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In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

Abstract Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.

To observe overall, training, and match injury incidence in female youth football. We also aimed to quantify the incidence of injuries by affected tissue and body location. The following databases were examined: PubMed, Web of Science, Scopus, SPORTDiscus, Cochrane and PEDro. Papers that reported overall injury incidence, training or match injury incidence were included. Additionally, studies had to be performed in adolescent female football players (13 19 years of age). The Newcastle-Ottawa Scale and the checklist of items that must be included in epidemiological football reports were used to assess methodological quality of the included articles. For the meta-analyses, a random effect model was used. A total of 13 studies were included. There were 2,333 injuries; incidence was higher during games (12.7/1000 h) compared to training sessions (2.3/1000 h). The injury match-to-training ratio was 5.8. The lower limbs were the region in which the greatest number of injuries occurred, with the ankle (1.2/1000 h) and knee (0.8/1000 h) having the most injuries. In relation to injured tissue, ligament injuries represented an incidence of 1.3/1000 h, followed by muscle injuries (0.9/1000 h). This study represents the first step towards the creation and implementation of preventative measures in female youth football. The results suggest that attention should be focused on ankle and knee injuries, since they are the most frequent and can lead to sport retirement in some cases depending on the severity.

Background: Air pollution exposure during pregnancy and childhood has been linked to executive function impairment in children, however, very few studies have assessed these two exposure periods jointly to identify susceptible periods of exposure. We sought to identify potential periods of susceptibility of nitrogen dioxide (NO2) exposure from conception to childhood on attentional function and working memory in school-aged children. Methods: Within the Spanish INMA Project, we estimated residential daily NO2 exposures during pregnancy and up to 6 years of childhood using land use regression models (n = 1,703). We assessed attentional function at 4–6 years and 6–8 years, using the Conners Kiddie Continuous Performance Test and the Attention Network Test, respectively, and working memory at 6–8 years, using the N-back task. We used distributed lag non-linear models to assess the periods of susceptibility of each outcome, adjusting for potential confounders and correcting for multiple testing. We also stratified all models by sex. Results: Higher exposure to NO2 between 1.3 and 1.6 years of age was associated with higher hit reaction time standard error (HRT-SE) (0.14 ms (95 % CI 0.05; 0.22) per 10 μg/m3 increase in NO2) and between 1.5 and 2.2 years of age with more omission errors (1.02 (95 % CI 1.01; 1.03) of the attentional function test at 4–6 years. Higher exposure to NO2 between 0.3 and 2.2 years was associated with higher HRT-SE (10.61 ms (95 % CI 3.46; 17.75) at 6–8 years only in boys. We found no associations between exposure to NO2 and working memory at 6–8 years. Conclusion: Our findings suggest that NO2 exposure during the first two years of life is associated with poorer attentional function in children from 4 to 8 years of age, especially in boys. These findings highlight the importance of exploring long-term effects of traffic-related air pollution exposure in older age groups.

Introduction: Ambient air temperature may affect birth outcomes adversely, but little is known about their impact on foetal growth throughout pregnancy. We evaluated the association between temperature exposure during pregnancy and foetal size and growth in three European birth cohorts. Methods: We studied 23,408 pregnant women from the English Born in Bradford cohort, Dutch Generation R Study, and Spanish INMA Project. Using the UrbClimTM model, weekly ambient air temperature exposure at 100x100m resolution at the mothers’ residences during pregnancy was calculated. Estimated foetal weight, head circumference, and femur length at mid and late pregnancy and weight, head circumference, and length at birth were converted into standard deviation scores (SDS). Foetal growth from mid to late pregnancy was calculated (grams or centimetres/week). Cohort/region-specific distributed lag non-linear models were combined using a random-effects meta-analysis and results presented in reference to the median percentile of temperature (14 °C). Results: Weekly temperatures ranged from −5.6 (Bradford) to 30.3 °C (INMA-Sabadell). Cold and heat exposure during weeks 1–28 were associated with a smaller and larger head circumference in late pregnancy, respectively (e.g., for 9.5 °C: −1.6 SDS [95 %CI −2.0; −0.4] and for 20.0 °C: 1.8 SDS [0.7; 2.9]). A susceptibility period from weeks 1–7 was identified for cold exposure and a smaller head circumference at late pregnancy. Cold exposure was associated with a slower head circumference growth from mid to late pregnancy (for 5.5 °C: −0.1 cm/week [-0.2; −0.04]), with a susceptibility period from weeks 4–12. No associations that survived multiple testing correction were found for other foetal or any birth outcomes. Conclusions: Cumulative exposure to cold and heat during pregnancy was associated with changes in foetal head circumference throughout gestation, with susceptibility periods for cold during the first pregnancy trimester. No associations were found at birth, suggesting potential recovery. Future research should replicate this study across different climatic regions including varying temperature profiles.

Abstract Background Asturias is one of the communities with the highest rates of hospital admission for asthma in Spain. The environmental pollution or people lifestyle are some of the factors that contribute to the appearance or aggravation of this illness. The aim of this study was to show the spatial distribution of asthma admissions risks in the central municipalities of Asturias and to analyze the observed spatial patterns. Methods Urgent hospital admissions for asthma and status asthmaticus occurred between 2016 to 2018 on the public hospitals of the central area of Asturias were used. Population data were assigned in 5 age groups. Standardised admission ratio (SAR), smoothed relative risk (SRR) and posterior risk probability (PP) were calculated for each census tract (CT). A spatial trend analysis was run, a spatial autocorrelation index (Morans I) was calculated and a cluster and outlier analysis (Anselin Local Morans I) was finally performed in order to analyze spatial clusters. Results The total number of hospital urgent asthma admissions during the study period was 2324, 1475 (63.46%) men and 849 (36.56%) women. The municipalities with the highest values of SRR and PP were located on the northwest area: Avilés, Gozón, Carreño, Corvera de Asturias, Castrillón and Illas. A high risk cluster was found for the municipalities of Avilés, Gozón y Corvera de Asturias. Conclusions The spatial analysis showed high risk of hospitalization for asthma on the municipalities of the northwest area of the study, which highlight the existence of spatial inequalities on the distribution of urgent hospital admissions.

Abstract Background Chronic obstructive pulmonary disease (COPD) is one of the major causes of mortality worldwide and also reports high morbidity rates and the global burden COPD has continued to rise over the last several decades. The best-known COPD risk factors are tobacco smoke and air pollution, but genetics, age, sex, and socioeconomic status are additional factors. This study aimed to assess the spatial distribution of unscheduled COPD hospital admissions of men and women in the central area of Asturias during 2016–2018 and identify trends, spatial patterns, or clusters in the area. Methods Unscheduled COPD hospital admissions in the central area of Asturias were registered, geocoded, and grouped by census tracts (CTs), age, and sex. Standardized admission ratio, smoothed relative risk, posterior risk probability, and spatial clusters between relative risks throughout the study area were calculated and mapped. Results The spatial distribution of COPD hospital admissions differed between men and women. For men, high-risk values were located primarily in the northwestern area of the study, whereas for women the cluster pattern was not as clear and high-risk CTs also reached central and southern areas. In both men and women, the north-northwest area included the majority of CTs with high-risk values. Conclusions The present study showed the existence of a spatial distribution pattern of unscheduled COPD hospital admissions in the central area of Asturias that was more pronounced for men than for women. This study could provide a starting point for generating knowledge about COPD epidemiology in Asturias.

AimThis study aimed to investigate whether there are subgroups of children with different clusters of cardiovascular disease (CVD) risk factors at 4 and 8 years of age, and their patterns of change between these two time points.MethodsThe analysis was conducted in 332 children who participated in the INMA-Asturias cohort (Spain) at 4 and at 8 years of age. The CVD risk factors were central obesity, dyslipidaemia, hyperglycaemia, and hypertension. Latent transition analysis was used to identify the different clusters and their probabilities of change.ResultsAt 4 years, three subgroups were identified: no disorders (prevalence of 55.9%); some disorders (21.2%), and central obesity (22.9%). Three distinct subgroups were identified at 8 years: no disorders (59.8%); hypertension (17.9%), and central obesity (22.3%). Central obesity at 4 years tends to appear simultaneously with dyslipidaemia, while at 8 years it tends to appear simultaneously with dyslipidaemia and/or hypertension. Children aged 4 years with no disorders had a 93.7% probability of remaining in the same status at 8 years of age. Children aged 4 who had some disorders had a 67.7% of probability of having only hypertension and a 32.3% of probability of having central obesity. Children aged 4 in the central obesity subgroup had a 32.4% of probability of having no disorders at 8 years of age, while 67.6% still had central obesity.ConclusionsThese exploratory findings suggest that children who do not present any disorder at 4 years of age tend to remain in that state at 8 years of age. And also that central obesity may play a major role in the development of other disorders, as the number of disorders with which it concomitantly occurs increases between the ages of 4 and 8 years.

Modern science is frequently based on the exploitation of large volumes of information storage in datasets and involving complex computational architectures. The statistical analyses of these datasets have to cope with specific challenges and frequently involve making informed but arbitrary decisions. Epidemiological papers have to be concise and focused on the underlying clinical or epidemiological results, not reporting the details behind relevant methodological decisions. In this work, we used an analysis of the cardiovascular-related measures tracked in 4–8-year-old children, using data from the INMA-Asturias cohort for illustrating how the decision-making process was performed and its potential impact on the obtained results. We focused on two particular aspects of the problem: how to deal with missing data and which regression model to use to evaluate tracking when there are no defined thresholds to categorize variables into risk groups. As a spoiler, we analyzed the impact on our results of using multiple imputation and the advantage of using quantile regression models in this context.

Elderly care home residents are particularly vulnerable to COVID-19 due to immune-senescence, pre-existing medical conditions, and the risk of transmission from staff and visitors. This study aimed to describe the outcomes of a COVID-19 outbreak in a long-term care facility for elderly persons following the initial vaccination. A single-center, retrospective, observational design was used to analyze the variables associated with hospitalization and death rate by logistic regression. Adjusted odds ratios (aOR) and their 95% confidence intervals (CI) were calculated. Sixty-eight residents received the first dose of the COVID-19 vaccine. Despite being negative six days after vaccination, the performance of a second test 4 days later revealed 51 positives (75.0%) among residents and 18 among workers (56.3%). A total of 65 of the 68 residents (95.58%) had positive results with symptoms, whereas 34.9% required hospitalization, and 25.8% died. The best-fitting model to explain the distribution of cases reflects three points at the time of infection.. The time from vaccination to symptom onset explains the hospitalization and mortality rates since a day elapsed halves the risk of hospitalization (aOR = 0.57; CI = 0.38−0.75) and the risk of death by a quarter (aOR = 0.74; CI = 0.63−0.88). Nursing homes present an elevated risk of transmission and severity of SARS-CoV-2 infection. Although vaccination reduces the risk of hospitalization and death, extreme prevention and control measures are essential in these institutions despite the high vaccination coverage.

Ingested inorganic arsenic (iAs) is a human carcinogen that is also linked to other adverse health effects, such as respiratory outcomes. Yet, among populations consuming low-arsenic drinking water, the impact of iAs exposure on childhood respiratory health is still uncertain. For a Spanish child study cohort (INfancia y Medio Ambiente—INMA), low-arsenic drinking water is usually available and ingestion of iAs from food is considered the major source of exposure. Here, we explored the association between iAs exposure and children’s respiratory outcomes assessed at 4 and 7 years of age (n = 400). The summation of 4-year-old children’s urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) was used as a biomarker of iAs exposure (∑As) (median of 4.92 μg/L). Children’s occurrence of asthma, eczema, sneeze, wheeze, and medication for asthma and wheeze at each assessment time point (i.e., 4- and 7-year) was assessed with maternal interviewer-led questionnaires. Crude and adjusted Poisson regression models using Generalized Estimating Equation (GEE) were performed to account for the association between natural logarithm transformed (ln) urinary ∑As in μg/L at 4 years and repeated assessments of respiratory symptoms at 4 and 7 years of age. The covariates included in the models were child sex, maternal smoking status, maternal level of education, sub-cohort, and children’s consumption of vegetables, fruits, and fish/seafood. The GEE—splines function using Poisson regression showed an increased trend of the overall expected counts of respiratory symptoms with high urinary ∑As. The adjusted expected counts (95% confidence intervals) at ln-transformed urinary ∑As 1.57 (average concentration) and 4.00 (99th percentile concentration) were 0.63 (0.36, 1.10) and 1.33 (0.61, 2.89), respectively. These exploratory findings suggest that even relatively low-iAs exposure levels, relevant to the Spanish and other populations, may relate to an increased number of respiratory symptoms during childhood.

Objectives: We investigated the association between outdoor air pollutants exposure in the first trimester of pregnancy, and growth and cardio-metabolic risk at four years of age, and evaluated the mediating role of birth weight. Methods: We included mother-child pairs (N = 1,724) from the Spanish INMA birth cohort established in 2003–2008. First trimester of pregnancy nitrogen dioxide (NO2) and fine particles (PM2.5) exposure levels were estimated. Height, weight, waist circumference, blood pressure, and lipids were measured at four years of age. Body mass index (BMI) trajectories from birth to four years were identified. Results: Increased PM2.5 exposure in the first trimester of pregnancy was associated with decreased z-scores of weight (zWeight) and BMI (zBMI) (zWeight change per interquartile range increase in PM2.5 exposure = −0.12; 95% CI: −0.23, −0.01; zBMI change = −0.12; 95% CI: −0.23, −0.01). Higher NO2 and PM2.5 exposure was associated to a reduced risk of being in a trajectory with accelerated BMI gain, compared to children with the average trajectory. Birth weight partially mediated the association between PM2.5 and zWeight and zBMI. PM2.5 and NO2 were not associated with the other cardio-metabolic risk factors. Conclusions: This comprehensive study of many growth and cardio-metabolic risk related outcomes suggests that air pollution exposure during pregnancy may be associated with delays in physical growth in the early years after birth. These findings imply that pregnancy exposure to air pollutants has a lasting effect on growth after birth and require follow-up at later child ages. Keywords: Air pollution, Prenatal exposure, Childhood growth, Childhood obesity, Particulate matter

Background: Breastfed children absorb persistent and toxic chemicals such as organohalogen compounds (OHCs) during the entire lactation period. Nursing is a main contributor to the burden of these pollutants in the first years of life, hence further assessments on the OHC load processes are needed. Objectives: To identify the determinants of OHC increase in children at four years of age, considering concentration gains, maternal venous concentrations and breastfeeding time. Methods: Concentrations of 19 organochlorine compounds (OCs) and 14 polybrominated diphenyl ethers (PBDEs) were analyzed in maternal venous (n = 466), cord blood (n = 326) and children venous serum at four years of age (n = 272) in the Asturias INMA cohort representing the Spanish general population. Data were evaluated considering the socio-demographic and individual information collected at recruitment and follow up surveys, as well as the OHC physical-chemical constants. Results: The four years-old children concentration gains of the most abundant OHCs showed strong correlations (R2 = 0.65–0.93) with the maternal concentrations during pregnancy and lactation period. The child gain/maternal transfer rates of most correlated pollutants were similar. Discussion: Between 65 and 93% of the variance of OCs in four years-old children was explained by the maternal concentrations during pregnancy and the lactation period. The compounds with log(Kow) > 3.7 (hydrophobic) showed analogous child gain/maternal transfer rates indicating similar processes of membrane lipid dissolution and passive diffusion from the epithelial cells into the milk. Molecular weight of these pollutants did not influence on these rates. Compounds with low log(Koa) such as hexachlorobenzene are more volatile and less retained, involving lower child gain/maternal transfer rates. These results may be useful to anticipate the increase of the concentrations of OCs in children using the maternal concentration of these compounds during pregnancy and the planned lactation period and to implement prophylactic measures in mothers with high venous pollutant concentrations. Keywords: Organochlorine compounds, Polybrominated diphenyl ethers, Breastfeeding, Maternal and children body burdens, Concentration gains of organochlorine compounds at four years, Physical-chemical constants influencing in maternal-child transfer

Background: The association between air pollution exposure and emotional and behavioural problems in children is unclear. We aimed to assess prenatal and postnatal exposure to several air pollutants and child's depressive and anxiety symptoms, and aggressive symptoms in children of 7–11 years. Methods: We analysed data of 13182 children from 8 European population-based birth cohorts. Concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter (PM) with diameters of ≤10 μm (PM10), ≤ 2.5 μm (PM2.5), and between 10 and 2.5 μm (PMcoarse), the absorbance of PM2.5 filters (PM2.5abs), and polycyclic aromatic hydrocarbons (PAHs) were estimated at residential addresses of each participant. Depressive and anxiety symptoms and aggressive symptoms were assessed at 7–11 years of age using parent reported tests. Children were classified in borderline/clinical range or clinical range using validated cut offs. Region specific models were adjusted for various socio-economic and lifestyle characteristics and then combined using random effect meta-analysis. Multiple imputation and inverse probability weighting methods were applied to correct for potential attrition bias. Results: A total of 1896 (14.4%) children were classified as having depressive and anxiety symptoms in the borderline/clinical range, and 1778 (13.4%) as having aggressive symptoms in the borderline/clinical range. Overall, 1108 (8.4%) and 870 (6.6%) children were classified as having depressive and anxiety symptoms, and aggressive symptoms in the clinical range, respectively. Prenatal exposure to air pollution was not associated with depressive and anxiety symptoms in the borderline/clinical range (e.g. OR 1.02 [95%CI 0.95 to 1.10] per 10 μg/m3 higher NO2) nor with aggressive symptoms in the borderline/clinical range (e.g. OR 1.04 [95%CI 0.96 to 1.12] per 10 μg/m3 higher NO2). Similar results were observed for the symptoms in the clinical range, and for postnatal exposures to air pollution. Conclusions: Overall, our results suggest that prenatal and postnatal exposure to air pollution is not associated with depressive and anxiety symptoms or aggressive symptoms in children of 7 to 11 years old. Keywords: Air pollution, Depressive symptoms, Anxiety symptoms, Aggressive symptoms, children's mental health

Objetivo: Analizar las variaciones en el proceso de confirmación diagnóstica entre unidades de cribado, las variaciones en los resultados de cada episodio y la relación entre las tasas de las diferentes pruebas de confirmación diagnóstica y las de detección de lesiones. Método: Estudio observacional de las variaciones de las tasas estandarizadas de pruebas diagnósticas y de detección de lesiones, en 34 unidades de cribado de los programas poblacionales de detección precoz de cáncer de mama, de tres comunidades autónomas, en el periodo de 2002 a 2011. Resultados: Las razones de variación entre los percentiles 25-75 en las tasas de realización de pruebas diagnósticas oscilaron entre 1,68 (recitaciones) y 3,39 (punción-aspiración con aguja fina). En las tasas de detección de lesiones benignas, carcinoma ductal in situ y cáncer invasivo fueron, respectivamente, 2,79, 1,99 y 1,36. Se encontró una relación positiva entre las tasas de realización de pruebas y las tasas de detección en punción-aspiración con aguja fina y lesiones benignas (R2: 0,53), punción-aspiración con aguja fina y carcinoma invasivo (R2: 0, 28), biopsias cerradas y lesiones benignas (R2: 0,64), biopsias cerradas y carcinoma ductal in situ (R2: 0,61), y biopsias cerradas y carcinoma invasivo (R2: 0,48). Conclusiones: Se observaron variaciones en la realización de pruebas invasivas entre las unidades de detección precoz de cáncer de mama de mayor magnitud que las de detección de lesiones. Las unidades con más pruebas de punción-aspiración con aguja fina tienen mayores tasas de detección de lesiones benignas, y las que realizan más biopsias cerradas detectan más lesiones benignas y cáncer.