline physical activity (low, intermediate, high), BMI-category [BMI < 18.4 (underweight), 18.5-24.9 (normal weight), 25.0-29.9 (overweight), 30+ (obese)] and incident type 2 diabetes were harmonized across studies. The associations between physical activity, BMI and incident type 2 diabetes were analyzed using Cox regression with a standardized analysis protocol including adjustments for age, gender, educational level, and smoking. Hazard ratios from individual studies were combined in a random-effects meta-analysis. RESULTS: Mean follow-up time was 9.1 years. A total of 11,237 incident type 2 diabetes cases were recorded. In mutually adjusted models, being overweight or obese (compared with normal weight) and having low physical activity (compared with high physical activity) were associated with an increased risk of incident type 2 diabetes (hazard ratios 2.33, 95 % CI 1.95-2.78; 6.10, 95 % CI: 4.63-8.04, and 1.23, 95 % CI: 1.09-1.39, respectively). Individuals who were both obese and had low physical activity had 7.4-fold (95 % CI 3.47-15.89) increased risk of type 2 diabetes compared with normal weight, high physically active participants. CONCLUSIONS: This harmonized meta-analysis shows the importance of maintaining a healthy weight and being physically active in diabetes prevention.

Adiposity, obesity, and arterial aging: longitudinal study of aortic stiffness in the Whitehall II cohort.

We sought to determine whether adiposity in later midlife is an independent predictor of accelerated stiffening of the aorta. Whitehall II study participants (3789 men; 1383 women) underwent carotid-femoral applanation tonometry at the mean age of 66 and again 4 years later. General adiposity by body mass index, central adiposity by waist circumference and waist:hip ratio, and fat mass percent by body impedance were assessed 5 years before and at baseline. In linear mixed models adjusted for age, sex, ethnicity, and mean arterial pressure, all adiposity measures were associated with aortic stiffening measured as increase in pulse wave velocity (PWV) between baseline and follow-up. The associations were similar in the metabolically healthy and unhealthy, according to Adult Treatment Panel-III criteria excluding waist circumference. C-reactive protein and interleukin-6 levels accounted for part of the longitudinal association between adiposity and PWV change. Adjusting for chronic disease, antihypertensive medication and risk factors, standardized effects of general and central adiposity and fat mass percent on PWV increase (m/s) were similar (0.14, 95% confidence interval: 0.05-0.24, P=0.003; 0.17, 0.08-0.27, P<0.001; 0.14, 0.05-0.22, P=0.002, respectively). Previous adiposity was associated with aortic stiffening independent of change in adiposity, glycaemia, and lipid levels across PWV assessments. We estimated that the body mass index-linked PWV increase will account for 12% of the projected increase in cardiovascular risk because of high body mass index. General and central adiposity in later midlife were strong independent predictors of aortic stiffening. Our findings suggest that adiposity is an important and potentially modifiable determinant of arterial aging.

Psychological distress and incidence of type 2 diabetes in high-risk and low-risk populations: the Whitehall II Cohort Study.

OBJECTIVE: We examined whether psychological distress predicts incident type 2 diabetes and if the association differs between populations at higher or lower risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prospective cohort of 5,932 diabetes-free adults (4,189 men and 1,743 women, mean age 54.6 years) with three 5-year data cycles (1991-2009): a total of 13,207 person-observations. Participants were classified into four groups according to their prediabetes status and Framingham Offspring Type 2 Diabetes Risk Score: normoglycemia with a risk score of 0-9, normoglycemia with a risk score of 10-19, prediabetes with a risk score of 10-19, and prediabetes with a risk score of >19. Psychological distress was assessed by the General Health Questionnaire. Incident type 2 diabetes was ascertained by 2-h oral glucose tolerance test, doctor diagnosis, or use of antihyperglycemic medication at the 5-year follow-up for each data cycle. Adjustments were made for age, sex, ethnicity, socioeconomic status, antidepressant use, smoking, and physical activity. RESULTS: Among participants with normoglycemia and among those with prediabetes combined with a low risk score, psychological distress did not predict type 2 diabetes. Diabetes incidence in these groups varied between 1.6 and 15.6%. Among participants with prediabetes and a high risk score, 40.9% of those with psychological distress compared with 28.5% of those without distress developed diabetes during the follow-up. The corresponding adjusted odds ratio for psychological distress was 2.07 (95% CI 1.19-3.62). CONCLUSIONS: These data suggest that psychological distress is associated with an accelerated progression to manifest diabetes in a subpopulation with advanced prediabetes.

Effect of secular trends on age-related trajectories of cardiovascular risk factors: the Whitehall II longitudinal study 1985-2009.

BACKGROUND: Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort. METHODS: Development of cardiovascular risk factors over the past three decades was analysed using serial measurements from 10 308 participants aged from 35 to 80 years over 25 years of follow-up from five clinical examination phases of the Whitehall II study. Changes of body mass index, waist circumference, blood pressure and total and high-density lipoprotein cholesterol distribution characteristics were analysed with quantile regression models in the 57-61 age group. Age-related trajectories of risk factors were assessed by fitting mixed-effects models with adjustment for year of birth to reveal secular trends. RESULTS: Average body mass index and waist circumference increased faster with age in women than in men, but the unfavourable secular trend was more marked in men. Distributions showed a fattening of the right tail in each consecutive phase, meaning a stronger increase in higher percentiles. Despite the higher obesity levels in younger birth cohorts, total cholesterol decreased markedly in the 57-61 age group along the entire distribution rather than in higher extremes only. CONCLUSION: The past three decades brought strong and heterogeneous changes in cardiovascular risk factor distributions. Secular trends appear to modify age-related trajectories of cardiovascular risk factors, which may be a source of bias in longitudinal analyses.

Association of lifecourse socioeconomic status with chronic inflammation and type 2 diabetes risk: the Whitehall II prospective cohort study.

BACKGROUND: Socioeconomic adversity in early life has been hypothesized to "program" a vulnerable phenotype with exaggerated inflammatory responses, so increasing the risk of developing type 2 diabetes in adulthood. The aim of this study is to test this hypothesis by assessing the extent to which the association between lifecourse socioeconomic status and type 2 diabetes incidence is explained by chronic inflammation. METHODS AND FINDINGS: We use data from the British Whitehall II study, a prospective occupational cohort of adults established in 1985. The inflammatory markers C-reactive protein and interleukin-6 were measured repeatedly and type 2 diabetes incidence (new cases) was monitored over an 18-year follow-up (from 1991-1993 until 2007-2009). Our analytical sample consisted of 6,387 non-diabetic participants (1,818 women), of whom 731 (207 women) developed type 2 diabetes over the follow-up. Cumulative exposure to low socioeconomic status from childhood to middle age was associated with an increased risk of developing type 2 diabetes in adulthood (hazard ratio [HR] = 1.96, 95% confidence interval: 1.48-2.58 for low cumulative lifecourse socioeconomic score and HR = 1.55, 95% confidence interval: 1.26-1.91 for low-low socioeconomic trajectory). 25% of the excess risk associated with cumulative socioeconomic adversity across the lifecourse and 32% of the excess risk associated with low-low socioeconomic trajectory was attributable to chronically elevated inflammation (95% confidence intervals 16%-58%). CONCLUSIONS: In the present study, chronic inflammation explained a substantial part of the association between lifecourse socioeconomic disadvantage and type 2 diabetes. Further studies should be performed to confirm these findings in population-based samples, as the Whitehall II cohort is not representative of the general population, and to examine the extent to which social inequalities attributable to chronic inflammation are reversible.

Influence of local exposure to static magnetic field on pain perception and bone turnover of osteoporotic patients with vertebral deformity - a randomized controlled trial.

PURPOSE: Static magnetic field (SMF) could improve pain sensation and bone turnover. In a single-center randomized double-blind placebo-controlled study we investigated the effects of SMF exposure on subjective pain and bone turnover. MATERIALS AND METHODS: Postmenopausal osteoporotic women (aged 50-70 years) with bone deformity and back pain were randomized to 10 weekly visits of 30-min SMF (n = 6) or treatment with non-magnetized pads (n = 5) on the back. Primary and secondary outcomes were changes in pain sensation on a visual analogue scale (VAS) during each visit and over 10 weeks, respectively. Tertiary outcomes were changes in osteocalcin and ß-crosslaps. SMF was inhomogeneous with 192 millitesla peak-to-peak value by 19 tesla/meter gradient of the magnetic flux density at 3 mm. RESULTS: Participants randomized to sham had higher VAS at baseline (mean difference: 2.8, 95% confidence interval (CI) 0.47-5.2 cm). Both SMF and sham similarly reduced short term pain (sham-SMF: 0.59, 95% CI - 0.31-1.49 cm, p = 0.195). VAS did not change in SMF, while it decreased in the sham group (between-group difference 0.27, 95% CI 0.04-0.50 cm/visit). Bone turnover markers remained stable. CONCLUSIONS: SMF as used in this investigation is not recommended for pain relief in postmenopausal women with vertebral deformity. The finding on long-term pain relief may relate to unbalanced randomization.

Does overall diet in midlife predict future aging phenotypes? A cohort study.

BACKGROUND: The impact of diet on specific age-related diseases has been studied extensively, but few investigations have adopted a more holistic approach to determine the association of diet with overall health at older ages. We examined whether diet, assessed in midlife, using dietary patterns and adherence to the Alternative Healthy Eating Index (AHEI), is associated with aging phenotypes, identified after a mean 16-year follow-up. METHODS: Data were drawn from the Whitehall II cohort study of 5350 adults (age 51.3±5.3 years, 29.4% women). Diet was assessed at baseline (1991-1993). Mortality, chronic diseases, and functioning were ascertained from hospital data, register linkage, and screenings every 5 years and were used to create 5 outcomes at follow-up: ideal aging (free of chronic conditions and high performance in physical, mental, and cognitive functioning tests; 4%), nonfatal cardiovascular event (12.7%), cardiovascular death (2.8%), noncardiovascular death (7.3%), [corrected] and normal aging (73.2%). RESULTS: Low adherence to the AHEI was associated with an increased risk of cardiovascular and noncardiovascular death. In addition, participants with a "Western-type" diet (characterized by high intakes of fried and sweet food, processed food and red meat, refined grains, and high-fat dairy products) had lower odds of ideal aging (odds ratio for top vs bottom tertile: 0.58; 95% confidence interval, 0.36-0.94; P=.02), independently of other health behaviors. CONCLUSIONS: By considering healthy aging as a composite of cardiovascular, metabolic, musculoskeletal, respiratory, mental, and cognitive function, the present study offers a new perspective on the impact of diet on aging phenotypes.

Contribution of modifiable risk factors to social inequalities in type 2 diabetes: prospective Whitehall II cohort study.

OBJECTIVE: To assess the contribution of modifiable risk factors to social inequalities in the incidence of type 2 diabetes when these factors are measured at study baseline or repeatedly over follow-up and when long term exposure is accounted for. DESIGN: Prospective cohort study with risk factors (health behaviours (smoking, alcohol consumption, diet, and physical activity), body mass index, and biological risk markers (systolic blood pressure, triglycerides and high density lipoprotein cholesterol)) measured four times and diabetes status assessed seven times between 1991-93 and 2007-09. SETTING: Civil service departments in London (Whitehall II study). PARTICIPANTS: 7237 adults without diabetes (mean age 49.4 years; 2196 women). MAIN OUTCOME MEASURES: Incidence of type 2 diabetes and contribution of risk factors to its association with socioeconomic status. RESULTS: Over a mean follow-up of 14.2 years, 818 incident cases of diabetes were identified. Participants in the lowest occupational category had a 1.86-fold (hazard ratio 1.86, 95% confidence interval 1.48 to 2.32) greater risk of developing diabetes relative to those in the highest occupational category. Health behaviours and body mass index explained 33% (-1% to 78%) of this socioeconomic differential when risk factors were assessed at study baseline (attenuation of hazard ratio from 1.86 to 1.51), 36% (22% to 66%) when they were assessed repeatedly over the follow-up (attenuated hazard ratio 1.48), and 45% (28% to 75%) when long term exposure over the follow-up was accounted for (attenuated hazard ratio 1.41). With additional adjustment for biological risk markers, a total of 53% (29% to 88%) of the socioeconomic differential was explained (attenuated hazard ratio 1.35, 1.05 to 1.72). CONCLUSIONS: Modifiable risk factors such as health behaviours and obesity, when measured repeatedly over time, explain almost half of the social inequalities in incidence of type 2 diabetes. This is more than was seen in previous studies based on single measurement of risk factors.

Physical activity and inflammatory markers over 10 years: follow-up in men and women from the Whitehall II cohort study.

BACKGROUND: Inflammatory processes are putative mechanisms underlying the cardioprotective effects of physical activity. An inverse association between physical activity and inflammation has been demonstrated, but no long-term prospective data are available. We therefore examined the association between physical activity and inflammatory markers over a 10-year follow-up period. METHODS AND RESULTS: Participants were 4289 men and women (mean age, 49.2 years) from the Whitehall II cohort study. Self-reported physical activity and inflammatory markers (serum high-sensitivity C-reactive protein and interleukin-6) were measured at baseline (1991) and follow-up (2002). Forty-nine percent of the participants adhered to standard physical activity recommendations for cardiovascular health (2.5 h/wk moderate to vigorous physical activity) across all assessments. Physically active participants at baseline had lower C-reactive protein and interleukin-6 levels, and this difference remained stable over time. Compared with participants who rarely adhered to physical activity guidelines over the 10-year follow-up, the high-adherence group displayed lower log(e) C-reactive protein (ß=-0.07; 95% confidence interval, -0.12 to -0.02) and log(e) interleukin-6 (ß=-0.07; 95% confidence interval, -0.10 to -0.03) at follow-up after adjustment for a range of covariates. Compared with participants who remained stable, those who reported an increase in physical activity of at least 2.5 h/wk displayed lower log(e) C-reactive protein (ß coefficient=-0.05; 95% confidence interval, -0.10 to -0.001) and log(e) interleukin-6 (ß coefficient=-0.06; 95% confidence interval, -0.09 to -0.03) at follow-up. CONCLUSIONS: Regular physical activity is associated with lower markers of inflammation over 10 years of follow-up and thus may be important in preventing the proinflammatory state seen with aging.