Airway Hyperresponsiveness to Inhaled Mannitol Identifies a Cluster of Noneosinophilic Asthma Patients with High Symptom Burden.

BACKGROUND: Patients with asthma are heterogeneous in clinical presentation and in response to treatment. Despite this, tools to guide treatment are limited and include mainly measures of eosinophilic inflammation and symptoms. Airway hyperresponsiveness (AHR) to mannitol is present in patients across inflammatory phenotypes and improve with inhaled corticosteroids. OBJECTIVE: To investigate whether measuring AHR to mannitol in addition to eosinophilic inflammation and symptoms adds information to the phenotypic characterization of patients with asthma. METHODS: A total of 317 patients with asthma from 6 different cohorts were included in the analysis. All patients had measures of AHR to mannitol, blood eosinophils, and Asthma Control Questionnaire 5 available. A cluster analysis using Ward minimum variance method was performed. The distribution of fraction of exhaled nitric oxide, immunoglobulin E, lung function, induced sputum inflammatory cell count, age of onset, and severity of disease was compared between clusters. RESULTS: Four clusters were identified. Three of the clusters had proportionate levels of AHR, eosinophilic inflammation, and symptoms, but 1 cluster presented with low levels of eosinophilic inflammation and a significant symptom burden. Half of the subjects in this cluster presented with AHR to inhaled mannitol. Lung function, fraction of exhaled nitric oxide, body mass index, and immunoglobulin E were normal. CONCLUSIONS: Information on AHR to mannitol in addition to blood eosinophils and symptoms identifies a subgroup of asthma patients with symptomatic, noneosinophilic disease. Airway hyperresponsiveness to mannitol may provide a treatable trait in a subgroup of patients with noneosinophilic asthma.

Smoking and stress in the general population in Denmark.

INTRODUCTION: The social pressure placed on smokers today might potentially lead to an increasing level of stress. We investigated if the proportion of persons with high stress level had increased over time more in smokers than in non-smokers. METHODS: Data were obtained from repeated cross-sectional surveys of The Capital Region Health Survey conducted in 2010, 2013 and 2017. Survey data were weighted for survey design and non-response, and linked to national register data. Cohens Perceived Stress Scale (PSS-10) score was used. Logistic regression analyses, based on 136608 citizens' self-reports, were adjusted for sex, age, education level, employment, and alcohol intake (and loneliness, in analysis investigating the associations between tobacco consumption and high stress level). RESULTS: A significantly higher proportion of citizens reported a high stress level in 2017 compared with 2010 and 2013 but there was not a greater increase in smokers than in non-smokers. Daily smoking men had 69% higher odds of reporting perceived high stress level and daily smoking women had 36% higher odds, than never smokers of the same sex. There was a significant trend between higher daily tobacco consumption and a higher proportion of smokers with high stress level. CONCLUSIONS: The increase in high stress level over time occurred independently of smoking status. Daily smokers had the highest odds of perceived high stress level, and a higher daily tobacco consumption was associated with a higher proportion of smokers with high stress level. Smoking cessation programs should, to a higher degree, consider implementing stress-coping elements to prevent relapse.

Should leisure-time sedentary behavior be replaced with sleep or physical activity for prevention of diabetes?

The aim was to examine the effects of replacing self-reported leisure-time sedentary behavior with sleep, light-to-moderate physical activity, or vigorous physical activity on incident diabetes among Danish adults using isotemporal substitution modeling. Participants ≥25 years from the Danish Capital Region Health Survey 2007 (N = 69 800, response rate 52.3%), 2010 (N = 95 150, response rate 52.3%), and 2013 (N = 95 150, response rate 43.5%) were included. Information on daily sleep duration, leisure-time sedentary behavior, and movement behaviors was collected by questionnaire. Information on incident diabetes was obtained from National registers. Analyses included Cox proportional hazards regression models and isotemporal substitution analyses, with time (in years) from baseline to incident diabetes or censoring December 31, 2017. Potential confounders, sex, age, BMI, ethnicity, education, smoking, inflammatory joint disease, perceived stress, physical and mental component scale and work status, were included. Out of N = 87 339 in the final study sample, n = 3007 had incident diabetes during a mean follow-up time of 7.4 years. Adults with incident diabetes included more men, higher mean age, and higher BMI, compared to respondents without incident diabetes. Theoretically substituting 30 minutes of leisure-time sedentary behavior with light-to-moderate PA (HR: 0.96; 95% CI: 0.94; 0.98) or with vigorous PA (HR: 0.82; 95% CI: 0.72; 0.94) decreased the risk of incident diabetes. We found no change in incident diabetes risk of substituting sedentary time with sleep (HR: 1.00; 95% CI: 0.97; 1.02). Substituting 30 minutes per day of leisure-time sedentary behavior with light-to-moderate or vigorous PA may significantly reduce the risk of incident diabetes among adults.

Impact of age and gender on the prevalence and prognostic importance of the metabolic syndrome and its components in Europeans. The MORGAM Prospective Cohort Project.

OBJECTIVE: To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS). METHODS: Using 36 cohorts from the MORGAM-Project with baseline between 1982-1997, 69094 men and women aged 19-78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5. RESULTS: The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19-39 years to 60-78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P=0.01/P=0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05). CONCLUSION: In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.

Do other cardiovascular risk factors influence the impact of age on the association between blood pressure and mortality? The MORGAM Project.

OBJECTIVE: To investigate age-related shifts in the relative importance of SBP and DBP as predictors of cardiovascular mortality and all-cause mortality and whether these relations are influenced by other cardiovascular risk factors. METHODS: Using 42 cohorts from the MORGAM Project with baseline between 1982 and 1997, 85 772 apparently healthy Europeans and Australians aged 19-78 years were included. During 13.3 years of follow-up, 9.2% died (of whom 7.2% died due to stroke and 21.1% due to coronary heart disease, CHD). RESULTS: Mortality risk was analyzed using hazard ratios per 10-mmHg/5-mmHg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, SBP and DBP were analyzed separately for blood pressure (BP) values above and below a cut-point wherein mortality risk was the lowest. For the total population, significantly positive associations were found between stroke mortality and SBP [hazard ratio = 1.19 (1.13-1.25)] and DBP at least 78 mmHg [hazard ratio = 1.08 (1.02-1.14)], CHD mortality and SBP at least 116 mmHg [1.20 (1.16-1.24)], and all-cause mortality and SBP at least 120 mmHg [1.09 (1.08-1.11)] and DBP at least 82 mmHg [1.03 (1.02-1.05)]. BP values below the cut-points were inversely related to mortality risk. Taking into account the age × BP interaction, there was a gradual shift from DBP (19-26 years) to both DBP and SBP (27-62 years) and to SBP (63-78 years) as risk factors for stroke mortality and all-cause mortality, but not CHD mortality. The age at which the importance of SBP exceeded DBP was for stroke mortality influenced by sex, cholesterol, and country risk. CONCLUSION: Age-related shifts to the superiority of SBP exist for stroke mortality and all-cause mortality, and for stroke mortality was this shift influenced by other cardiovascular risk factors.

Impact of age on the importance of systolic and diastolic blood pressures for stroke risk: the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project.

This study investigates age-related shifts in the relative importance of systolic (SBP) and diastolic (DBP) blood pressures as predictors of stroke and whether these relations are influenced by other cardiovascular risk factors. Using 34 European cohorts from the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) Project with baseline between 1982 and 1997, 68 551 subjects aged 19 to 78 years, without cardiovascular disease and not receiving antihypertensive treatment, were included. During a mean of 13.2 years of follow-up, stroke incidence was 2.8%. Stroke risk was analyzed using hazard ratios per 10-mm Hg/5-mm Hg increase in SBP/DBP by multivariate-adjusted Cox regressions, including SBP and DBP simultaneously. Because of nonlinearity, DBP was analyzed separately for DBP ≥ 71 mm Hg and DBP <71 mm Hg. Stroke risk was associated positively with SBP and DBP ≥ 71 mm Hg (SBP/DBP ≥ 71 mm Hg; hazard ratios: 1.15/1.06 [95% CI: 1.12-1.18/1.03-1.09]) and negatively with DBP <71 mm Hg (0.88[0.79-0.98]). The hazard ratio for DBP decreased with age (P<0.001) and was not influenced by other cardiovascular risk factors. Taking into account the age × DBP interaction, both SBP and DBP ≥ 71 mm Hg were significantly associated with stroke risk until age 62 years, but in subjects older than 46 years the superiority of SBP for stroke risk exceeded that of DBP ≥ 71 mm Hg and remained significant until age 78 years. DBP <71 mm Hg became significant at age 50 years with an inverse relation to stroke risk. In Europeans, stroke risk should be assessed by both SBP and DBP until age 62 years with increased focus on SBP from age 47 years. From age 62 years, emphasis should be on SBP without neglecting the potential harm of very low DBP.

A registry-based follow-up study, comparing the incidence of cardiovascular disease in native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia: do social inequalities play a role?

BACKGROUND: This study compared the incidence of cardiovascular disease (CVD) and acute myocardial infarction (AMI) between native Danes and immigrants born in Turkey, Pakistan and the former Yugoslavia. Furthermore, we examined whether different indicators of socioeconomic status (SES), such as employment, income and housing conditions influenced potential differences. METHODS: In this registry-based follow-up study individuals were identified in a large database that included individuals from two major regions in Denmark, corresponding to about 60% of the Danish population. Incident cases of CVD and AMI included fatal and non-fatal events and were taken from registries. Using Cox regression models, we estimated incidence rates at 5-year follow-up. RESULTS: Immigrant men and women from Turkey and Pakistan had an increased incidence of CVD, compared with native Danish men. In the case of AMI, a similar pattern was observed; however, differences were more pronounced. Pakistanis and Turks with a shorter duration of residence had a lower incidence, compared with those of a longer residence. Generally, no notable differences were observed between former Yugoslavians and native Danes. In men, differences in CVD and AMI were reduced after adjustment for SES, in particular, among Turks regarding CVD. In women, effects were particularly reduced among Yugoslavians in the case of CVD and in Turks in the case of CVD and AMI after adjustment for SES. CONCLUSIONS: In conclusion, country of birth-related differences in the incidence of CVD and AMI were observed. At least some of the differences that we uncovered were results of a socioeconomic effect. Duration of residence also played a certain role. Future studies should collect and test different indicators of SES in studies of CVD among immigrants.

Stroke risk estimation across nine European countries in the MORGAM project.

BACKGROUND: Previous tools for stroke risk assessment have either been developed for specific populations or lack data on non-fatal events or uniform data collection. The purpose of this study was to develop a stepwise model for the estimation of 10 year risk of stroke in nine different countries across Europe. METHODS: Using data from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, sex-specific models estimating 10 year risk of stroke were developed using a Cox regression model stratified by country and including modelling of competing risks. Models were developed in a stepwise manner first using only data from questionnaires, and then adding data from physical examinations and finally data from blood samples. RESULTS: During 1,176,296 years of observation, 2928 incident fatal and non-fatal events of stroke were registered. The developed model showed good calibration and accuracy of prediction. The discrimination of the model varied between sex and country but increased with increasing number of variables used (area under the receiver operating characteristic curve between 0.77 and 0.79 in men and between 0.75 and 0.80 in women). CONCLUSION: The present study shows that using a large multicountry cohort from nine European countries it is possible to develop a stepwise risk estimation model for 10 year risk of stroke tailored to different availability of risk factors and still obtain valid measures of risk even in the simplest form of the model, with increasing performance of the model following increasing complexity. The methods chosen which separate this model from previous models (competing risk and stepwise approach) should be considered for future risk estimation models.

Cardiovascular risk estimation tailored to different clinical settings - the Tromsø study.

OBJECTIVE: To develop a cardiovascular risk model simulating different clinical settings using a staged approach. DESIGN: Using data from 27,477 men and women from the Norwegian Tromsø Study in 1986-1987 and 1994-1995, Cox regression models for either myocardial infarction (MI) or stroke combined with a similar model for the competing event a risk model that assess ten-year risk of MI and stroke was developed. Explanatory variables (questions, simple examinations and blood samples) were added gradually. The model was validated using Hosmer-Lemeshow test, the Brier score, c-index, integrated discrimination improvement (IDI) and Net Reclassification Improvement (NRI). RESULTS: In total, 1,298 events of MI and 769 events of stroke were registered. For MI the model showed excellent discrimination in each step with c-index from 0.833 to 0.946. For stroke the c-index ranged between 0.817 and 0.898. IDI showed significant increases in discrimination. The Brier scores and goodness of fit test showed well calibrated models in all steps for all sex- and end-point specific models (p>0.05). CONCLUSIONS: Although the predictive and discriminative ability of the models increased with each step, even the simplest model containing only data from questions or blood samples alone yielded valid estimates of cardiovascular risk.

Urinary creatinine concentration is inversely related to glycaemic control and the presence of some diabetic complications in patients with newly diagnosed Type 2 diabetes.

BACKGROUND: The ratio between urinary albumin concentration (UAC) and urinary creatinine concentration (UCC) is widely used to estimate renal involvement. We examined how UAC and UCC associate with each other, with other risk factors, and with diabetic complications in a population-based sample of Type 2 diabetic patients. METHODS: A freshly voided morning urine specimen was provided by 1,284 consecutive, newly diagnosed diabetic patients aged 40 years or over in general practice. Albumin was measured by a polyethyleneglycol radioimmunoassay and creatinine by a modified Jaffe method. RESULTS: In a multivariate model including UAC, UCC, age, sex, HbA1c, and urinary glucose concentration, UAC increased with both age (P=.042) and HbA1c (P=.014), while UCC decreased (P<.001 and P<.001, respectively). In two regression models, the prevalence of diabetic retinopathy (P<.001) and relatively high resting heart rate (P<.001) increased with increasing UAC but decreased with increasing UCC (P=.002 and P=.005, respectively). CONCLUSION: The use of albumin/creatinine ratio (ACR) may introduce bias of unpredictable size and direction in comparisons of ACR with variables that are associated with UCC in their own right. In daily clinical practice, renal involvement in the individual patient can be estimated reliably with UAC or ACR measured in a freshly voided morning urine specimen, especially when considered together. However, the associations of the combined measure ACR should be interpreted with great caution in clinical and epidemiological research.