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Although culture-independent techniques have shown that the lungs are not sterile, little is known about the lung microbiome in chronic obstructive pulmonary disease (COPD). We used pyrosequencing of 16S amplicons to analyze the lung microbiome in two ways: first, using bronchoalveolar lavage (BAL) to sample the distal bronchi and air-spaces; and second, by examining multiple discrete tissue sites in the lungs of six subjects removed at the time of transplantation. We performed BAL on three never-smokers (NS) with normal spirometry, seven smokers with normal spirometry (\"healthy smokers\", HS), and four subjects with COPD (CS). Bacterial 16 s sequences were found in all subjects, without significant quantitative differences between groups. Both taxonomy-based and taxonomy-independent approaches disclosed heterogeneity in the bacterial communities between HS subjects that was similar to that seen in healthy NS and two mild COPD patients. The moderate and severe COPD patients had very limited community diversity, which was also noted in 28% of the healthy subjects. Both approaches revealed extensive membership overlap between the bacterial communities of the three study groups. No genera were common within a group but unique across groups. Our data suggests the existence of a core pulmonary bacterial microbiome that includes Pseudomonas, Streptococcus, Prevotella, Fusobacterium, Haemophilus, Veillonella, and Porphyromonas. Most strikingly, there were significant micro-anatomic differences in bacterial communities within the same lung of subjects with advanced COPD. These studies are further demonstration of the pulmonary microbiome and highlight global and micro-anatomic changes in these bacterial communities in severe COPD patients.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22–1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33–1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.

We assess the UK Biobank (UKB) Polygenic Risk Score (PRS) Release, a set of PRSs for 28 diseases and 25 quantitative traits that has been made available on the individuals in UKB, using a unified pipeline for PRS evaluation. We also release a benchmarking software tool to enable like-for-like performance evaluation for different PRSs for the same disease or trait. Extensive benchmarking shows the PRSs in the UKB Release to outperform a broad set of 76 published PRSs. For many of the diseases and traits we also validate the PRS algorithms in a separate cohort (100,000 Genomes Project). The availability of PRSs for 53 traits on the same set of individuals also allows a systematic assessment of their properties, and the increased power of these PRSs increases the evidence for their potential clinical benefit.

Hospital-acquired infections cause substantial morbidity in inpatient settings. On the basis of a 1-day point-prevalence survey, CDC investigators report the burden and types of health care–associated infection in 183 hospitals across 10 geographically diverse states. Elimination of health care–associated infections is a priority of the Department of Health and Human Services. 1 Considerable success in prevention has been reported for some infections, particularly central-catheter–associated bloodstream infections. 2 – 5 Continued improvements in patient safety depend on maintaining a comprehensive understanding of the epidemiology of health care–associated infections. Currently, no single U.S. surveillance system can provide estimates of the burden of all types of such infections across acute care patient populations. The most recent estimate produced by the Centers for Disease Control and Prevention (CDC) and published in 2007 — 1.7 million health care–associated infections per year — relied . . .

Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism 1 – 5 , yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study ( n  = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases. A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.

John Perry and colleagues identify genetic variants at 19 genomic regions associated with mosaic loss of the Y chromosome (mLOY) in blood. They further highlight a shared genetic architecture between mLOY and cancer susceptibility, and infer a causal effect of smoking on mLOY. The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions ( P < 5 × 10 −8 ) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women ( n = 96,123; P = 4 × 10 −6 ). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis ( NPAT ), DNA damage response ( ATM ), mitosis ( PMF1 , CENPN and MAD1L1 ) and apoptosis ( TP53 ). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.

Background Preschool-aged children’s physical activity (PA) and screen time (ST) are important health-related behaviours likely influenced by PA opportunities, parental perceptions of neighbourhood safety and parenting practices pertaining to PA and ST. How these factors interact to impact on young children’s PA and ST, and whether their effects are generalisable across cultures and geographical location is not known. This study addressed these knowledge gaps by conducting pooled analyses of comparable data from two culturally and geographically diverse samples – Chinese parent-child dyads from an ultra-dense city (Hong Kong, China) and Latino parent-child dyads from a low-density city (Houston, USA). Methods The analytical sample consisted of 164 Hong Kong Chinese and 84 US Latino parent-child dyads with data on socio-demographic characteristics, parent-perceived neighbourhood destinations and facilities for children’s PA, physical and social safety-related neighbourhood attributes, PA-related parenting practices and child’s ST and accelerometer-assessed PA. Generalised linear models with robust standard errors accounting for neighbourhood-level clustering were used to estimate associations and interaction effects. Results Hong Kong Chinese children accumulated less PA than US Latino children, although the latter had more ST. Hong Kong Chinese parents reported more parenting practices promoting inactivity. Neighbourhood PA opportunities were positively related to children’s PA only if parental perceptions of neighbourhood safety were favourable, and the associations of physical neighbourhood environment characteristics with children’s PA and ST depended on PA-related parenting practices. Community cohesion was positively related to children’s PA and negatively related to ST, while parental promotion of ST was positively associated with children’s ST. Correlates of children’s PA and ST did not differ by city. Conclusions The substantial differences in activity patterns between Hong Kong Chinese and US Latino preschool-aged children observed in this study are likely due to a combination of cultural and built environmental factors. However, the fact that no between-city differences in correlates of PA and ST were detected indicates that both populations of children are equally affected by parent-perceived neighbourhood environmental characteristics and parenting practices. Overall, this study highlights the importance of considering how various individual-, home- and neighbourhood physical and social factors interact to influence young children’s health-promoting activity levels.

Thompson et al discuss the elevated clozapine levels and toxic effects after SARS-CoV-2 vaccination. Here, a case study of a 51-year-old man with schizoaffective disorder treated with clozapine for more than 10 years and was living at a mental health residential facility is offered. The patient was a nonsmoker and had received yearly influenza vaccinations without complications.