Abstract: BACKGROUND: Raised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. We estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher. METHODS: For this analysis, we pooled national, subnational, or community population-based studies that had measured blood pressure in adults aged 18 years and older. We used a Bayesian hierarchical model to estimate trends from 1975 to 2015 in mean systolic and mean diastolic blood pressure, and the prevalence of raised blood pressure for 200 countries. We calculated the contributions of changes in prevalence versus population growth and ageing to the increase in the number of adults with raised blood pressure. FINDINGS: We pooled 1479 studies that had measured the blood pressures of 19.1 million adults. Global age-standardised mean systolic blood pressure in 2015 was 127.0 mm Hg (95% credible interval 125.7-128.3) in men and 122.3 mm Hg (121.0-123.6) in women; age-standardised mean diastolic blood pressure was 78.7 mm Hg (77.9-79.5) for men and 76.7 mm Hg (75.9-77.6) for women. Global age-standardised prevalence of raised blood pressure was 24.1% (21.4-27.1) in men and 20.1% (17.8-22.5) in women in 2015. Mean systolic and mean diastolic blood pressure decreased substantially from 1975 to 2015 in high-income western and Asia Pacific countries, moving these countries from having some of the highest worldwide blood pressure in 1975 to the lowest in 2015. Mean blood pressure also decreased in women in central and eastern Europe, Latin America and the Caribbean, and, more recently, central Asia, Middle East, and north Africa, but the estimated trends in these super-regions had larger uncertainty than in high-income super-regions. By contrast, mean blood pressure might have increased in east and southeast Asia, south Asia, Oceania, and sub-Saharan Africa. In 2015, central and eastern Europe, sub-Saharan Africa, and south Asia had the highest blood pressure levels. Prevalence of raised blood pressure decreased in high-income and some middle-income countries; it remained unchanged elsewhere. The number of adults with raised blood pressure increased from 594 million in 1975 to 1.13 billion in 2015, with the increase largely in low-income and middle-income countries. The global increase in the number of adults with raised blood pressure is a net effect of increase due to population growth and ageing, and decrease due to declining age-specific prevalence. INTERPRETATION: During the past four decades, the highest worldwide blood pressure levels have shifted from high-income countries to low-income countries in south Asia and sub-Saharan Africa due to opposite trends, while blood pressure has been persistently high in central and eastern Europe. FUNDING: Wellcome Trust.

Abstract: Women with hypertensive disorders in pregnancy are at increased lifetime risk for cardiovascular disease. We examined the offspring's cardiovascular risk profile in young adulthood and their siblings' cardiovascular risk profile. From the HUNT study (Nord-Trondelag Health Study) in Norway, 15 778 participants (mean age: 29 years), including 210 sibling groups, were linked to information from the Medical Birth Registry of Norway. Blood pressure, anthropometry, serum lipids, and C-reactive protein were assessed. Seven hundred and six participants were born after exposure to maternal hypertension in pregnancy: 336 mothers had gestational hypertension, 343 had term preeclampsia, and 27 had preterm preeclampsia. Offspring whose mothers had hypertension in pregnancy had 2.7 (95% confidence interval, 1.8-3.5) mm Hg higher systolic blood pressure, 1.5 (0.9-2.1) mm Hg higher diastolic blood pressure, 0.66 (0.31-1.01) kg/m2 higher body mass index, and 1.49 (0.65-2.33) cm wider waist circumference, compared with offspring of normotensive pregnancies. Similar differences were observed for gestational hypertension and term preeclampsia. Term preeclampsia was also associated with higher concentrations of non-high-density lipoprotein cholesterol (0.14 mmol/L, 0.03-0.25) and triglycerides (0.13 mmol/L, 0.06-0.21). Siblings born after a normotensive pregnancy had nearly identical risk factor levels as siblings born after maternal hypertension. Offspring born after maternal hypertension in pregnancy have a more adverse cardiovascular risk profile in young adulthood than offspring of normotensive pregnancies. Their siblings, born after a normotensive pregnancy, have a similar risk profile, suggesting that shared genes or lifestyle may account for the association, rather than an intrauterine effect. All children of mothers who have experienced hypertension in pregnancy may be at increased lifetime risk of cardiovascular disease.

Abstract: BACKGROUND: When s-iron and s-transferrin are used to diagnose empty iron stores, the measurements are usually combined in the calculation of s-transferrin saturation. This may not be the best way to utilize the information in s-iron and s-transferrin, as s-transferrin alone has a better diagnostic accuracy than s-transferrin saturation. We suggest that unbound iron binding capacity (UIBC), which is s-total iron binding capacity (2 times s-transferrin) minus s-iron could be used for diagnosing empty iron stores. METHODS: To test this hypothesis, we used ROC curve analysis to compare the diagnostic accuracy of s-iron, s-transferrin, s-transferrin saturation and s-UIBC in diagnosing empty iron stores in 3029 women of childbearing age. Empty iron stores were defined as s-ferritin less than 10 mug/L or less than 15 mug/L. RESULTS: At both definitions of empty iron stores s-UIBC had a better diagnostic accuracy than the other tests, with area under the ROC curve of 0.80-0.87. This was also the trend in a subpopulation of 172 anemic women, where the area under the ROC curve of s-UIBC was 0.92. CONCLUSION: When diagnosing empty iron stores calculation of s-UIBC is a better way to utilize the information in s-iron and s-transferrin than is calculation of s-transferrin saturation.

Abstract: Earlier studies have shown evidence for various sources of observed spousal similarity regarding different traits and characteristics. We explored the relative contribution of non-random mating and convergence to spouse similarity with respect to global mental health, life satisfaction, optimism, and type A personality. We used population-based data collected for the Nord-Trondelag Health Study (1984-1986) and prospective registry information about when and with whom people entered into marriage/cohabitation between 1970 and 2000 for 19,599 married/cohabitating couples and 1,551 future couples that entered into marriage/cohabitation during the 16 years after data collection. Couples were categorized by interval between data collection and entry into marriage/cohabitation. Age-adjusted polychoric correlations calculated for each group were used as the dependent variables in non-linear, segmented regression analysis, with time since or until marriage/cohabitation as the independent variable. Initial correlations between partners-to-be were low to moderate, typically around one-half of the values estimated in existing couples, indicating both non-random mating and early convergence. There appeared to be moderate divergence during the first 20 years of marriage/cohabitation and moderate convergence during the rest of life.

Abstract: OBJECTIVE: In a mortality follow-up of the HUNT Study, serum TSH within the reference range was positively associated with the risk of coronary death in women. We now aimed to confirm the association of high serum TSH with the risk of coronary heart disease, using hospital-based diagnoses of myocardial infarction. DESIGN: Prospective population-based study with linkage to hospital information on myocardial infarction and to the national Cause of Death Registry. PARTICIPANTS: A total of 26, 707 people without previously known thyroid or cardiovascular disease or diabetes at baseline. MEASUREMENTS: Hazard ratios (HR) of coronary death and HRs of hospitalization with a first-time acute myocardial infarction, by baseline thyroid function. RESULTS: During 12, years of follow-up, 960 (3.6%) participants had been hospitalized with first-time myocardial infarction and 558 (2.1%) had died from coronary heart disease. High TSH within the reference range was associated with increased risk of coronary death in women (P(trend) 0.005), but not in men. The risk of coronary death was also increased among women with subclinical hypothyroidism or subclinical hyperthyroidism, compared to women with TSH of 0.50-1.4 mU/l. However, thyroid function was not associated with the risk of being hospitalized with myocardial infarction. CONCLUSIONS: High serum TSH was associated with increased mortality from coronary heart disease in women, but we found no association of thyroid function with the risk of being hospitalized with myocardial infarction. Thus, the morbidity finding does not confirm the suggestion that low thyroid function within the clinically normal range is associated with increased risk of coronary heart disease.

Abstract: CONTEXT: Serum TSH in the upper part of the reference range may sometimes be a response to autoimmune thyroiditis in early stage and may therefore predict future hypothyroidism. Conversely, relatively low serum TSH could predict future hyperthyroidism. OBJECTIVE: The objective of the study was to assess TSH within the reference range and subsequent risk of hypothyroidism and hyperthyroidism. DESIGN AND SETTING: This was a prospective population-based study with linkage to the Norwegian Prescription Database. SUBJECTS: A total of 10,083 women and 5,023 men without previous thyroid disease who had a baseline TSH of 0.20-4.5 mU/liter and who participated at a follow-up examination 11 yr later. MAIN OUTCOME MEASURES: Predicted probabilities of developing hypothyroidism or hyperthyroidism during follow-up, by categories of baseline TSH, were estimated. RESULTS: During 11 yr of follow-up, 3.5% of women and 1.3% of men developed hypothyroidism, and 1.1% of women and 0.6% of men developed hyperthyroidism. In both sexes, the baseline TSH was positively associated with the risk of subsequent hypothyroidism. The risk increased gradually from TSH of 0.50-1.4 mU/liter [women, 1.1%, 95% confidence interval (CI) 0.8-1.4; men, 0.3%, 95% CI 0.1-0.6] to a TSH of 4.0-4.5 mU/liter (women, 31.5%, 95% CI 24.6-39.3; men, 14.7%, 95% CI 7.7-26.2). The risk of hyperthyroidism was higher in women with a baseline TSH of 0.20-0.49 mU/liter (3.9%, 95% CI 1.8-8.4) than in women with a TSH of 0.50-0.99 mU/liter (1.4%, 95% CI 0.9-2.1) or higher ( approximately 1.0%). CONCLUSION: TSH within the reference range is positively and strongly associated with the risk of future hypothyroidism. TSH at the lower limit of the reference range may be associated with an increased risk of hyperthyroidism.

Abstract: BACKGROUND: Earlier studies have revealed a high prevalence of dementia among nursing home patients. We conducted a descriptive study of dementia and neuropsychiatric symptoms among patients in nursing homes in Nord-Trondelag County, Norway. MATERIAL AND METHODS: 704 nursing home patients were included and studied with the Norwegian versions of the clinical demential rating scale (CDR) and the neuropsychiatric inventory (NPI). RESULTS: The study indicated that 575 patients (82%) had dementia. Of these, 430 patients (75%) had at least one clinically significant neuropsychiatric syndrome in addition, most commonly delusions, apathy or irritability. The neuropsychiatric symptoms could be grouped in four categories: psychosis, apathy, affective symptoms and agitation. INTERPRETATION: The findings are comparable with earlier studies of Norwegian nursing home patients. The high prevalence of dementia and neuropsychiatric symptoms is of significance for the clinical practice, running and planning of nursing homes.

Abstract: BACKGROUND: COPD is a major cause of morbidity and mortality across the world and new estimates of prevalence and trend are of great importance. We aimed to estimate the prevalence and trend of COPD from 1995-1997 to 2006-2008 in Norwegian adults >/=40 years from the Nord-Trondelag Health Study. MATERIAL AND METHODS: COPD was assessed using a fixed-ratio and lower limit of normal (LLN) criteria. Pre-bronchodilator spirometry was performed during 1995-1997 (n=7158) and 2006-2008 (n=8788). The prevalence of COPD was weighted using the inverse probability of selection and predicted probability of response. RESULTS: The prevalence of pre-bronchodilator COPD was 16.7% in 1995-1997 and 14.8% in 2006-2008 using fixed-ratio criteria, and 10.4% in 1995-1997 and 7.3% in 2006-2008 using LLN criteria. The prevalence of LLN COPD was higher among men (13.0% in 1995-1997, 7.7% in 2006-2008) than women (8.0% in 1995-1997, 6.9% in 2006-2008). From 1995-1997 to 2006-2008, the prevalence decreased among men but remained relatively stable among women. Over the 11-year period, the cumulative incidence of pre-bronchodilator COPD using LLN criteria was 3.3% and 2.7% among men and women respectively. The prevalence of self-reported asthma and respiratory symptoms increased. CONCLUSIONS: The prevalence declined in men but not in women from 1995-1997 to 2006-2008, and was consistently higher among men than women.

Abstract: BACKGROUND: Our aim was to assess the influence of age, gender and lifestyle factors on the effect of the obesity-promoting alleles of FTO and MCR4. METHODS: The HUNT study comprises health information on the population of Nord-Trondelag county, Norway. Extreme phenotype participants (gender-wise lower and upper quartiles of waist-hip-ratio and BMI >/= 35 kg/m2) in the third survey, HUNT3 (2006-08), were genotyped for the single-nucleotide polymorphisms rs9939609 (FTO) and rs17782313 (MC4R); 25686 participants were successfully genotyped. Extreme sampling was chosen to increase power to detect genetic and gene-environment effects on waist-hip-ratio and BMI. Statistical inference was based on linear regression models and a missing-covariate likelihood approach for the extreme phenotype sampling design. Environmental factors were physical activity, diet (artificially sweetened beverages) and smoking. Longitudinal analysis was performed using material from HUNT2 (1995-97). RESULTS: Cross-sectional and longitudinal genetic effects indicated stronger genetic associations with obesity in young than in old, as well as differences between women and men. We observed larger genetic effects among physically inactive compared to active individuals. This interaction was age-dependent and seen mainly in 20-40 year olds. We observed a greater FTO effect among men with a regular intake of artificially sweetened beverages, compared to non-drinkers. Interaction analysis of smoking was mainly inconclusive. CONCLUSIONS: In a large all-adult and area-based population survey the effects of obesity-promoting minor-alleles of FTO and MCR4, and interactions with life style factors are age- and gender-related. These findings appear relevant when designing individualized treatment for and prophylaxis against obesity.

Abstract: BACKGROUND: There is little knowledge about how factors early in life affect the development of migraine and tension-type headache. We aimed to examine whether growth restriction in utero is associated with development of migraine and frequent tension-type headache in adults. METHODS: The population-based Nord-Trondelag Health Study (HUNT 3) contained a validated headache questionnaire, which differentiated between migraine and tension-type headache. These data were linked to information on weight and gestational age at birth from the Norwegian Medical Birth Registry. In total 4557 females and 2789 males, aged 19-41 years, were included in this registry-based study. Participants were categorized as appropriate for gestational age (AGA, 10th-90th percentile), small for gestational age (SGA, 3rd-10th percentile) or very small for gestational age (VSGA, < 3rd percentile). Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for migraine and tension-type headache, with exposure being growth restriction at birth. RESULTS: The effect of growth restriction on migraine was modified by sex, with a significant association in males (p<0.001), but not in females (p = 0.20). In particular, males born VSGA were at increased risk of developing migraine (OR 2.73, 95% CI 1.63-4.58, p<0.001), with an intermediate risk among those born SGA (OR 1.50, 95% CI 0.96-2.35, p = 0.08) compared to those born AGA. There was no significant association between growth restriction and frequent TTH (p = 0.051). CONCLUSION: Growth restriction was associated with increased risk of migraine in adulthood among males, but not among females. This suggests that migraine might, in part, be influenced by early life events, and that males seem to be particularly vulnerable.

Abstract: BACKGROUND AND OBJECTIVE: People with asthma may seek advice about physical activity. However, the benefits of leisure time physical activity on lung function are unclear. We investigated the association between leisure time physical activity and lung function decline in adults with asthma. METHODS: In a population-based cohort study in Norway, we used multiple linear regressions to estimate the annual mean decline in lung function (and 95% CI) in 1329 people with asthma over a mean follow-up of 11.6 years. The durations of light and hard physical activity per week in the last year were collected by questionnaire. Inactive participants did not report any light or hard activity, while active participants reported light or hard activity. RESULTS: The mean decline in forced expiratory volume in 1 s (FEV1 ) was 37 mL/year among inactive participants and 32 mL/year in active participants (difference: -5 mL/year (95% CI: -13 to 3)). The mean decline in forced vital capacity (FVC) was 33 mL/year among inactive participants and 31 mL/year in active participants (difference: -2 mL/year (95% CI: -11 to 7)). The mean decline in FEV1 /FVC ratio was 0.36%/year among inactive participants and 0.22%/year in active participants (difference: -0.14%/year (95% CI: -0.27 to -0.01)). The mean decline in peak expiratory flow (PEF) was 14 mL/year among the inactive participants and 10 mL/year in active participants (difference: -4 mL/year (95% CI: -9 to 1)). CONCLUSION: We observed slightly less decline in lung function in physically active than inactive participants with asthma, particularly for FEV1 , FEV1 /FVC ratio and PEF.

Abstract: AIMS: To examine the associations of self-reported visual impairment and physical activity (PA) with all-cause mortality. METHODS: This prospective cohort study included 65,236 Norwegians aged 20 years who had participated in the Nord-Trondelag Health Study (HUNT2, 1995-1997). Of these participants, 11,074 (17.0%) had self-reported visual impairment (SRVI). The participants' data were linked to Norway's Cause of Death Registry and followed throughout 2012. Hazard ratios and 95% confidence intervals (CI) were assessed using Cox regression analyses with age as the time-scale. The Cox models were fitted for restricted age groups (<60, 60-84, 85 years). RESULTS: After a mean follow-up of 14.5 years, 13,549 deaths were identified. Compared with adults with self-reported no visual impairment, the multivariable hazard ratios among adults with SRVI were 2.47 (95% CI 1.94-3.13) in those aged <60 years, 1.22 (95% CI 1.13-1.33) in those aged 60-84 years and 1.05 (95% CI 0.96-1.15) in those aged 85 years. The strength of the associations remained similar or stronger after additionally controlling for PA. When examining the joint associations, the all-cause mortality risk of SRVI was higher for those who reported no PA than for those who reported weekly hours of PA. We found a large, positive departure from additivity in adults aged <60 years, whereas the departure from additivity was small for the other age groups. CONCLUSIONS: Adults with SRVI reporting no PA were associated with an increased all-cause mortality risk. The associations attenuated with age.

Abstract: Aerobic fitness, measured as maximal oxygen uptake (VO2max), is a good indicator of cardiovascular health, and a strong predictor of cardiovascular mortality. Biomarkers associated with low VO2max may therefore represent potential early markers of future cardiovascular disease (CVD). The aim of this study was to assess whether circulating microRNAs (miRs) are associated with VO2max-level in healthy individuals. In a screening study, 720 miRs were measured in serum samples from healthy individuals (40-45 yrs) with high (n = 12) or low (n = 12) VO2max matched for gender, age and physical activity. Candiate miRs were validated in a second cohort of subjects with high (n = 38) or low (n = 38) VO2max. miR-210 and miR-222 were found to be higher in the low VO2max-group (p<0.05). In addition, miR-21 was increased in male participants with low VO2max (p<0.05). There were no correlations between traditional risk factors for CVD (blood pressure, cholesterol, smoking habit, or obesity) and miR-21, miR-210 and miR-222. DIANA-mirPath identified 611 potential gene-targets of miR-21, miR-210 and miR-222, and pathway analysis indicated alterations in several important signaling systems in subjects with low VO2max. Potential bias involve that blood was collected from non-fasting individuals, and that 8 performed exercise within 24 h before sampling. In conclusion, we found that miR-210, miR-21, and miR-222 were increased in healthy subjects with low VO2max. The lack of association between these three miRs, and other fitness related variables as well as traditional CVD risk factors, suggests that these miRs may have a potential as new independent biomarkers of fitness level and future CVD.