Effects of testosterone and sex hormone binding globulin on lung function in males and females: a multivariable Mendelian Randomisation study.

BACKGROUND: Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function. METHODS: We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank. FINDINGS: In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV1 in both males and females, but a moderate detrimental effect of SHBG on FEV1 and FEV1/FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG. INTERPRETATION: These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males.

Pre-pregnancy obesity among immigrant and non-immigrant women in Norway: Prevalence, trends, and subgroup variations.

INTRODUCTION: This study assessed prevalence and time trends of pre-pregnancy obesity in immigrant and non-immigrant women in Norway and explored the impact of immigrants' length of residence on pre-pregnancy obesity prevalence. MATERIAL AND METHODS: Observational data from the Medical Birth Registry of Norway and Statistics Norway for the years 2016-2021 were analyzed. Immigrants were categorized by their country of birth and further grouped into seven super regions defined by the Global Burden of Disease study. Pre-pregnancy obesity was defined as a body mass index ≥30.0 kg/m2, with exceptions for certain Asian subgroups (≥27.5 kg/m2). Statistical analysis involved linear regressions for trend analyses and log-binomial regressions for prevalence ratios (PRs). RESULTS: Among 275 609 pregnancies, 29.6% (N = 81 715) were to immigrant women. Overall, 13.6% were classified with pre-pregnancy obesity: 11.7% among immigrants and 14.4% among non-immigrants. Obesity prevalence increased in both immigrants and non-immigrants during the study period, with an average yearly increase of 0.62% (95% confidence interval [CI]: 0.55, 0.70). Obesity prevalence was especially high in women from Pakistan, Chile, Somalia, Congo, Nigeria, Ghana, Sri Lanka, and India (20.3%-26.9%). Immigrant women from "Sub-Saharan Africa" showed a strong association between longer residence length and higher obesity prevalence (≥11 years (23.1%) vs. <1 year (7.2%); adjusted PR = 2.40; 95% CI: 1.65-3.48), particularly in women from Kenya, Eritrea, and Congo. CONCLUSIONS: Prevalence of maternal pre-pregnancy obesity increased in both immigrant and non-immigrant women from 2016 to 2021. Several immigrant subgroups displayed a considerably elevated obesity prevalence, placing them at high risk for adverse obesity-related pregnancy outcomes. Particular attention should be directed towards women from "Sub-Saharan Africa", as their obesity prevalence more than doubled with longer residence.

Long-term effect of asthma on the development of obesity among adults: an international cohort study, ECRHS.

INTRODUCTION: Obesity is a known risk factor for asthma. Although some evidence showed asthma causing obesity in children, the link between asthma and obesity has not been investigated in adults. METHODS: We used data from the European Community Respiratory Health Survey (ECRHS), a cohort study in 11 European countries and Australia in 3 waves between 1990 and 2014, at intervals of approximately 10 years. We considered two study periods: from ECRHS I (t) to ECRHS II (t+1), and from ECRHS II (t) to ECRHS III (t+1). We excluded obese (body mass index≥30 kg/m2) individuals at visit t. The relative risk (RR) of obesity at t+1 associated with asthma at t was estimated by multivariable modified Poisson regression (lag) with repeated measurements. Additionally, we examined the association of atopy and asthma medication on the development of obesity. RESULTS: We included 7576 participants in the period ECRHS I-II (51.5% female, mean (SD) age of 34 (7) years) and 4976 in ECRHS II-III (51.3% female, 42 (8) years). 9% of participants became obese in ECRHS I-II and 15% in ECRHS II-III. The risk of developing obesity was higher among asthmatics than non-asthmatics (RR 1.22, 95% CI 1.07 to 1.38), and particularly higher among non-atopic than atopic (1.47; 1.17 to 1.86 vs 1.04; 0.86 to 1.27), those with longer disease duration (1.32; 1.10 to 1.59 in >20 years vs 1.12; 0.87 to 1.43 in ≤20 years) and those on oral corticosteroids (1.99; 1.26 to 3.15 vs 1.15; 1.03 to 1.28). Physical activity was not a mediator of this association. CONCLUSION: This is the first study showing that adult asthmatics have a higher risk of developing obesity than non-asthmatics, particularly those non-atopic, of longer disease duration or on oral corticosteroids.

Oral bacterial composition associated with lung function and lung inflammation in a community-based Norwegian population.

BACKGROUND: The oral cavity is the gateway to the bacteria community in the lung. Disruption of the symbiotic balance of the oral microbiota has been associated with respiratory diseases. However, little is known about the relationship between oral bacteria and respiratory outcomes in the general population. We aimed to describe the associations between oral bacteria, lung function, and lung inflammation in a community-based population. METHODS: Oral (gingival) samples were collected concurrently with spirometry tests in 477 adults (47% males, median age 28 years) from the RHINESSA study in Bergen, Norway. Bacterial DNA from the 16S rRNA gene from gingival fluid were sequenced by Illumina®MiSeq. Lung function was measured using spirometry and measurement of fractional exhaled nitric oxide (FeNO) were performed to examine airway inflammation. Differential abundance analysis was performed using ANCOM-BC, adjusting for weight, education, and smoking. RESULTS: The abundance of the genera Clostridiales, Achromobacter, Moraxella, Flavitalea and Helicobacter were significantly different among those with low FEV1 (< lower limit of normal (LLN)) as compared to normal FEV1 i.e. ≥ LLN. Twenty-three genera differed in abundance between among those with low FVC < LLN as compared to normal FEV1 ≥ LLN. The abundance of 27 genera from phyla Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria and Sacchribacteria differed significantly between elevated FeNO levels (≥ 50 ppb) compared to FeNO ≤ 25 ppb. CONCLUSION: Oral bacterial composition was significantly different for those with low FEV or FVC as compared to those with normal lung function equal to or higher than LLN. Differential bacterial composition was also observed for elevated FeNO levels.

Breathlessness across generations: results from the RHINESSA generation study.

BACKGROUND: Breathlessness is a major cause of suffering and disability globally. The symptom relates to multiple factors including asthma and lung function, which are influenced by hereditary factors. No study has evaluated potential inheritance of breathlessness itself across generations. METHODS: We analysed the association between breathlessness in parents and their offspring in the Respiratory Health in Northern Europe, Spain and Australia generation study. Data on parents and offspring aged ≥18 years across 10 study centres in seven countries included demographics, self-reported breathlessness, asthma, depression, smoking, physical activity level, measured Body Mass Index and spirometry. Data were analysed using multivariable logistic regression accounting for clustering within centres and between siblings. RESULTS: A total of 1720 parents (mean age at assessment 36 years, 55% mothers) and 2476 offspring (mean 30 years, 55% daughters) were included. Breathlessness was reported by 809 (32.7%) parents and 363 (14.7%) offspring. Factors independently associated with breathlessness in parents and offspring included obesity, current smoking, asthma, depression, lower lung function and female sex. After adjusting for potential confounders, parents with breathlessness were more likely to have offspring with breathlessness, adjusted OR 1.8 (95% CI 1.1 to 2.9). The association was not modified by sex of the parent or offspring. CONCLUSION: Parents with breathlessness were more likely to have children who developed breathlessness, after adjusting for asthma, lung function, obesity, smoking, depression and female sex in both generations. The hereditary components of breathlessness need to be further explored.

Prenatal and prepubertal exposures to tobacco smoke in men may cause lower lung function in future offspring: a three-generation study using a causal modelling approach.

Mechanistic research suggests that lifestyle and environmental factors impact respiratory health across generations by epigenetic changes transmitted through male germ cells. Evidence from studies on humans is very limited.We investigated multigeneration causal associations to estimate the causal effects of tobacco smoking on lung function within the paternal line. We analysed data from 383 adult offspring (age 18-47 years; 52.0% female) and their 274 fathers, who had participated in the European Community Respiratory Health Survey (ECRHS)/Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study and had provided valid measures of pre-bronchodilator lung function. Two counterfactual-based, multilevel mediation models were developed with: paternal grandmothers' smoking in pregnancy and fathers' smoking initiation in prepuberty as exposures; fathers' forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), or FEV1/FVC z-scores as potential mediators (proxies of unobserved biological mechanisms that are true mediators); and offspring's FEV1 and FVC, or FEV1/FVC z-scores as outcomes. All effects were summarised as differences (Δ) in expected z-scores related to fathers' and grandmothers' smoking history.Fathers' smoking initiation in prepuberty had a negative direct effect on both offspring's FEV1 (Δz-score -0.36, 95% CI -0.63- -0.10) and FVC (-0.50, 95% CI -0.80- -0.20) compared with fathers' never smoking. Paternal grandmothers' smoking in pregnancy had a negative direct effect on fathers' FEV1/FVC (-0.57, 95% CI -1.09- -0.05) and a negative indirect effect on offspring's FEV1/FVC (-0.12, 95% CI -0.21- -0.03) compared with grandmothers' not smoking before fathers' birth nor during fathers' childhood.Fathers' smoking in prepuberty and paternal grandmothers' smoking in pregnancy may cause lower lung function in offspring. Our results support the concept that lifestyle-related exposures during these susceptibility periods influence the health of future generations.

Exposures during the prepuberty period and future offspring's health: evidence from human cohort studies†.

Emerging evidence suggests that exposures in prepuberty, particularly in fathers-to-be, may impact the phenotype of future offspring. Analyses of the RHINESSA cohort find that offspring of father's exposed to tobacco smoking or overweight that started in prepuberty demonstrate poorer respiratory health in terms of more asthma and lower lung function. A role of prepuberty onset smoking for offspring fat mass is suggested in the RHINESSA and ALSPAC cohorts, and historic studies suggest that ancestral nutrition during prepuberty plays a role for grand-offspring's health and morbidity. Support for causal relationships between ancestral exposures and (grand-)offspring's health in humans has been enhanced by advancements in statistical analyses that optimize the gain while accounting for the many complexities and deficiencies in human multigeneration data. The biological mechanisms underlying such observations have been explored in experimental models. A role of sperm small RNA in the transmission of paternal exposures to offspring phenotypes has been established, and chemical exposures and overweight have been shown to influence epigenetic programming in germ cells. For example, exposure of adolescent male mice to smoking led to differences in offspring weight and alterations in small RNAs in the spermatozoa of the exposed fathers. It is plausible that male prepuberty may be a time window of particular susceptibility, given the extensive epigenetic reprogramming taking place in the spermatocyte precursors at this age. In conclusion, epidemiological studies in humans, mechanistic research, and biological plausibility, all support the notion that exposures in the prepuberty of males may influence the phenotype of future offspring.

Early menarche is associated with lower adult lung function: A longitudinal cohort study from the first to sixth decade of life.

BACKGROUND AND OBJECTIVE: Early menarche is increasing in prevalence worldwide, prompting clinical and public health interest on its links with pulmonary function. We aimed to investigate the relationship between early menarche and lung function in middle age. METHODS: The population-based Tasmanian Longitudinal Health Study (born 1961; n = 8583), was initiated in 1968. The 5th Decade follow-up data (mean age: 45 years) included age at menarche and complex lung function testing. The 6th Decade follow-up (age: 53 years) repeated spirometry and gas transfer factor. Multiple linear regression and mediation analyses were performed to determine the association between age at menarche and adult lung function and investigate biological pathways, including the proportion mediated by adult-attained height. RESULTS: Girls reporting an early menarche (<12 years) were measured to be taller with greater lung function at age 7 years compared with those reporting menarche ≥12 years. By 45 years of age, they were shorter and had lower post-bronchodilator (BD) forced expiratory volume in 1 s (adjusted mean difference: -133 mL; 95% CI: -233, -33), forced vital capacity (-183 mL; 95% CI: -300, -65) and functional residual capacity (-168 mL; 95% CI: -315, -21). Magnitudes of spirometric deficits were similar at age 53 years. Forty percent of these total effects were mediated through adult-attained height. CONCLUSION: Early menarche was associated with reduced adult lung function. This is the first study to investigate post-BD outcomes and quantify the partial role of adult height in this association.

Age at menopause and lung function: a Mendelian randomisation study.

In observational studies, early menopause is associated with lower forced vital capacity (FVC) and a higher risk of spirometric restriction, but not airflow obstruction. It is, however, unclear if this association is causal. We therefore used a Mendelian randomisation (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function.We included 94 742 naturally post-menopausal women from the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1 s (FEV1), FVC, FEV1/FVC, spirometric restriction (FVC

Leisure-time vigorous physical activity is associated with better lung function: the prospective ECRHS study.

OBJECTIVE: We assessed associations between physical activity and lung function, and its decline, in the prospective population-based European Community Respiratory Health Survey cohort. METHODS: FEV1 and FVC were measured in 3912 participants at 27-57 years and 39-67 years (mean time between examinations=11.1 years). Physical activity frequency and duration were assessed using questionnaires and used to identify active individuals (physical activity ≥2 times and ≥1 hour per week) at each examination. Adjusted mixed linear regression models assessed associations of regular physical activity with FEV1 and FVC. RESULTS: Physical activity frequency and duration increased over the study period. In adjusted models, active individuals at the first examination had higher FEV1 (43.6 mL (95% CI 12.0 to 75.1)) and FVC (53.9 mL (95% CI 17.8 to 89.9)) at both examinations than their non-active counterparts. These associations appeared restricted to current smokers. In the whole population, FEV1 and FVC were higher among those who changed from inactive to active during the follow-up (38.0 mL (95% CI 15.8 to 60.3) and 54.2 mL (95% CI 25.1 to 83.3), respectively) and who were consistently active, compared with those consistently non-active. No associations were found for lung function decline. CONCLUSION: Leisure-time vigorous physical activity was associated with higher FEV1 and FVC over a 10-year period among current smokers, but not with FEV1 and FVC decline.

Maternal age at delivery, lung function and asthma in offspring: a population-based survey.

There is limited information about potential impact of maternal age on the respiratory health of offspring. We investigated the association of maternal age at delivery with adult offspring's lung function, respiratory symptoms and asthma, and potential differences according to offspring sex.10 692 adults from 13 countries participating in the European Community Respiratory Health Survey (ECRHS) II responded to standardised interviews and provided lung function measurements and serum for IgE measurements at age 25-55 years. In logistic and linear multilevel mixed models we adjusted for participants' characteristics (age, education, centre, number of older siblings) and maternal characteristics (smoking in pregnancy, education) while investigating for differential effects by sex. Maternal age was validated in a subsample using data from the Norwegian birth registry.Increasing maternal age was associated with increasing forced expiratory volume in 1 s (2.33 mL per year, 95% CI 0.34-4.32 mL per year), more consistent in females (ptrend 0.025) than in males (ptrend 0.14). Asthma (OR 0.85, 95% CI 0.79-0.92) and respiratory symptoms (OR 0.87, 95% CI 0.82-0.92) decreased with increasing maternal age (per 5 years) in females, but not in males (pinteraction 0.05 and 0.001, respectively). The results were consistent across centres and not explained by confounding factors.Maternal ageing was related to higher adult lung function and less asthma/symptoms in females. Biological characteristics in offspring related to maternal ageing are plausible and need further investigation.

Menopause Is Associated with Accelerated Lung Function Decline.

RATIONALE: Menopause is associated with changes in sex hormones, which affect immunity, inflammation, and osteoporosis and may impair lung function. Lung function decline has not previously been investigated in relation to menopause. OBJECTIVES: To study whether lung function decline, assessed by FVC and FEV1, is accelerated in women who undergo menopause. METHODS: The population-based longitudinal European Community Respiratory Health Survey provided serum samples, spirometry, and questionnaire data about respiratory and reproductive health from three study waves (n = 1,438). We measured follicle-stimulating hormone and luteinizing hormone and added information on menstrual patterns to determine menopausal status using latent class analysis. Associations with lung function decline were investigated using linear mixed effects models, adjusting for age, height, weight, pack-years, current smoking, age at completed full-time education, spirometer, and including study center as random effect. MEASUREMENTS AND MAIN RESULTS: Menopausal status was associated with accelerated lung function decline. The adjusted mean FVC decline was increased by -10.2 ml/yr (95% confidence interval [CI], -13.1 to -7.2) in transitional women and -12.5 ml/yr (95% CI, -16.2 to -8.9) in post-menopausal women, compared with women menstruating regularly. The adjusted mean FEV1 decline increased by -3.8 ml/yr (95% CI, -6.3 to -2.9) in transitional women and -5.2 ml/yr (95% CI, -8.3 to -2.0) in post-menopausal women. CONCLUSIONS: Lung function declined more rapidly among transitional and post-menopausal women, in particular for FVC, beyond the expected age change. Clinicians should be aware that respiratory health often deteriorates during reproductive aging.

Menopause as a predictor of new-onset asthma: A longitudinal Northern European population study.

BACKGROUND: There is limited and conflicting evidence on the effect of menopause on asthma. OBJECTIVES: We sought to study whether the incidence of asthma and respiratory symptoms differ by menopausal status in a longitudinal population-based study with an average follow-up of 12 years. METHODS: The Respiratory Health in Northern Europe study provided questionnaire data pertaining to respiratory and reproductive health at baseline (1999-2001) and follow-up (2010-2012). The study cohort included women aged 45 to 65 years at follow-up, without asthma at baseline, and not using exogenous hormones (n = 2322). Menopausal status was defined as nonmenopausal, transitional, early postmenopausal, and late postmenopausal. Associations with asthma (defined by the use of asthma medication, having asthma attacks, or both) and respiratory symptoms scores were analyzed by using logistic (asthma) and negative binomial (respiratory symptoms) regressions, adjusting for age, body mass index, physical activity, smoking, education, and study center. RESULTS: The odds of new-onset asthma were increased in women who were transitional (odds ratio, 2.40; 95% CI, 1.09-5.30), early postmenopausal (odds ratio, 2.11; 95% CI, 1.06-4.20), and late postmenopausal (odds ratio, 3.44; 95% CI, 1.31-9.05) at follow-up compared with nonmenopausal women. The risk of respiratory symptoms increased in early postmenopausal (coefficient, 0.40; 95% CI, 0.06-0.75) and late postmenopausal (coefficient, 0.69; 95% CI, 0.15-1.23) women. These findings were consistent irrespective of smoking status and across study centers. CONCLUSIONS: New-onset asthma and respiratory symptoms increased in women becoming postmenopausal in a longitudinal population-based study. Clinicians should be aware that respiratory health might deteriorate in women during reproductive aging.

Oxygen desaturation in 6-min walk test is a risk factor for adverse outcomes in COPD.

The 6-min walk test (6MWT) is an exercise test that measures functional status in chronic obstructive pulmonary disease (COPD) patients and provides information on oxygen desaturation. We investigated oxygen desaturation during 6MWT as a risk factor for important COPD outcomes: mortality, frequency of exacerbations, decline in lung function and decline in lean body mass.433 COPD patients were included in the Bergen COPD Cohort Study 2006-2009, and followed-up for 3 years. Patients were characterised using spirometry, bioelectrical impedance measurements, Charlson comorbidity score, exacerbation history, smoking and arterial blood gases. 370 patients completed the 6MWT at the baseline of the study. Information on all-cause mortality was collected in 2011.Patients who experienced oxygen desaturation during the 6MWT had an approximately twofold increased risk of death (hazard ratio 2.4, 95% CI 1.2-5.1), a 50% increased risk for experiencing later COPD exacerbations (incidence rate ratio 1.6, 95% CI 1.1-2.2), double the yearly rate of decline in both forced vital capacity and forced expiratory volume in 1 s (3.2% and 1.7% versus 1.7% and 0.9%, respectively) and manifold increased yearly rate of loss of lean body mass (0.18 kg·m(-2) versus 0.03 kg·m(-2) among those who did not desaturate).Desaturating COPD patients had a significantly worse prognosis than non-desaturating COPD patients, for multiple important disease outcomes.

Lower lung function associates with cessation of menstruation: UK Biobank data.

Little is known about the effect of cessation of menstruation on lung function. The aims of the study were to examine the association of lung function with natural and surgical cessation of menstruation, and assess whether lower lung function is associated with earlier age at cessation of menstruation.The study was performed in 141 076 women from the UK Biobank, who had provided acceptable and reproducible spirometry measurements and information on menstrual status. The associations of lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), spirometric restriction (FVC < lower limit of normal (LLN)), airflow obstruction (FEV1/FVC

Fathers' preconception smoking and offspring DNA methylation.

BACKGROUND: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father's preconception smoking. METHODS: We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7-50 years) on father's any preconception smoking (n = 875 offspring) and father's pubertal onset smoking < 15 years (n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father's smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure. RESULTS: Father's smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) < 0.05) in PRR5 and CENPP. Father's pubertal onset smoking was associated with 19 CpGs (FDR < 0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (p < 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father's smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR < 0.05), and all sites remained significant (p < 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure. CONCLUSION: Father's preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.

Gender differences in prevalence, diagnosis and incidence of allergic and non-allergic asthma: a population-based cohort.

BACKGROUND: Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population. METHODS: Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8-10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens. RESULTS: Asthma was 20% more frequent in women than in men over the age of 35 years. Possible under-diagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma. CONCLUSIONS: This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.

Lifelong exposure to residential greenspace and the premenstrual syndrome: A population-based study of Northern European women.

BACKGROUND: The premenstrual syndrome (PMS) causes clinically relevant psychological and physical symptoms in up to 20% of women of reproductive age. To date, no studies have investigated the relationship between PMS and residential surrounding greenspace, although a green living environment has been reported to have beneficial associations with overall and reproductive health. OBJECTIVE: To investigate whether lifelong exposure to residential surrounding greenspace is associated with PMS and whether such an association is mediated by BMI, air pollution or physical activity. METHODS: This study used data collected in 2013-2015 from 1069 Scandinavian women aged 18-49 years, participating in RHINESSA, a European multi-centre and population-based cohort. Satellite-derived Normalised Difference Vegetation Index was used as a proxy of greenspace. Presence of eight common PMS symptoms and their sum (PMS symptom count) were used as outcomes. The associations were assessed by adjusted multilevel logistic and negative binomial regressions. Subsequently we carried out mediation analyses for physical activity, BMI and air pollution exposure. RESULTS: Higher exposure to residential surrounding greenspace was associated with "Anxiety or tension" (Odds Ratio 0.82, 95% Confidence Interval (CI): 0.70 - 0.95), "Depression or hopelessness" (0.84, 0.73 - 0.98), "Difficulty with sleeping" (0.82, 0.68 - 1.00) and "Breast tenderness and abdominal bloating" (0.84, 0.71 - 0.99) before or around the start of the menstrual period. There was also an association with a lower PMS symptom count (Risk Ratio: 0.94, 95% CI: 0.91 - 0.99). These associations were robust to sensitivity analyses and were not mediated by BMI, physical activity or air pollution. CONCLUSIONS: Living in greener areas may be beneficial against PMS symptoms. Further studies are needed to confirm these novel findings and to explore the underlying biological mechanisms.

Parental Prepuberty Overweight and Offspring Lung Function.

In a recent study we found that fathers' but not mothers' onset of overweight in puberty was associated with asthma in adult offspring. The potential impact on offspring's adult lung function, a key marker of general and respiratory health, has not been studied. We investigated the potential causal effects of parents' overweight on adult offspring's lung function within the paternal and maternal lines. We included 929 offspring (aged 18-54, 54% daughters) of 308 fathers and 388 mothers (aged 40-66). Counterfactual-based multi-group mediation analyses by offspring's sex (potential moderator) were used, with offspring's prepubertal overweight and/or adult height as potential mediators. Unknown confounding was addressed by simulation analyses. Fathers' overweight before puberty had a negative indirect effect, mediated through sons' height, on sons' forced expiratory volume in one second (FEV1) (beta (95% CI): -144 (-272, -23) mL) and forced vital capacity (FVC) (beta (95% CI): -210 (-380, -34) mL), and a negative direct effect on sons' FVC (beta (95% CI): -262 (-501, -9) mL); statistically significant effects on FEV1/FVC were not observed. Mothers' overweight before puberty had neither direct nor indirect effects on offspring's lung function. Fathers' overweight starting before puberty appears to cause lower FEV1 and FVC in their future sons. The effects were partly mediated through sons' adult height but not through sons' prepubertal overweight.