Abstract: BACKGROUND: An association between psoriasis and osteoporosis has been reported. OBJECTIVES: To investigate, in a large prospective population-based Norwegian study, whether psoriasis is associated with increased risk of forearm or hip fracture; to investigate the cross-sectional association between psoriasis and bone mineral density (BMD) T-score in a subpopulation. METHODS: Hospital-derived fracture data from Nord-Trondelag County (1995-2013) were linked to psoriasis information, BMD measurements and lifestyle factors from the third survey of the Nord-Trondelag Health Study 2006-08 (HUNT3); socioeconomic data from the National Education Database; and use of medication from the Norwegian Prescription Database. RESULTS: Among 48 194 participants in HUNT3, we found no increased risk of forearm or hip fracture in 2804 patients with self-reported psoriasis [overall age- and sex-adjusted hazard ratio 1.03, 95% confidence interval (CI) 0.82-1.31]. No clear association was found between psoriasis and mean BMD T-score; overall age- and sex-adjusted differences in total hip, femoral neck and lumbar spine BMD T-scores were 0.02 (95% CI -0.11 to 0.14), 0.05 (95% CI -0.06 to 0.17) and 0.07 (95% CI -0.09 to 0.24), respectively. No clear association was found between psoriasis and prevalent osteoporosis in either total hip, femoral neck or lumbar spine; overall age- and sex-adjusted odds ratio was 0.77 (95% CI 0.54-1.10). Associations did not change substantially after adjustment for education, smoking, systemic steroid use and body mass index. CONCLUSIONS: We found no association between psoriasis and risk of fracture. The study did not indicate reduced BMD T-score or higher prevalence of osteoporosis among patients with psoriasis.

Abstract: BACKGROUND: Recommendations on interpreting tests of bronchodilator responsiveness (BDR) are conflicting. We investigated the dependence of BDR criteria on sex, age, height, ethnicity, and severity of respiratory impairment. METHODS: BDR test data were available from clinical patients in the Netherlands, New Zealand, and the United States (n = 15,278; female subjects, 51.7%) and from surveys in Canada, Norway, and five Latin-American countries (n = 16,250; female subjects, 54.7%). BDR calculated according to FEV1, FVC, and FEV1/FVC was expressed as absolute change, a percentage of the baseline level (% baseline), a percentage of the predicted value (% predicted), and z score. RESULTS: Change (Delta) in FEV1 and FVC, in milliliters, was unrelated to the baseline value but was biased toward age, height, sex, and level of airways obstruction; DeltaFEV1 was significantly lower in African Americans. In 1,106 subjects with low FEV1 (200-1,621 mL) the FEV1 increased by 12% to 44.7% relative to baseline but < 200 mL. Expressing BDR as a percentage of the predicted value or as a z score attenuated the bias and made the 200-mL criterion redundant, but reduced positive responses by half. DeltaFEV1 % baseline increased with the level of airflow obstruction but decreased with severe obstruction when expressed as z scores or % predicted; DeltaFVC, however expressed, increased with the level of airflow obstruction. CONCLUSIONS: Expressing FEV1 responsiveness as % baseline spuriously suggests that responsiveness increases with the severity of respiratory impairment. Expressing change in FEV1 or FVC as % predicted or as z scores eliminates this artifact and renders the required 200-mL minimum increase redundant. In severe airways obstruction DeltaFVC should be critically evaluated as an index of clinically important relief of hyperinflation, with implications for bronchodilator drug trials.

Abstract: Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.

Abstract: OBJECTIVES/HYPOTHESIS: To study the prevalence and usefulness of audiometric notches in the diagnosis of noise-induced hearing loss (NIHL). STUDY DESIGN: Audiograms and data on noise exposure from 23,297 men and 26,477 women, aged 20 to 101 years, from the Nord-Trondelag Hearing Loss Study, 1996-1998. METHODS: The prevalence of four types of audiometric notches (Coles, Hoffman, Wilson) and 4 kHz notch were computed in relation to occupational noise exposure, age, sex, and report of recurrent ear infections. RESULTS: The prevalence of notches in the 3 to 6 kHz range (Wilson, Hoffman, and Coles) ranged from 50% to 60% in subjects without occupational noise exposure, and 60% to 70% in the most occupationally noise-exposed men. The differences were statistically significant only for bilateral notches. For 4 kHz notches, the prevalence varied from 25% in occupationally nonexposed to 35% in the most occupationally exposed men, and the differences were statistically significant for both bilateral and unilateral notches. For women, the prevalence of notches was lower than in men, especially for 4 kHz notches, and the differences between occupationally noise exposed and nonexposed were smaller. Recreational exposure to high music was not associated with notched audiograms. CONCLUSIONS: The detection of bilateral notches and unilateral 4 kHz notches is of some value in diagnosing NIHL, especially in men. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:1442-1450, 2017.

Abstract: OBJECTIVE: To assess the predictive value of estimated cardiorespiratory fitness (eCRF) and evaluate the additional contribution of traditional risk factors in cardiovascular disease (CVD) mortality prediction. PARTICIPANTS AND METHODS: The study included healthy men (n=18,721) and women (n=19,759) aged 30 to 74 years. A nonexercise algorithm estimated cardiorespiratory fitness. Cox proportional hazards models evaluated the primary (CVD mortality) and secondary (all-cause, ischemic heart disease, and stroke mortality) end points. The added predictive value of traditional CVD risk factors was evaluated using the Harrell C statistic and net reclassification improvement. RESULTS: After a median follow-up of 16.3 years (range, 0.04-17.4 years), there were 3863 deaths, including 1133 deaths from CVD (734 men and 399 women). Low eCRF was a strong predictor of CVD and all-cause mortality after adjusting for established risk factors. The C statistics for eCRF and CVD mortality were 0.848 (95% CI, 0.836-0.861) and 0.878 (95% CI, 0.862-0.894) for men and women, respectively, increasing to 0.851 (95% CI, 0.839-0.863) and 0.881 (95% CI, 0.865-0.897), respectively, when adding clinical variables. By adding clinical variables to eCRF, the net reclassification improvement of CVD mortality was 0.014 (95% CI, -0.023 to 0.051) and 0.052 (95% CI, -0.023 to 0.127) in men and women, respectively. CONCLUSION: Low eCRF is independently associated with CVD and all-cause mortality. The inclusion of traditional clinical CVD risk factors added little to risk discrimination and did not improve the classification of risk beyond this simple eCRF measurement, which may be proposed as a practical and cost-effective first-line approach in primary prevention settings.

Abstract: As possible markers of biological age, telomere length (TL) has been associated with age-related diseases such as myocardial infarction (MI) with conflicting findings. We sought to assess the relationship between TL and risk of future MI in 915 healthy participants (51.7% women) 65 years or older from a population-based prospective cohort (the HUNT 2 study, Norway). Mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio, and log-transformed. During a mean follow up of 13.0 (SD, 3.2) years and 11,923 person-years, 82 participants were diagnosed with MI. We used Cox proportional hazard regressions to estimate hazard ratios (HR) and 95% confidence interval (CI). Relative TL was associated with age in women (P=0.01), but not in men (P=0.43). Using relative TL as a continuous variable, we observed a higher risk of MI in participants with longer telomeres with HRs of 2.46 (95% CI; 1.13 to 4.54) in men, and 2.93 (95% CI; 1.41 to 6.10) in women. Each 1-SD change in relative TL was associated with an HR of 1.54 (95% CI; 1.15 to 2.06) and 1.67 (95% CI; 1.18 to 2.37) in men and women, respectively. Compared with the bottom tertile of relative TL, HR of incident MI in top tertile was 2.71 (95% CI; 1.25 to 5.89) in men, and 3.65 (95% CI; 1.35 to 9.90) in women. Longer telomeres in healthy participants 65 years or older are associated with a high risk of incident MI. Future large scale prospective studies are needed to confirm these findings and explore the potential association between TL and MI.

Abstract: OBJECTIVE: The association of insomnia with subsequent breast cancer risk is largely unknown. Therefore, we assessed whether different symptoms of insomnia and their combination are associated with incident breast cancer in a large population-based study. METHODS: In a prospective cohort study, 33,332 women were followed to monitor the occurrence of their first invasive breast cancer identified by the Cancer Registry of Norway. Insomnia symptoms including () nonrestorative sleep and () difficulty initiating and () maintaining sleep were self-reported using a study specific measure reflecting the current Diagnostic and Statistical Manual of Mental Disorders criteria. Hazard ratios and 95% confidence intervals were calculated using multiadjusted Cox proportional hazards models. RESULTS: A total of 862 incident breast cancer cases occurred during a mean follow-up of 14.7 years. No consistent association was observed between the individual insomnia symptoms and breast cancer risk. However, compared to women reporting no insomnia complaints, those who reported having all three aspects of insomnia simultaneously were at increased risk (hazard ratio, 2.38; 95% confidence interval = 1.11-5.09). CONCLUSION: Our results suggest that having only some aspects of insomnia may not predispose someone to breast cancer. In contrast, experiencing all insomnia symptoms simultaneously might confer considerable excess risk.

Abstract: OBJECTIVE: Tobacco smoking is a risk factor for gastroesophageal reflux, but whether other tobacco products increase the risk is unclear. The aim of this study was to investigate if snus increases the risk of gastroesophageal reflux symptoms (GERS). MATERIAL AND METHODS: The study was based on the third Nord-Trondelag health study (HUNT3), a population-based study of all adult residents in Nord-Trondelag County, Norway, performed in 2006-2009. The association between self-reported severe heartburn/regurgitation and snus use was assessed by logistic regression. RESULTS: Compared to never snus users, daily snus users had a reduced risk of GERS (OR 0.77, 95% confidence interval [CI] 0.64-0.93), while previous snus users and those using <2 boxes of snus/month had an increased risk (OR 1.20, 95% CI 1.00-1.46 and OR 1.41, 95% CI 1.02-1.96, respectively). There was no association between age when starting using snus and GERS. Snus users who started using snus to quit or cut down on cigarette smoking, who started using both snus and cigarettes or cigarettes alone had an increased risk of GERS. Snus users <30 years of age had an increased risk of GERS (OR 1.49, 95% CI 1.02-2.16), while those aged between 50-60 and 60-70 years had a reduced risk (OR 0.67, 95% CI 0.49-0.93 and OR 0.51, 95% CI 0.28-0.94, respectively). CONCLUSIONS: Daily snus users had a reduced risk of GERS. However, previous snus users and subgroups of snus users had an increased risk of GERS indicating reverse causality, such that snus use could increase the risk of GERS.

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: OBJECTIVE: Depression is strongly linked to increased mortality in individuals with type 2 diabetes. Despite high rates of co-occurring anxiety and depression, the risk of death associated with comorbid anxiety in individuals with type 2 diabetes is poorly understood. This study documented the excess mortality risk associated with symptoms of depression and/or anxiety comorbid with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using data for 64,177 Norwegian adults from the second wave of the Nord-Trondelag Health Study (HUNT2), with linkage to the Norwegian Causes of Death Registry, we assessed all-cause mortality from survey participation in 1995 through to 2013. We used Cox proportional hazards models to examine mortality risk over 18 years associated with type 2 diabetes status and the presence of comorbid affective symptoms at baseline. RESULTS: Three clear patterns emerged from our findings. First, mortality risk in individuals with diabetes increased in the presence of depression or anxiety, or both. Second, mortality risk was lowest for symptoms of anxiety, higher for comorbid depression-anxiety, and highest for depression. Lastly, excess mortality risk associated with depression and anxiety was observed in men with diabetes but not in women. The highest risk of death was observed in men with diabetes and symptoms of depression only (hazard ratio 3.47, 95% CI 1.96, 6.14). CONCLUSIONS: This study provides evidence that symptoms of anxiety affect mortality risk in individuals with type 2 diabetes independently of symptoms of depression, in addition to attenuating the relationship between depressive symptoms and mortality in these individuals.

Abstract: BACKGROUND: To compare associations of conventional risk factors with cardiovascular death within couples and in the population as a whole. METHODS: We analysed baseline data (1995-97) from the HUNT2 Study in Norway linked to the national Causes of Death Registry. We compared risk within couples using stratified Cox regression. RESULTS: During 914776 person-years, 3964 cardiovascular deaths occurred, and 1658 of the deaths occurred among 1494 couples. There were consistently stronger associations of serum lipids and blood pressure with cardiovascular mortality within couples compared to the population as a whole. For instance, for systolic blood pressure (per 20mmHg), the hazard ratio (HR) within couples was 1.28 (95% confidence interval: 1.17, 1.40) compared to 1.16 (1.12, 1.20) in the total population, and for diastolic pressure (per 10mmHg), the corresponding HRs were 1.16 (1.07, 1.26) and 1.11 (1.08, 1.13). Anthropometric factors (BMI, waist circumference, waist-hip ratio) as well as diabetes, smoking, physical activity, and education, showed nearly identical positive associations within couples and in the total population. CONCLUSIONS: Prospective population studies may tend to slightly underestimate associations of these factors with cardiovascular mortality.

Abstract: BACKGROUND: We hypothesized that circulating markers reflecting monocyte/macrophage and T cell activation are associated with increased risk of myocardial infarction (MI) in apparently healthy individuals. METHODS: Serum monocyte/macrophage and T cell activation markers soluble (s) CD163, sCD14, Gal3BP, sCD25 and sCD166 were analyzed by enzyme-immunoassay in a case-control study nested within the population-based HUNT2 cohort in Norway. Among 58,761 apparently healthy men and women followed a median 11.3years, 1587 incident MI cases were registered, and compared to 3959 age- and sex-matched controls. RESULTS: Higher serum sCD163 (Q4 vs. Q1 OR: 1.27, P-trend 0.002), sCD14 (Q4 vs. Q1 OR: 1.38, P-trend<0.001), and especially sCD25 (Q4 vs. Q1 OR: 1.45, P-trend<0.001), were associated with increased MI risk in the age-and sex adjusted models. However, after additional adjustment for cardiovascular risk factors these associations were strongly attenuated (Q4 vs Q1 ORs between 1.02 and 1.12, P-trends between 0.30 and 0.58). CONCLUSIONS: sCD163, sCD14 and sCD25 may reflect leukocyte activation and inflammatory mechanisms related to atherogenesis, but do not predict MI risk above and beyond conventional cardiovascular risk factors.