Night work during pregnancy and small for gestational age: a Danish nationwide register-based cohort study.

OBJECTIVE: The aim was to investigate the association between night work during pregnancy and risk of having a small for gestational age (SGA) child. METHODS: This cohort study had payroll data with detailed information on working hours for employees in all Danish administrative regions (primarily hospital employees) between 2007 and 2015, retrieved from the Danish Working Hour Database. Pregnancies, covariates and outcome were identified from the national birth registry. We used logistic regression to investigate the association between intensity and duration of night work during the first 32 pregnancy weeks and SGA. The adjusted model included age, body mass index, socioeconomic status and smoking. Using quantitative bias analysis and G-estimation, we explored potential healthy worker survivor bias (HWSB). RESULTS: The final cohort comprised 24 548 singleton pregnancies in 19 107 women, primarily nurses and medical doctors. None of the dimensions of night work were associated with an increased risk of SGA. We found a tendency towards higher risk of SGA in pregnancies where the women stopped having night shifts during pregnancy. Using G-estimation we found an OR<1 for the association between night work and SGA if all workers continued having night work during pregnancy compared with daywork only. CONCLUSION: We found no increased risk of SGA in association with night work during pregnancy among healthcare workers. G-estimation was not precise enough to estimate the observed indication of HWSB. We need better data on pregnancy discomforts and complications to be able to safely rule out HWSB.

Historical Asbestos Measurements in Denmark-A National Database.

OBJECTIVES: Due to the long lag-time for health outcomes, historical asbestos exposure measurements are valuable to support assessments of associated occupational health effects, and also to assess time trends and effects of preventive measures. METHODS: Different sources of stored data were collated, assessed and refined to create a harmonized database on historical asbestos fibre concentrations measured in specific work tasks and different industries. The final database contains 9236 asbestos measurements from Danish workplaces collected from 1971 to 1997. RESULTS: The geometric mean of asbestos concentrations in different occupations and tasks ranged from 0.003 to 35 fibres cm-3. Highest concentrations were registered during handling of asbestos products in the construction services during the period 1981-1997. Although all the measured asbestos exposures without the use of respiratory equipment by the worker in the period of 1971-1997 exceeded the current 8-h time-weighted average exposure limit of 0.1 fibres cm-3, the majority of samples collected in the earlier period of 1971 to 1980 did not exceed the exposure limit of 2 fibres cm-3, which was in place at the time. All exposure data obtained from 1980 and onwards were found to be one seventh of the mean fibre concentrations in the previous measurement period. The impact of time shows a clear exponentially decreasing trend-line. CONCLUSIONS: Despite limitations in coverage of different occupations and tasks associated with the inventoried historical asbestos measurements, the data are helpful to identify specific work scenarios within an industry, where relatively high asbestos exposure levels may still occur or have occurred from 1971 to 1997.

Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study.

INTRODUCTION: The risk of asbestosis, malignant mesothelioma and lung cancer among motor vehicle mechanics is of concern because of potential exposure to chrysotile asbestos during brake, clutch and gasket repair and maintenance. Asbestos has also been used in insulation and exhaust systems. METHODS: We examined the long-term risk of incident mesothelioma, lung cancer, asbestosis and other lung diseases and mortality due to mesothelioma, lung cancer, asbestosis and other lung diseases in a nationwide cohort of all men registered as motor vehicle mechanics since 1970 in Denmark. This was compared with the corresponding risk in a cohort of male workers matched 10:1 by age and calendar year, with similar socioeconomic status (instrument makers, dairymen, upholsterers, glaziers, butchers, bakers, drivers, farmers and workers in the food industry, trade or public services). RESULTS: Our study included 138 559 motor vehicle mechanics (median age 24 years; median follow-up 20 years (maximum 45 years)) and 1 385 590 comparison workers (median age 25 years; median follow-up 19 years (maximum 45 years)). Compared with other workers, vehicle mechanics had a lower risk of morbidity due to mesothelioma/pleural cancer (n=47 cases) (age-adjusted and calendar-year-adjusted HR=0.74 (95% CI 0.55 to 0.99)), a slightly increased risk of lung cancer (HR=1.09 (95% CI 1.03 to 1.14)), increased risk of asbestosis (HR=1.50 (95% CI 1.10 to 2.03)) and a chronic obstructive pulmonary disease risk close to unity (HR=1.02 (95% CI 0.99 to 1.05)). Corresponding HRs for mortality were 0.86 (95% CI 0.64 to 1.15) for mesothelioma/pleural cancer, 1.06 (95% CI 1.01 to 1.12) for lung cancer, 1.79 (95% CI 1.10 to 2.92) for asbestosis, 1.06 (95% CI 0.86 to 1.30) for other lung diseases caused by external agents and 1.00 (95% CI 0.98 to 1.01) for death due to all causes. CONCLUSIONS: We found that the risk of asbestosis was increased among vehicle mechanics. The risk of malignant mesothelioma/pleural cancers was not increased among vehicle mechanics.

Occupational inhalant exposures and longitudinal lung function decline.

BACKGROUND: Airborne exposures at the workplace are believed to be associated with lung function decline. However, longitudinal studies are few, and results are conflicting. METHODS: Participants from two general population-based cohorts, the Copenhagen City Heart Study and the Copenhagen General Population Study, with at least two lung function measurements were followed for a mean of 9 years (range 3-27 years). Occupational exposure was assigned to each year of follow-up between the two lung function measurements by a job exposure matrix. Associations between mean occupational exposure per year and mean annual decline in forced expiratory volume in 1 s (FEV1) were investigated using linear mixed-effects models according to cohort and time period (1976-1983 and 2003-2015). We adjusted for sex, height, weight, education, baseline FEV1 and pack-years of smoking per year during follow-up. RESULTS: A total of 16 144 individuals were included (mean age 48 years and 43% male). Occupational exposure to mineral dusts, biological dusts, gases and fumes and a composite category was not associated with FEV1 decline in analyses with dichotomised exposure. In analyses with an indexed measure of exposure, gases and fumes were associated with an FEV1 change of -5.8 mL per unit per year (95% CI -10.8- -0.7 mL per unit per year) during 1976-1983, but not during 2001-2015. CONCLUSION: In two cohorts from the Danish general population, occupational exposure to dusts, gases and fumes was not associated with excess lung function decline in recent years but might have been of importance decades ago.

Chronic productive cough and inhalant occupational exposure-a study of the general population.

PURPOSE: Occupational inhalant exposures have been linked with a higher occurrence of chronic productive cough, but recent studies question the association. METHODS: We included participants from two general population studies, the Copenhagen City General Population Study and the Copenhagen City Heart Study, to assess contemporary (year 2003-2017) and historical (1976-1983) occupational inhalant hazards. Job titles one year prior to study inclusion and an airborne chemical job-exposure matrix (ACE JEM) were used to estimate occupational exposure. The association between occupational exposures and self-reported chronic productive cough was studied using generalized estimating equations stratified by smoking status and cohort. RESULTS: The population consisted of 5210 working individuals aged 20-65 from 1976 to 1983 and 64,279 from 2003 to 2017. In smokers, exposure to high levels of mineral dust, biological dust, gases & fumes and the composite variable vapours, gases, dusts or fumes (VGDF) were associated with chronic productive cough in both cohorts with odds ratios in the range of 1.2 (95% confidence interval, 1.0;1.4) to 1.6 (1.2;2.1). High levels of biological dust were only associated with an increased risk of a chronic productive cough in the 2003-2017 cohort (OR 1.5 (1.1;2.0)). In non-smokers, high levels of VGDF (OR 1.5 (1.0;2.3)) and low levels of mineral dust (OR 1.7 (1.1;2.4)) were associated with chronic productive cough in the 1976-1983 cohort, while no associations were seen in non-smokers in the 2003-2017 cohort. CONCLUSION: Occupational inhalant exposure remains associated with a modestly increased risk of a chronic productive cough in smokers, despite declining exposure levels during the past four decades.

Health-Related Quality of Life in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Nationwide Population-Based Survey in Denmark.

Previous studies have clarified that many patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) have burdensome symptom profiles and accordingly impaired functioning and quality of life (QoL). In Denmark, all MPN patients are affiliated with public hospitals and because of a healthcare system financed by taxpayers these patients do not have any financial costs related to the hematological disease. Diagnoses are recorded for all patients in hospitals, and diagnosis codes are communicated to the National Patient Register (NPR). Owing to this, it was possible to contribute to the elucidation of Philadelphia-negative MPN patients' health-related quality of life (HRQoL), by conducting a nationwide, population-based, cross-sectional HRQoL survey of these patients with cost-free access to the best available, suitable medical treatment. The survey contained validated questionnaires covering functioning, symptom burden, symptom profile, QoL, and additional questions on lifestyle. Information on comorbid diagnoses was obtained from the NPR. The participants' HRQoL was compared to the general population. Moreover, differences in HRQoL across essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN participants were investigated, adjusted for age, sex, comorbidity, and lifestyle. To the best of our knowledge this is the first survey of HRQoL in patients with unclassifiable MPN. A total of 2228 Philadelphia-negative MPN patients participated. The participants reported their HRQoL to be inferior to the general population, but the difference was minor. The differences in HRQoL across groups of participants with different MPN subtypes were subtle. Fatigue and sexual problems were prevalent and burdensome. Overall, participants reported a slightly healthier lifestyle compared to the general population.

Risk of Inflammatory Bowel Disease in Patients with Chronic Myeloproliferative Neoplasms: A Danish Nationwide Cohort Study.

An association between hematological cancers and inflammatory bowel disease (IBD) has previously been suggested, but the risk of IBD in patients with myeloproliferative neoplasms (MPNs) is unknown. We conducted a nationwide population-based cohort study using Danish registries, to estimate the risk of IBD in individuals diagnosed with essential thrombocythemia, polycythemia vera, myelofibrosis or unclassifiable MPN during 1994-2013. MPN patients were matched 1:10 with sex- and age-matched comparisons. Everyone was followed until a diagnosis of IBD, death/emigration, or 31 December 2013. The risk of IBD overall and according to MPN subtype was calculated using Cox regression and presented as hazard ratios (HRs) with 95% confidence intervals (CI). Of 8207 MPN patients followed for 45,232 person-years, 80 were diagnosed with IBD (61 ulcerative colitis, 19 Crohn's disease). The rate of IBD per 1000 person-years was 1.8 (95% CI:1.4-2.2) in patients vs. 0.8 (95% CI:0.7-0.8) in comparisons, and the absolute 10-year risk of IBD was 0.8% (95% CI:0.6-1.0) in patients vs. 0.4% (95% CI:0.4-0.5) in comparisons. The HR of IBD was 2.4 (95% CI:2.1-2.9) with similar HRs for ulcerative colitis and Crohn's disease. MPN subtype risks varied from 2.1 (95% CI:1.6-2.7) to 2.8 (95% CI:2.1-3.7). Our unselected cohort study showed a more than 2-fold increased risk of IBD in MPN patients.

Body Mass Index and Total Symptom Burden in Myeloproliferative Neoplasms Discovery of a U-shaped Association.

Elevated body mass index (BMI) is a global health problem, leading to enhanced mortality and the increased risk of several cancers including essential thrombocythemia (ET), a subtype of the Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). Furthermore, evidence states that BMI is associated with the severity of symptom burden among cancer patients. MPN patients often suffer from severe symptom burden. The purpose of this study was to examine whether deviations from a normal BMI in an MPN population are associated with higher symptom burden and reduced quality of life (QoL). A combined analysis of two large cross-sectional surveys, the Danish Population-based Study, MPNhealthSurvey (n = 2044), and the international Fatigue Study (n = 1070), was performed. Symptoms and QoL were assessed using the validated Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Analysis of covariance was used to estimate the effects of different BMI categories on symptom scores while adjusting for age, sex, and MPN subtype. A U-shaped association between BMI and Total Symptom Burden was observed in both datasets with significantly higher mean scores for underweight and obese patients relative to normal weight (mean difference: underweight 5.51 (25.8%), p = 0.006; obese 5.70 (26.6%) p < 0.001). This is an important finding, as BMI is a potentially modifiable factor in the care of MPN patients.

Per- and polyfluoroalkyl substances and male reproductive health: a systematic review of the epidemiological evidence.

Exposure to environmental pollutants may produce impairment of male reproductive health. The epidemiological literature evaluating potential consequences of human exposure to per- and polyfluoroalkyl substances (PFAS) has grown in recent years with concerns for both pre- and postnatal influences. The aim of this systematic review was to assess available evidence on associations between PFAS exposures in different stages of life and semen quality, reproductive hormones, cryptorchidism, hypospadias, and testicular cancer. A systematic search of literature published prior to March 9th, 2020, was performed in the databases PubMed and Embase®. Predefined criteria for eligibility were applied by two authors screening study records independently. Among the 242 study records retrieved in the literature search, 26 studies were eligible for qualitative assessment. While several investigations suggested weak associations for single compounds and specific outcomes, a lack of consistency across studies limited conclusions of overall evidence. The current gap in knowledge is particularly obvious regarding exposures prior to adulthood, exposure to combinations of both PFAS and other types of environmental chemicals, and outcomes such as cryptorchidism, hypospadias, and testicular cancer. Continued efforts to clarify associations between PFAS exposure and male reproductive health through high-quality epidemiological studies are needed.

Influence of errors in job codes on job exposure matrix-based exposure assessment in the register-based occupational cohort DOC*X.

Objective Job-exposure matrices (JEM) may be efficient for exposure assessment in occupational epidemiological studies, but they rely on valid job information. We evaluated the agreement between JEM-based exposure estimates according to self-reported job titles converted to DISCO-88 codes and according to register-based DISCO-88 codes in the Danish Occupational Cohort with eXposure data (DOC*X). Furthermore, we evaluated the agreement between these two sets of DISCO-88 codes. Methods We used JEM regarding wood dust, lifting, standing/walking, arm elevation >90°, and noise from DOC*X. Participants from previous questionnaire studies were assigned JEM-based exposure estimates using (i) self-reported job titles converted to DISCO-88 codes and (ii) DISCO-88 codes registered in DOC*X, in four time periods (1976-78: N=7707; 1981-83: N=2193; 1991-94: N=2664; 2004: N=11 782). Agreement between the exposure estimates and between the DISCO-88 codes (four-digit levels, 1-4) was evaluated by kappa (κ) statistics. Sensitivities were calculated using the self-reported observation as the gold standard. Results We found substantial agreement (κ>0.60) between exposure estimates for all types of job-exposures and all time periods except for one κ. Low sensitivity (30-65%) was found for the period 1981-83, but for the other time periods the sensitivities varied between 60-91%. For individual 4-digit DISCO-88 codes, the sensitivities varied substantially and overall the sensitivities increased by lower digit level of DISCO-88. Conclusion The validity of the DISCO-88 codes in DOC*X was generally high. Substantial agreement was found for the JEM-based exposure estimates and the DISCO-88 codes per se, although the DISCO-88 code-specific agreement varied across digit levels and time periods.

Ovarian cortical follicle density in infertile women with low anti-Müllerian hormone.

PURPOSE: To evaluate the association between anti-Müllerian hormone (AMH) and follicle density in infertile women with diminished ovarian reserve (DOR) versus women with normal ovarian reserve? METHODS: Case-control study comparing follicle densities in ovarian cortex from 20 infertile women with DOR (AMH ≤ 5 pmol/L) and 100 controls with presumed normal ovarian reserve. RESULTS: For all women > 25 years, the follicle densities correlated positively with AMH levels. For each single picomole per liter increase in AMH the follicle density increased by 6% (95% CI 3.3-8.5%) when adjusted for age. This was similar for women with DOR and controls. The follicle density was 1.8 follicles/mm3 cortical tissue in women with DOR versus 7.0 in age-paired controls (p = 0.04). The women with DOR had a median AMH of 1.8 pmol/L versus 14.4 pmol/L in the age-paired control group (p < 0.001). The ratio of AMH/follicle density was 1:1 (1.8/1.8) in women with DOR and 2:1 (14.4/7.0) in the age-paired controls. Analyses for gonadotropin receptor polymorphisms could not explain the characteristics of women with DOR. The proportion of secondary follicles was higher in women with DOR compared with controls (4.6% versus 1.4%, p = 0.0003). Pooling all patients, the follicle density decreased significantly by 7.7% for every year added (p < 0.0001). The women with DOR had lower follicle densities than the controls, but the slopes were equal in the two cohorts. CONCLUSIONS: Follicle density and AMH concentrations correlate also when AMH is low. However, AMH is only a reliable marker for the true ovarian reserve when age is included in the estimation and women with DOR may have more follicles than their AMH levels imply.

Biopsying, fragmentation and autotransplantation of fresh ovarian cortical tissue in infertile women with diminished ovarian reserve.

STUDY QUESTION: Can ovarian biopsying per se and/or autotransplantation of fragmented ovarian cortical tissue activate dormant follicles and increase the number of recruitable follicles for IVF/ICSI in women with diminished ovarian reserve (DOR)? SUMMARY ANSWER: Ovarian biopsying followed by immediate autotransplantation of fragmented cortical tissue failed to increase the number of recruitable follicles for IVF/ICSI 10 weeks after the procedure either at the graft site or in the biopsied ovary, but 12 of the 20 women subsequently had a clinical pregnancy during the 1-year follow-up. WHAT IS KNOWN ALREADY: Infertile women with DOR constitute a group of patients with poor reproductive outcome mainly due to the low number of mature oocytes available for IVF/ICSI. Recent studies have shown that in vitro activation of residual dormant follicles by both chemical treatment and tissue fragmentation has resulted in return of menstrual cycles and pregnancies in a fraction of amenorrhoeic women with premature ovarian insufficiency. STUDY DESIGN, SIZE, DURATION: This is a prospective clinical cohort study including 20 women with DOR treated at the fertility clinic, Rigshospitalet, Denmark, during April 2016-December 2017. Non-pregnant patients were on average followed for 280 days (range 118-408), while women who conceived were followed until delivery. Study follow-up of non-pregnant patients ended in September 2018. PARTICIPANTS, MATERIALS, SETTING, METHODS: The study included infertile women aged 30-39 years with preserved menstrual cycles, indication for IVF/ICSI and repeated serum measurements of anti-Müllerian hormone (AMH) ≤ 5 pmol/L. Patients were randomized to have four biopsies taken from either the left or the right ovary by laparoscopy followed by fragmentation of the cortical tissue to an approximate size of 1 mm3 and autotransplanted to a peritoneal pocket. The other ovary served as a control. Patients were followed weekly for 10 weeks with recording of hormone profile, antral follicle count (AFC), ovarian volume and assessment for ectopic follicle growth. After 10 weeks, an IVF/ICSI-cycle with maximal ovarian stimulation was initiated. MAIN RESULTS AND THE ROLE OF CHANCE: No difference in the number of mature follicles after ovarian stimulation 10 weeks after the procedure in the biopsied versus the control ovaries was observed (1.0 vs. 0.7 follicles, P = 0.35). In only three patients, growth of four follicles was detected at the graft site 24-268 days after the procedure. From one of these follicles, a metaphase II (MII) oocyte was retrieved and fertilized, but embryonic development failed. Overall AMH levels did not change significantly after the procedure (P = 0.2). The AFC increased by 0.14 (95% CI: 0.06;0.21) per week (P < 0.005), and the biopsied ovary had on average 0.6 (95% CI: 0.3;-0.88) follicles fewer than the control ovary (P = 0.01). Serum levels of androstenedione and testosterone increased significantly by 0.63 nmol/L (95% CI: 0.21;1.04) and 0.11 nmol/L (95% CI: 0.01;0.21) 1 week after the procedure, respectively, and testosterone increased consecutively over the 10 weeks by 0.0095 nmol/L (95% CI: 0.0002;0.0188) per week (P = 0.045). In 7 of the 20 patients, there was a serum AMH elevation 5 to 8 weeks after the procedure. In this group, mean AMH increased from 2.08 pmol/L (range 1.74-2.34) to 3.94 pmol/L (range 3.66-4.29) from Weeks 1-4 to Weeks 5-8. A clinical pregnancy was obtained in 12 of the 20 (60%) patients with and without medically assisted reproduction (MAR) treatments. We report a cumulated live birth rate per started IVF/ICSI cycle of 18.4%. LIMITATIONS, REASON FOR CAUTION: Limitations of the study were the number of patients included and the lack of a non-operated control group. Moreover, 9 of the 20 women had no male partner at inclusion and were treated with donor sperm, but each of these women had an average of 6.8 (range 4-9) unsuccessful MAR treatments with donor sperm prior to inclusion. WIDER IMPLICATIONS OF THE FINDINGS: Although 12 out of 20 patients became pregnant during the follow-up period, the current study does not indicate that biopsying, fragmenting and autotransplanting of ovarian cortical tissue increase the number of recruitable follicles for IVF/ICSI after 10 weeks. However, a proportion of the patients may have a follicular response in Weeks 5-8 after the procedure. It could therefore be relevant to perform a future study on the possible effects of biopsying per se that includes stimulation for IVF/ICSI earlier than week 10. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. The funders had no role in the study design, data collection and interpretation, or decision to submit the work for publication. None of the authors have a conflict of interest. TRIAL REGISTRATION NUMBER: NCT02792569.

Associations of different molecular forms of antimüllerian hormone and biomarkers of polycystic ovary syndrome and normal women.

OBJECTIVE: To study different antimüllerian hormone (AMH) isoforms in women with polycystic ovary syndrome (PCOS) and healthy regularly cycling women and to investigate whether levels of AMH isoforms combined with baseline characteristics can predict PCOS. DESIGN: Cross-sectional study. SETTING: Fertility clinic. PATIENT(S): Eighty-eight women with PCOS and 24 age- and body mass index (BMI)-matched normal control subject women recruited from April 2010 to February 2013. AMH isoforms were analyzed in biobanked serum samples collected at Holbaek Fertility Clinic, Denmark. All study participants went through a baseline examination including gynecologic history, objective examination, transvaginal ultrasound, and blood sampling. Each woman was characterized by measurement of total T, free T, SHBG, A, DHEAS, FSH, LH, E2, PRL, TSH, serum insulin, plasma glucose, and C-peptide. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Serum levels of three different AMH isoforms. RESULT(S): Levels of AMH measured with each of three AMH ELISAs were significantly higher in women with PCOS compared with control women. The ratio between AMH isoforms showed significant associations with metabolic parameters (BMI, SHBG, C-peptide, cholesterols, triglycerides, and the modified homeostasis-model assessment). Prediction of PCOS showed a high precision with areas under the receiver operating characteristic curve of 97% when AMH measurements were combined with androgens and BMI. CONCLUSION(S): Three ELISAs detecting different parts of the AMH molecule all detected significantly higher levels in women with PCOS compared with control women. The relative distribution of AMH isoforms did not differ between women with PCOS and control women. AMH isoforms alone and in combination with baseline characteristics predicted PCOS with close to 100% area under the receiver operating characteristic curve.

Anxiety and depression in patients with Philadelphia-negative myeloproliferative neoplasms: a nationwide population-based survey in Denmark.

OBJECTIVE: We sought to determine the prevalence and severity of anxiety and depression among patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) and respective associations of anxiety and depression with demographic and lifestyle factors, comorbidity burden, duration of MPN disease, financial difficulties, and health-related quality of life (QoL). METHODS: This study used data from a nationwide, population-based, cross-sectional survey of health-related QoL in MPN patients in Denmark called the MPNhealthSurvey. Individuals with a diagnosis of MPN in the National Patient Register were invited. The Hospital Anxiety and Depression Scale was used to assess the prevalence and severity of anxiety and depression. The associations of anxiety and depression with age, sex, education, body mass index (BMI), smoking, alcohol intake, physical activity, comorbidity burden, duration of MPN disease, financial difficulties, symptom burden, sexual problems, fatigue, functioning, and global health/QoL were examined. RESULTS: In total, 2,029 patients completed the Hospital Anxiety and Depression Scale. The prevalence of anxiety, depression, and both was 21%, 12%, and 8%, respectively. Many participants who reported anxiety or depression exhibited mild symptoms. Middle-aged and elderly participants had lower odds of experiencing anxiety and depression when compared to younger participants, and females had higher odds of anxiety compared to males. Participants with higher education had lower odds of anxiety compared to those with lower education. Current smokers and ex-smokers had higher odds of anxiety and depression compared to those who had never smoked, and sedentary participants and participants with a lower level of physical activity had higher odds of anxiety and depression compared to participants who performed hard training several times a week. Higher comorbidity burden increased the odds of depression, and greater financial difficulties increased the odds of anxiety and depression. Higher total symptom burden and fatigue burden and higher level of sexual problems increased the odds of anxiety and depression. Finally, lower functional level and global health/quality of life increased the odds of anxiety and depression. BMI, alcohol intake, comorbidity burden, and duration of disease were not substantially associated with anxiety, whereas sex, educational level, and duration of MPN disease were not substantially associated with depression. CONCLUSION: There may be an unmet need in handling psychological distress in MPN patients. Future research might explore the utility of screening for psychological distress and the effectiveness of lifestyle interventions, rehabilitation, and MPN-symptom reduction in preventing and treating psychological distress.

Job-exposure matrices addressing lifestyle to be applied in register-based occupational health studies.

OBJECTIVES: Information about lifestyle factors in register-based occupational health studies is often not available. The objective of this study was therefore to develop gender, age and calendar-time specific job-exposure matrices (JEMs) addressing five selected lifestyle characteristics across job groups as a tool for lifestyle adjustment in register-based studies. METHODS: We combined and harmonised questionnaire and interview data on lifestyle from several Danish surveys in the time period 1981-2013 for 264 054 employees registered with a DISCO-88 code (the Danish version of International Standard Classification of Occupations (ISCO)-88) in a nationwide register-based Danish Occupational Cohort. We modelled the probability of specified lifestyles in mixed models for each level of the four-digit DISCO code with age and sex as fixed effects and assessed variation in terms of intraclass correlation coefficients (ICCs) and exposure-level percentile ratios across jobs for six different time periods from 1981 through 2013. RESULTS: The ICCs were overall low (0.26%-7.05%) as the within-job group variation was large relative to the between job group variation, but across jobs the calendar period-specific ratios between highest and lowest predicted levels were ranging from 1.2 to 6.9, and for the 95%/1% and the 75%/5% percentile ratios ranges were 1.1-2.8 and 1.1-1.6, respectively, thus indicating substantial contrast for some lifestyle exposures and some occupations. CONCLUSIONS: The lifestyle JEMs may prove a useful tool for control of lifestyle-related confounding in register-based occupational health studies where lacking information on individual lifestyle factors may compromise internal validity.

Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms.

Importance: It has been suggested that systemic inflammation increases the risk of age-related macular degeneration (AMD). Given that chronic immune modulation is present in patients with myeloproliferative neoplasms (MPNs), the risk of AMD in these patients may be increased. Objective: To compare the risk of AMD in patients with MPNs with the risk of AMD in matched controls from the general population. Design, Setting, and Participants: A nationwide population-based cohort study using Danish registers was conducted of all patients in Denmark who received a diagnosis between January 1, 1994, and December 31, 2013, of essential thrombocythemia, polycythemia vera, myelofibrosis, or unclassifiable MPNs. For each patient, 10 age- and sex-matched controls were included. All patients without prior AMD were followed up from the date of diagnosis (or corresponding entry date for the controls) until the first AMD diagnosis, death or emigration, or December 31, 2013, whichever occurred first. Data analysis was performed from April 1, 2015, to October 31, 2016. Main Outcomes and Measures: Incidence of AMD recorded in specialized hospital-based care. The rates and absolute risk of AMD were calculated. Using Cox proportional hazards regression models, smoking and risk-time adjusted hazard ratios (HRs) between patients and controls were calculated. In addition, HRs of neovascular AMD after 2006 were calculated since antivascular endothelial growth factor treatment was introduced nationwide at hospitals thereafter. Results: A total of 7958 patients with MPNs (4279 women [53.8%] and 3679 men [46.2%]; mean [SD] age at diagnosis, 66.4 [14.3] years) were included in the study. The rate of AMD per 1000 person-years at risk was 5.2 (95% CI, 4.6-5.9) for patients with MPNs (2628 with essential thrombocythemia, 3063 with polycythemia vera, 547 with myelofibrosis, and 1720 with unclassifiable MPNs) and 4.3 (95% CI, 4.1-4.4) for the 77 445 controls, while the 10-year risk of AMD was 2.4% (95% CI, 2.1%-2.8%) for patients with MPNs and 2.3% (95% CI, 2.2%-2.4%) for the controls. The risk of AMD was increased overall for patients with MPNs (adjusted HR, 1.3; 95% CI, 1.1-1.5), with adjusted HRs for the subtypes of 1.2 (95% CI, 1.0-1.6) for essential thrombocythemia, 1.4 (95% CI, 1.2-1.7) for polycythemia vera, 1.7 (95% CI, 0.8-4.0) for myelofibrosis, and 1.5 (95% CI, 1.1-2.1) for unclassifiable MPNs. In addition, patients with MPNs had a higher risk of neovascular AMD (adjusted HR, 1.4; 95% CI, 1.2-1.6). Conclusions and Relevance: Our results suggest that patients with MPNs are at increased risk of AMD, supporting the possibility that systemic inflammation is involved in the pathogenesis of AMD.

A nationwide population-based cross-sectional survey of health-related quality of life in patients with myeloproliferative neoplasms in Denmark (MPNhealthSurvey): survey design and characteristics of respondents and nonrespondents.

OBJECTIVE: The Department of Hematology, Zealand University Hospital, Denmark, and the National Institute of Public Health, University of Southern Denmark, created the first nationwide, population-based, and the most comprehensive cross-sectional health-related quality of life (HRQoL) survey of patients with myeloproliferative neoplasms (MPNs). In Denmark, all MPN patients are treated in public hospitals and treatments received are free of charge for these patients. Therefore, MPN patients receive the best available treatment to the extent of its suitability for them and if they wish to receive the treatment. The aims of this article are to describe the survey design and the characteristics of respondents and nonrespondents. MATERIAL AND METHODS: Individuals with MPN diagnoses registered in the Danish National Patient Register (NPR) were invited to participate. The registers of the Danish Civil Registration System and Statistics Denmark provided information regarding demographics. The survey contained 120 questions: validated patient-reported outcome (PRO) questionnaires and additional questions addressing lifestyle. RESULTS: A total of 4,704 individuals were registered with MPN diagnoses in the NPR of whom 4,236 were eligible for participation and 2,613 (62%) responded. Overall, the respondents covered the broad spectrum of MPN patients, but patients 70-79 years old, living with someone, of a Danish/Western ethnicity, and with a higher level of education exhibited the highest response rate. CONCLUSION: A nationwide, population-based, and comprehensive HRQoL survey of MPN patients in Denmark was undertaken (MPNhealthSurvey). We believe that the respondents broadly represent the MPN population in Denmark. However, the differences between respondents and nonrespondents have to be taken into consideration when examining PROs from the respondents. The results of the investigation of the respondents' HRQoL in this survey will follow in future articles.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

BACKGROUND: More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE: The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS: A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES: The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS: The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.

A new internet-based tool for reporting and analysing patient-reported outcomes and the feasibility of repeated data collection from patients with myeloproliferative neoplasms.

PURPOSE: An Internet-based tool for reporting and analysing patient-reported outcomes (PROs) has been developed. The tool enables merging PROs with blood test results and allows for computation of treatment responses. Data may be visualized by graphical analysis and may be exported for downstream statistical processing. The aim of this study was to investigate, whether patients with myeloproliferative neoplasms (MPNs) were willing and able to use the tool and fill out questionnaires regularly. METHODS: Participants were recruited from the outpatient clinic at the Department of Haematology, Roskilde University Hospital, Denmark. Validated questionnaires that were used were European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Myeloproliferative Neoplasm Symptom Assessment Form, Brief Fatigue Inventory and Short Form 36 Health Survey. Questionnaires were filled out ≥ 6 months online or on paper according to participant preference. Regularity of questionnaire submission was investigated, and participant acceptance was evaluated by focus-group interviews. RESULTS: Of 135 invited patients, 118 (87 %) accepted participation. One hundred and seven participants (91 %) preferred to use the Internet-based tool. Of the 118 enrolled participants, 104 (88 %) submitted PROs regularly ≥ 6 months. The focus-group interviews revealed that the Internet-based tool was well accepted. CONCLUSION: The Internet-based approach and regular collection of PROs are well accepted with a high participation rate, persistency and adherence in a population of MPN patients. The plasticity of the platform allows for adaptation to patients with other medical conditions.