Lipid metabolism and functional somatic disorders in the general population. The DanFunD study.

OBJECTIVES: Earlier studies on the association between plasma lipid profiles and functional somatic disorders (FSD) are mainly small case control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study was to investigate the associations between various FSDs and plasma lipid profiles (total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides) in a large, unselected population. DESIGN: A cross-sectional general population-based study. SETTING: The Danish Study of Functional Somatic Disorders (DanFunD) conducted in 2011-2015 in 10 municipalities in the western part of greater Copenhagen, Denmark. PARTICIPANTS: A total of 8,608 men and women aged 18-76 years were included in the analyses. Various delimitations of FSD such as chronic fatigue, chronic widespread pain, irritable bowel, and bodily distress syndrome were measured using validated self-administrated questionnaires. Lipid parameters were measured from fasting plasma samples using colorimetric slide methods with Vitros 4600/5600 Ortho Clinical Diagnostics. OUTCOME MEASURES: Logistic regression analyses were used to calculate possible associations between plasma lipids and the various delimitations of FSD. Associations are presented by OR (95% CI) and shown in boxplots. RESULTS: We found a positive association between bodily distress syndrome and triglycerides and non-HDL cholesterol and a negative association with HDL-cholesterol, but no consistent association with total cholesterol. A similar pattern was observed for persons with chronic fatigue, and to some degree for persons with chronic widespread pain, whereas persons with irritable bowel did not show a clear association with the lipid profiles. CONCLUSION: This is the first major study on plasma lipid profiles and FSD indicating an association between some delimitations of FSD and an unfavorable lipid profile. Due to the cross-sectional design, it cannot be determined whether the findings are consequences or determinants of FSD. Further studies-preferable prospective studies-are needed.

Prospective relationship between occupational physical activity and risk of ischaemic heart disease: are men and women differently affected?

AIMS: High occupational physical activity (OPA) seems to increase risk of cardiovascular diseases among men. However, findings are mixed, and it is not known if women are differently affected. Therefore, the aim of this study is to investigate the relationship between OPA and risk for ischaemic heart disease (IHD), and whether it differs across sex. METHODS AND RESULTS: This prospective cohort study was based on 1399 women and 1706 men, aged 30-61 years, participating in the Danish Monica 1 study in 1982-84, actively employed, without prior IHD and answering an OPA question. The information on incidence of IHD, before and during the 34-years follow-up, was retrieved by individual linkage to the Danish National Patient Registry. Cox proportional hazards models were used to investigate the association between OPA and IHD. Compared to women with sedentary work, women in all other OPA categories had lower hazard ratio (HR) for IHD. Among men, the risk of IHD was 22% higher among those with light OPA, and 42% and 46% higher among those with moderate OPA with some lifting or strenuous work with heavy lifting, respectively, compared to men with sedentary OPA. Compared to women with sedentary work, HR for IHD was higher among men in all OPA categories. There was statistically significant interaction between OPA and sex. CONCLUSION: Demanding or strenuous OPA seems to be a risk factor for IHD among men, whereas a higher level of OPA seems to protect women from IHD. This emphasizes the importance of taking sex differences into account in studies of health effects of OPA.

In the Danish Monica I study among 1399 women and 1706 men, we investigated whether high physical activity at work was associated with higher risk of ischaemic heart disease and whether this association was different among men and women. The association between occupational physical activity and ischaemic heart disease was different among men and women. High physical activity at work was associated with around 45% higher risk of ischaemic heart disease in men, but with around 65% lower risk in women. The underlying mechanisms for this difference, e.g. differences in exposure and physiology, should be further investigated in future studies.

Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden.

OBJECTIVES: To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases. METHODS: Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000-2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country. RESULTS: Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar. CONCLUSIONS: Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.

Mental vulnerability, Helicobacter pylori, and incidence of hospital-diagnosed peptic ulcer over 28 years in a population-based cohort.

OBJECTIVE: To examine whether mental vulnerability, an enduring personality characteristic, predicts incident hospital-diagnosed ulcer over three decades. MATERIALS AND METHODS: A population-based cohort study enrolled 3365 subjects with no ulcer history, ages 30-60, in 1982-3. Mental vulnerability, Helicobacter pylori IgG antibodies, socioeconomic status, and sleep duration were determined at baseline; non-steroidal antiinflammatory drug use, smoking, leisure time physical activity, and alcohol consumption both at baseline and in 1993-4. Hospital diagnoses of incident ulcer through 2011 were detected using the Danish National Patient Registry. RESULTS: Ulcers were diagnosed in 166 subjects, including 83 complicated by bleeding or perforation. Age-, gender-, and socioeconomic status-adjusted associations were significant for mental vulnerability (Hazard Ratio (HR) 2.0, 95% Confidence Interval 1.4-2.8), Helicobacter pylori (HR 1.7, CI 1.2-2.3), smoking (HR 2.0, CI 1.3-3.1), heavy drinking (HR 1.6, CI 1.1-2.4), abstinence (HR 1.6, CI 1.1-2.5), non-steroidal antiinflammatory drugs (HR 2.1, CI 1.5-3.0), and sedentary lifestyle (HR 1.9, CI 1.4-2.7). Adjusted for all behavioral mediators, the HR for mental vulnerability was 1.5 (CI 1.0-2.2, p = .04). Mental vulnerability raised risk in Helicobacter pylori seropositive subjects and those exposed to neither Helicobacter pylori nor non-steroidal antiinflammatory drugs; its impact was virtually unchanged when analysis was limited to complicated ulcers. CONCLUSIONS: A vulnerable personality raises risk for hospital-diagnosed peptic ulcer, in part because of an association with health risk behaviors. Its impact is seen in 'idiopathic' and Helicobacter pylori-associated ulcers, and in acute surgical cases.

Effect of general health screening and lifestyle counselling on incidence of diabetes in general population: Inter99 randomised trial.

We aimed to examine the effect of a large population-based multifactorial screening and lifestyle intervention programme on 10-year incidence of diabetes. In a randomised trial of the general Danish population initiated in 1999-2001 59,616 men and women aged 30-60years were assigned to a five year screening and lifestyle counselling programme (n=11,629) or control group (n=47,987) and followed for ten years in nationwide registers. Intention to treat was applied and risk of diabetes was modeled by Cox regression and expressed as hazard ratios (HRs). We found that 1692 individuals had diabetes at baseline. Among 57,924 individuals without diabetes at baseline, 1267 emigrated, 2593 died and 3369 (Intervention group=684, Control group=2685) developed diabetes. We saw no significant difference in diabetes incidence between the groups after 10-year follow-up (Grey's test: p=0.22). In the first year of follow-up, incidence of diabetes was significantly higher in the intervention group than the control group (HR=1.68, 95%CI 1.29 to 2.29). We observed no difference in incidence of diabetes between the groups in the follow-up intervals from 1 to 6years or after 6-10years (HR=0.94, 0.83 to 1.06; HR=1.03, 0.91 to 1.17). Inviting the general population to participate in a repeated screening and lifestyle counselling programme over five years did not result in lower incidence of diabetes after 10years of follow-up. As expected, significantly more individuals were diagnosed with diabetes in the intervention group during the first year, but this was not followed by a decrease in the following years. TRIALS REGISTRATION: Clinical trials NCT00289237.

Does access to invasive examination and treatment influence socioeconomic differences in case fatality for patients admitted for the first time with non-ST-elevation myocardial infarction or unstable angina?

AIMS: Our aim was to investigate whether there is social inequality in access to invasive examination and treatment, and whether access explains social inequality in case fatality in a nationwide sample of patients admitted for the first time with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) in Denmark. METHODS AND RESULTS: All patients admitted for the first time with NSTEMI (n=16,625) or unstable angina (n=8,800) from 2001 to 2009 in Denmark were included. We measured time from admission to coronary angiography (CAG), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The outcomes were 30-day and one-year case fatality. We found social inequality in access to CAG and one-year case fatality for both NSTEMI and unstable angina patients, but the time waited for CAG did not explain the social inequality in case fatality. CONCLUSIONS: Despite nominal equal access to health care, social inequality in case fatality after NSTEMI and unstable angina exists in Denmark. The patients with the shortest education waited longer for angio-graphy; however, this did not seem to explain inequality in case fatality. This register-based study was approved by the Danish Data Protection Agency (Approval number 2010-41-5263). Register-based studies do not need approval by a medical ethics committee in Denmark.

Psychological stress increases risk for peptic ulcer, regardless of Helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs.

BACKGROUND & AIMS: There is controversy over whether psychological stress contributes to development of peptic ulcers. We collected data on features of life stress and ulcer risk factors from a defined population in Denmark and compared these with findings of confirmed ulcers during the next 11-12 years. METHODS: We collected blood samples and psychological, social, behavioral, and medical data in 1982-1983 from a population-based sample of 3379 Danish adults without a history of ulcer participating in the World Health Organization's MONICA study. A 0- to 10-point stress index scale was used to measure stress on the basis of concrete life stressors and perceived distress. Surviving eligible participants were reinterviewed in 1987-1988 (n = 2809) and 1993-1994 (n = 2410). Ulcer was diagnosed only for patients with a distinct breach in the mucosa. All diagnoses were confirmed by review of radiologic and endoscopic reports. Additional cases of ulcer were detected in a search of all 3379 subjects in the Danish National Patient Register. RESULTS: Seventy-six subjects were diagnosed with ulcer. On the basis of the stress index scale, ulcer incidence was significantly higher among subjects in the highest tertile of stress scores (3.5%) than the lowest tertile (1.6%) (adjusted odds ratio, 2.2; 95% confidence interval [CI], 1.2-3.9; P < .01). The per-point odds ratio for the stress index (1.19; 95% CI, 1.09-1.31; P < .001) was unaffected after adjusting for the presence of immunoglobulin G antibodies against Helicobacter pylori in stored sera, alcohol consumption, or sleep duration but lower after adjusting for socioeconomic status (1.17; 95% CI, 1.07-1.29; P < .001) and still lower after further adjustments for smoking, use of nonsteroidal anti-inflammatory drugs, and lack of exercise (1.11; 95% CI, 1.01-1.23; P = .04). The risk for ulcer related to stress was similar among subjects who were H pylori seropositive, those who were H pylori seronegative, and those exposed to neither H pylori nor nonsteroidal anti-inflammatory drugs. On multivariable analysis, stress, socioeconomic status, smoking, H pylori infection, and use of nonsteroidal anti-inflammatory drugs were independent predictors of ulcer. CONCLUSIONS: In a prospective study of a population-based Danish cohort, psychological stress increased the incidence of peptic ulcer, in part by influencing health risk behaviors. Stress had similar effects on ulcers associated with H pylori infection and those unrelated to either H pylori or use of nonsteroidal anti-inflammatory drugs.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.

OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Effect of screening and lifestyle counselling on incidence of ischaemic heart disease in general population: Inter99 randomised trial.

OBJECTIVE: To investigate the effect of systematic screening for risk factors for ischaemic heart disease followed by repeated lifestyle counselling on the 10 year development of ischaemic heart disease at a population level. DESIGN: Randomised controlled community based trial. SETTING: Suburbs of Copenhagen, Denmark. PARTICIPANTS: 59,616 people aged 30-60 years randomised with different age and sex randomisation ratios to an intervention group (n = 11,629) and a control group (n = 47,987). INTERVENTION: The intervention group was invited for screening, risk assessment, and lifestyle counselling up to four times over a five year period. All participants with an unhealthy lifestyle had individually tailored lifestyle counselling at all visits (at baseline and after one and three years); those at high risk of ischaemic heart disease, according to predefined criteria, were furthermore offered six sessions of group based lifestyle counselling on smoking cessation, diet, and physical activity. After five years all were invited for a final counselling session. Participants were referred to their general practitioner for medical treatment, if relevant. The control group was not invited for screening. MAIN OUTCOME MEASURES: The primary outcome measure was incidence of ischaemic heart disease in the intervention group compared with the control group. Secondary outcome measures were stroke, combined events (ischaemic heart disease, stroke, or both), and mortality. RESULTS: 6091 (52.4%) people in the intervention group participated at baseline. Among 5978 people eligible at five year follow-up (59 died and 54 emigrated), 4028 (67.4%) attended. A total of 3163 people died in the 10 year follow-up period. Among 58,308 without a history of ischaemic heart disease at baseline, 2782 developed ischaemic heart disease. Among 58,940 without a history of stroke at baseline, 1726 developed stroke. No significant difference was seen between the intervention and control groups in the primary end point (hazard ratio for ischaemic heart disease 1.03, 95% confidence interval 0.94 to 1.13) or in the secondary endpoints (stroke 0.98, 0.87 to 1.11; combined endpoint 1.01, 0.93 to 1.09; total mortality 1.00, 0.91 to 1.09). CONCLUSION: A community based, individually tailored intervention programme with screening for risk of ischaemic heart disease and repeated lifestyle intervention over five years had no effect on ischaemic heart disease, stroke, or mortality at the population level after 10 years.Trial registration Clinical trials NCT00289237.