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Background The assessment of small airways obstruction (SAO) using spirometry is practiced in population-based studies. However, it is not clear what are the most used parameters and cut-offs to define abnormal results. Methods We searched three databases (Medline, Web of Science, Google Scholar) for population-based studies, published by 1 May 2021, that used spirometry parameters to identify SAO and/or provided criteria for defining SAO. We systematically reviewed these studies and summarised evidence to determine the most widely used spirometry parameter and criteria for defining SAO. In addition, we extracted prevalence estimates and identified associated risk factors. To estimate a pooled prevalence of SAO, we conducted a meta-analysis and explored heterogeneity across studies using meta regression. Results Twenty-five studies used spirometry to identify SAO. The most widely utilised parameter (15 studies) was FEF 25–75 , either alone or in combination with other measurements. Ten studies provided criteria for the definition of SAO, of which percent predicted cut-offs were the most common (5 studies). However, there was no agreement on which cut-off value to use. Prevalence of SAO ranged from 7.5% to 45.9%. As a result of high heterogeneity across studies (I 2  = 99.3%), explained by choice of spirometry parameter and WHO region, we do not present a pooled prevalence estimate. Conclusion There is a lack of consensus regarding the best spirometry parameter or defining criteria for identification of SAO. The value of continuing to measure SAO using spirometry is unclear without further research using large longitudinal data. PROSPERO registration number CRD42021250206

Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males. MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10(-5)) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10(-4)), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking. This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.

Small airways obstruction (SAO) has been associated with occupational exposures. Whether exposure to harmful occupational agents impacts the survival of people with SAO is unknown. Our aim was to estimate the mortality risk associated with occupational exposures among people with SAO. We used data from UK Biobank participants with SAO, defined as a ratio of forced expiratory volume in three seconds to forced expiratory volume in six seconds (FEV3/FEV6) below the lower limit of normal. We assigned lifetime occupational exposures to participants with available occupational histories using the ALOHA+ Job Exposure Matrix. Mortality data were provided by the National Death Registries. We used Cox regression to assess the association of all-cause mortality with lifetime occupational exposures (vapours, gases, dusts, fumes-VGDF; solvents; pesticides; metals), adjusting for potential confounders. The 13,942 participants with SAO had a mean age of 56±7 years, 59% were females and 94.2% were of White ancestry. Overall, there were 457 deaths over a median follow-up of 12.8 years. A greater mortality risk was associated with exposure to VGDF, with hazard ratios of 1.32 (95%CI: 1.04-1.78) for low levels and 1.41 (95%CI: 1.11-1.78) for moderate levels of cumulative exposure. There was no evidence of association for the other occupational exposures. Lifetime occupational exposure to VGDF in people with SAO may have a detrimental effect on their survival. Future respiratory health surveillance programmes of people exposed to VGDF should consider assessment for SAO and focus on primary prevention through adequate exposure control.

The role of systemic inflammation in the pathogenesis of respiratory diseases is increasingly recognized, but the relationship between individual inflammatory markers, lung function and respiratory symptoms is not well established. We studied 1,238 adults participating in the first follow-up of the Burden of Obstructive Lung Disease (BOLD) cohort study in Sweden, Norway, Iceland, and Estonia in 2019–2021. Systemic inflammation was assessed using total white blood cell (WBC) count and WBC sub-populations (neutrophils, lymphocytes, monocytes, eosinophils, basophils and neutrophil-to-lymphocyte ratio (NLR)). In regression models adjusted for gender, age, smoking status, body mass index and study site, all WBC sub-populations, except for lymphocytes, were associated with chronic airflow obstruction (CAO) and wheeze. In never smokers, increased neutrophils were associated with reduced lung volumes (FEV 1 β coef. with 95%CI -1.95 (-3.33, -0.57) p  = 0.006; FVC − 1.94 (-3.18, -0.69) p  = 0.002), but not CAO. Only increased basophils were associated with CAO in never smokers (OR with 95%CI 2.70 (1.28, 5.72) p  = 0.009). In former smokers, increased neutrophils, monocytes and eosinophils were significantly associated with reduced FEV 1 , reduced FVC, CAO and wheeze. In current smokers, inflammatory markers were associated with cough (neutrophils OR with 95%CI 1.49 (1.10, 2.01) p  = 0.010; monocytes 1.24 (0.99, 1.55) p  = 0.058; basophils 2.56 (1.12, 5.86) p  = 0.026). Systemic inflammation may be related to both obstructive and restrictive respiratory impairment in the general population, with associations that vary by smoking status.

Background and Aims Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. Methods The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. Results Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; ptrend=5×10−6), arsenic (OR 2.02, 95% CI 1.08 to 3.78; ptrend=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; ptrend=3×10−5) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; ptrend=8×10−11) and nickel (OR 0.27, 95% CI 0.12 to 0.59; ptrend=2×10−4) were inversely associated with the risk of EPC. Conclusion Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.

Background Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies ( N > 82,000). Results We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

Background Whether restricted spirometry, i.e. low Forced Vital Capacity (FVC), predicts chronic cardiometabolic disease is not definitely known. In this international population-based study, we assessed the relationship between restricted spirometry and cardiometabolic comorbidities. Methods A total of 23,623 subjects (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) from five continents (33 sites in 29 countries) participating in the Burden of Obstructive Lung Disease (BOLD) study were included. Restricted spirometry was defined as post-bronchodilator FVC < 5th percentile of reference values. Self-reports of physician-diagnosed cardiovascular disease (CVD; heart disease or stroke), hypertension, and diabetes were obtained through questionnaires. Results Overall 31.7% of participants had restricted spirometry. However, prevalence of restricted spirometry varied approximately ten-fold, and was lowest (8.5%) in Vancouver (Canada) and highest in Sri Lanka (81.3%). Crude odds ratios for the association with restricted spirometry were 1.60 (95% CI 1.37–1.86) for CVD, 1.53 (95% CI 1.40–1.66) for hypertension, and 1.98 (95% CI 1.71–2.29) for diabetes. After adjustment for age, sex, education, Body Mass Index (BMI) and smoking, the odds ratios were 1.54 (95% CI 1.33–1.79) for CVD, 1.50 (95% CI 1.39–1.63) for hypertension, and 1.86 (95% CI 1.59–2.17) for diabetes. Conclusion In this population-based, international, multi-site study, restricted spirometry associates with cardiometabolic diseases. The magnitude of these associations appears unattenuated when cardiometabolic risk factors are taken into account.

Objective Tuberculosis (TB) is a leading cause of death globally, with approximately 1.5 million deaths in 2020. TB often coexists with chronic communicable and non-communicable diseases, but data to determine the extent of comorbid diseases are limited. In this study, we aimed to assess the prevalence of TB multimorbidity and its risk factors in a tertiary hospital in Sierra Leone. This is a cross-sectional study of 240 adults with microbiologically-confirmed TB at Connaught Hospital in Freetown, between March and May 2022. Logistic regression analysis was used to identify factors associated with TB multimorbidity. Results The mean age of the patients was 37 years. More than two-thirds were males and about the same number had two or more chronic diseases. The most common were hypertension (47.9%) and diabetes (24.2%). Patients under 35 years of age were less likely to have TB multimorbidity (< 25 years: adjusted OR 0.07, 95%CI 0.01–0.6; 25–34 years: adjusted OR 0.2, 95%CI 0.01–0.9). We report a high prevalence of comorbid diseases among TB patients in the largest treatment center in Sierra Leone, with hypertension and diabetes being the most common. These findings support the current call for addressing comorbid non-communicable diseases in TB patients through integrated care.

Background: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are common chronic diseases that are associated with chronic and intermittent hypoxemia, respectively. Patients affected by the overlap of COPD and OSA have a particularly unfavourable prognosis. The L-arginine/nitric oxide (NO) pathway plays an important role in regulating pulmonary vascular function. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) interfere with NO production. Methods: We analysed the serum concentrations of ADMA, SDMA, L-arginine, L-citrulline, and L-ornithine in a large sample of the Icelandic general population together with chronic airflow obstruction (CAO), a key physiological marker of COPD that was assessed by post-bronchodilator spirometry (FEV1/FVC < LLN). OSA risk was determined by the multivariable apnoea prediction (MAP) index. Results: 713 individuals were analysed, of whom 78 (10.9%) showed CAO and 215 (30%) had MAP > 0.5. SDMA was significantly higher in individuals with CAO (0.518 [0.461–0.616] vs. 0.494 [0.441–0.565] µmol/L; p = 0.005), but ADMA was not. However, ADMA was significantly associated with decreasing FEV1 percent predicted among those with CAO (p = 0.002). ADMA was 0.50 (0.44–0.56) µmol/L in MAP ≤ 0.5 versus 0.52 (0.46–0.58) µmol/L in MAP > 0.5 (p = 0.008). SDMA was 0.49 (0.44–0.56) µmol/L versus 0.51 (0.46–0.60) µmol/L, respectively (p = 0.004). The highest values for ADMA and SDMA were observed in individuals with overlap of CAO and MAP > 0.5, which was accompanied by lower L-citrulline levels. Conclusions: The plasma concentrations of ADMA and SDMA are elevated in COPD patients with concomitant intermittent hypoxaemia. This may account for impaired pulmonary NO production, enhanced pulmonary vasoconstriction, and disease progression.