Childhood adversity and the risk of gestational diabetes: A population-based cohort study of nulliparous pregnant women.

AIMS: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, and though it may be linked to childhood adversity, the effect of different types of adversity remains unclear. Childhood adversity is linked to a younger maternal age, which may hide the overall impact of adversity on GDM risk. We therefore aimed to explore the association between different types of childhood adversity and GDM while accounting for the potential impact of maternal age. METHODS: We used Danish nation-wide register data, including 208,207 women giving birth for the first time from 2004 to 2018. Five adversity groups were used to examine the effect of childhood adversity on GDM risk: (1) low (referent group), (2) early life material deprivation, (3) persistent deprivation, (4) loss or threat of loss within the family and (5) high adversity. RESULTS: 5375 women were diagnosed with GDM in the study population (2.6% absolute risk). Compared to women who experienced low adversity, the other adversity groups had a higher GDM risk (absolute difference [%]) directly; early material deprivation (0.64% [95% CI 0.44; 0.84]), persistent deprivation (0.63% [0.41; 0.86]), loss or threat of loss (0.73% [0.42; 1.05]) and high adversity (0.80% [0.32; 1.27]). The indirect effect of maternal age attenuated the total effect of childhood adversity on GDM by an absolute difference of 0.25%-0.46%. CONCLUSIONS: Experiencing childhood adversity to any extent is associated with a higher risk of GDM. Interventions aimed at preventing childhood adversity may have a positive effect in reducing GDM burden and the associated health risks.

Building Numeracy Skills: Associations between DUPLO® Block Construction and Numeracy in Early Childhood.

Research shows that children's block construction skills are positively associated with their concurrent and later mathematics performance. Furthermore, there is evidence that block construction training is particularly beneficial for improving early mathematics skills in children from low-Socio Economic Status (SES) groups who are known to have lower maths performance than their peers. The current study investigates (a) the association between block construction and mathematics in children just before the start of formal schooling (4 years-of-age in the UK) and (b) whether the association between block construction and mathematics differs between children from more compared to less affluent families. Participants in this study included 116 children (M = 3 years 11 months, SD = 3 months) who all completed numeracy, block construction, and receptive vocabulary tasks. Socio-economic status and demographic information (child age, gender, ethnicity) were also obtained from parents. Findings show a strong positive association between block construction and early numeracy skills. Block construction skills explained approximately 5% of the variation in numeracy, even after controlling for age in months, household income, and child receptive vocabulary. When separated by SES group, for children from less affluent families, block construction explained a significant amount of variability (14.5%) in numeracy performance after covariates. For children from more affluent families, block construction did not explain a significant amount of variation in numeracy. These findings suggest that, interventions involving block construction skills may help to reduce SES-based attainment gaps in UK children's mathematics achievement.

Convergent somatic evolution commences in utero in a germline ribosomopathy.

Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.

Ratiometric Inclusion of Fibroblasts Promotes Both Castration-Resistant and Androgen-Dependent Tumorigenic Progression in Engineered Prostate Cancer Tissues.

To investigate the ratiometric role of fibroblasts in prostate cancer (PCa) progression, this work establishes a matrix-inclusive, 3D engineered prostate cancer tissue (EPCaT) model that enables direct coculture of neuroendocrine-variant castration-resistant (CPRC-ne) or androgen-dependent (ADPC) PCa cells with tumor-supporting stromal cell types. Results show that the inclusion of fibroblasts within CRPC-ne and ADPC EPCaTs drives PCa aggression through significant matrix remodeling and increased proliferative cell populations. Interestingly, this is observed to a much greater degree in EPCaTs formed with a small number of fibroblasts relative to the number of PCa cells. Fibroblast coculture also results in ADPC behavior more similar to the aggressive CRPC-ne condition, suggesting fibroblasts play a role in elevating PCa disease state and may contribute to the ADPC to CRPC-ne switch. Bulk transcriptomic analyses additionally elucidate fibroblast-driven enrichment of hallmark gene sets associated with tumorigenic progression. Finally, the EPCaT model clinical relevancy is probed through a comparison to the Cancer Genome Atlas (TCGA) PCa patient cohort; notably, similar gene set enrichment is observed between EPCaT models and the patient primary tumor transcriptome. Taken together, study results demonstrate the potential of the EPCaT model to serve as a PCa-mimetic tool in future therapeutic development efforts.

Gestational diabetes mellitus and its impact on the mother-infant relationship: A cohort study in the postnatal period.

Women with gestational diabetes mellitus (GDM) are at increased risk of poor perinatal mental health outcomes. However, the association between GDM and the mother-infant relationship is unclear. This study aimed to examine whether GDM itself impacts the mother-infant relationship and maternal mental health using a cohort study design. We used data from the Cohort of Newborns in Emilia-Romagna (CoNER) study, which included 642 women recruited in Bologna, Italy. Psychological data were collected at 6 and 15 months postnatally using a purpose designed measure to examine the mother-infant relationship. We used linear fixed effects and mixed-effects models to assess the effect of GDM on relationship scores at 6 and 15 months postpartum. Women with GDM had significantly lower relationship scores at 15 months postpartum [ß - 1.75 95% CrI (-3.31; -0.21)] but not at 6 months [ß - 0.27 95% CrI (-1.37; 0.81)]. Mother-infant relationship scores were significantly lower overall at 15 months compared to 6 months postpartum [ß - 0.29 95% CrI (-0.56; -0.02)]. Our findings suggest that there may be a delayed effect on the mother-infant relationship in response to the experience of GDM. Future research using large birth cohorts should investigate this further to confirm these findings, and whether women with GDM would benefit from early interventions to improve relationships taking into account length of time postpartum.

Saving time and money in biomedical publishing: the case for free-format submissions with minimal requirements.

BACKGROUND: Manuscript preparation and the (re)submission of articles can create a significant workload in academic jobs. In this exploratory analysis, we estimate the time and costs needed to meet the diverse formatting requirements for manuscript submissions in biomedical publishing. METHODS: We reviewed 302 leading biomedical journals' submission guidelines and extracted information on the components that tend to vary the most among submission guidelines (the length of the title, the running title, the abstract, and the manuscript; the structure of the abstract and the manuscript, number of items and references allowed, whether the journal has a template). We estimated annual research funding lost due to manuscript formatting by calculating hourly academic salaries, the time lost to reformatting articles, and quantifying the total number of resubmissions per year. We interviewed several researchers and senior journal editors and editors-in-chief to contextualize our findings and develop guidelines that could help both biomedical journals and researchers work more efficiently. RESULTS: Among the analyzed journals, we found a huge diversity in submission requirements. By calculating average researcher salaries in the European Union and the USA, and the time spent on reformatting articles, we estimated that ~ 230 million USD were lost in 2021 alone due to reformatting articles. Should the current practice remain unchanged within this decade, we estimate ~ 2.5 billion USD could be lost between 2022 and 2030-solely due to reformatting articles after a first editorial desk rejection. In our interviews, we found alignment between researchers and editors; researchers would like the submission process alignment between researchers and editors; researchers would like the submission process to be as straightforward and simple as possible, and editors want to easily identify strong, suitable articles and not waste researchers' time. CONCLUSIONS: Based on the findings from our quantitative analysis and contextualized by the qualitative interviews, we conclude that free-format submission guidelines would benefit both researchers and editors. However, a minimum set of requirements is necessary to avoid manuscript submissions that lack structure. We developed our guidelines to improve the status quo, and we urge the publishers and the editorial-advisory boards of biomedical journals to adopt them. This may also require support from publishers and major international organizations that govern the work of editors.

Higher depression risks in medium- than in high-density urban form across Denmark.

Urban areas are associated with higher depression risks than rural areas. However, less is known about how different types of urban environments relate to depression risk. Here, we use satellite imagery and machine learning to quantify three-dimensional (3D) urban form (i.e., building density and height) over time. Combining satellite-derived urban form data and individual-level residential addresses, health, and socioeconomic registers, we conduct a case-control study (n = 75,650 cases and 756,500 controls) to examine the association between 3D urban form and depression in the Danish population. We find that living in dense inner-city areas did not carry the highest depression risks. Rather, after adjusting for socioeconomic factors, the highest risk was among sprawling suburbs, and the lowest was among multistory buildings with open space in the vicinity. The finding suggests that spatial land-use planning should prioritize securing access to open space in densely built areas to mitigate depression risks.

Cancer burden among adolescents and young adults in relation to childhood adversity: a nationwide life-course cohort study of 1.2 million individuals.

Background: Childhood adversity such as poverty, loss of a parent, and dysfunctional family dynamics may be associated with exposure to environmental and behavioral hazards, interfere with normal biological functions, and affect cancer care and outcomes. To explore this hypothesis, we assessed the cancer burden among young men and women exposed to adversity during childhood. Methods: We undertook a population-based study using Danish nationwide register data on childhood adversity and cancer outcomes. Children who were alive and resident in Denmark until their 16th birthday were followed into young adulthood (16-38 years). Group-based multi-trajectory modelling was used to categorize individuals into five distinct groups: low adversity, early material deprivation, persistent material deprivation, loss/threat of loss, and high adversity. We assessed the association with overall cancer incidence, mortality, and five-year case fatality; and cancer specific outcomes for the four most common cancers in this age group in sex-stratified survival analyses. Findings: 1,281,334 individuals born between Jan 1, 1980, and Dec 31, 2001, were followed up until Dec 31, 2018, capturing 8229 incident cancer cases and 662 cancer deaths. Compared to low adversity, women who experienced persistent material deprivation carried a slightly lower risk of overall cancer (hazard ratio (HR) 0.90; 95% CI 0.82; 0.99), particularly due to malignant melanoma and brain and central nervous system cancers, while women who experienced high adversity carried a higher risk of breast cancer (HR 1.71; 95% CI 1.09; 2.70) and cervical cancer incidence (HR 1.82; 95% CI 1.18; 2.83). While there was no clear association between childhood adversity and cancer incidence in men, those men who had experienced persistent material deprivation (HR 1.72; 95% CI 1.29; 2.31) or high adversity (HR 2.27; 95% CI 1.38; 3.72) carried a disproportionate burden of cancer mortality during adolescence or young adulthood compared to men in the low adversity group. Interpretation: Childhood adversity is associated with a lower risk of some subtypes of cancer and a higher risk of others, particular in women. Persistent deprivation and adversity are also associated with a higher risk of adverse cancer outcomes for men. These findings may relate to a combination of biological susceptibility, health behaviors and treatment-related factors. Funding: None.

The complexities of suicide: a multilevel survival analysis examining individual, familial and neighbourhood determinants of suicide risk using Danish register-based data.

BACKGROUND: Suicide risk is complex and nuanced, and how place impacts suicide risk when considered alongside detailed individual risk factors remains uncertain. We aimed to examine suicide risk in Denmark with both individual and neighbourhood level risk factors. METHODS: We used Danish register-based data to identify individuals born in Denmark from 1972, with full parental information and psychiatric diagnosis history. We fitted a two-level survival model to estimate individual and neighbourhood determinants on suicide risk. RESULTS: We identified 1723 cases of suicide in Denmark during the follow-up period from 1982 to 2015. Suicide risk was explained mainly by individual determinants. Parental comorbidities, particularly maternal schizophrenia [incidence rate ratio (IRR): 2.29, 95% CI 1.56-3.16] and paternal death (2.29, 95% CI 1.31-3.72) partly explained suicide risk when adjusted for all other determinants. The general contextual effect of suicide risk across neighbourhoods showed a median incidence rate ratio (MRR) of 1.13 (1.01-1.28), which was further reduced with full adjustment. Suicide risk increased in neighbourhoods with a higher proportion of manual workers (IRR: 1.08; 1.03-1.14), and decreased with a higher population density (IRR: 0.89; 0.83-0.96). CONCLUSION: Suicide risk varies mainly between individuals, with parental comorbidities having the largest effect on suicide risk. Suicide risk was less impacted by neighbourhood, though, albeit to a lesser extent than individual determinants, some characteristics were associated with suicide risk. Suicide prevention policies might consider targeting interventions towards individuals more vulnerable due to particular parental comorbidities, whilst taking into account that some neighbourhood characteristics might exacerbate this risk further.

Exploring Interrelations Between Person-Centered Care and Quality of Life Following a Transition Into Long-Term Residential Care: A Meta-Ethnography.

BACKGROUND AND OBJECTIVES: Globally, a culture change in long-term residential care (LTRC) moving toward person-centered care (PCC) has occurred in an attempt to improve resident quality of life (QoL). However, a clear understanding of how different aspects contributing to a PCC approach are interrelated with resident QoL is still lacking. This review explores interrelating aspects between PCC and QoL in LTRC using qualitative synthesis. RESEARCH DESIGN AND METHODS: Ten relevant primary studies were identified from a search of interdisciplinary research databases providing qualitative information. Studies were critically reviewed for key themes and concepts by the research team. We used a meta-ethnography approach to inductively interpret findings across multiple studies and reinterpreted the information using a constructivist approach. RESULTS: We identified 5 second-order constructs sharing commonalities suggesting interrelations between PCC and QoL: (a) maintaining dignity, autonomy, and independence; (b) knowing the whole person; (c) creating a "homelike" environment; (d) establishing a caring culture; and (e) integrating families and nurturing internal and external relationships. Synthesis translation led to the following third-order constructs: (a) personalizing care within routines, (b) optimizing resident environments, and (c) giving residents a voice. DISCUSSION AND IMPLICATIONS: There are many interrelating aspects of PCC and QoL following a permanent transition into LTRC, but successful implementation of PCC, which enhances QoL, presents challenges due to organizational routines and constraints. However, by prioritizing resident voices to include their needs and preferences in care, QoL can be supported following a transition into LTRC.

Exploring resident experiences of person-centred care at mealtimes in long-term residential care: a rapid ethnography.

INTRODUCTION: Poor nutrition is a common ongoing problem in long-term residential care, often resulting in reduced quality of life. Previous research has concluded that the content of the meal, dining environment, service style and general atmosphere all add to the mealtime experience, suggesting that person-centred mealtimes are optimal. However, knowledge about which elements of person-centred care can be achieved in a mealtime setting in a given context is currently lacking. We aimed to understand the mealtime experience in long-term residential care by exploring (missed) opportunities for person-centred care in different settings. METHODS: As part of the TRANS-SENIOR research network, rapid ethnographies, were conducted across multiple sites (including interviews, observations and informal conversations), in a long-term residential care home in the UK, Switzerland and the Netherlands between October 2020 and December 2021.  RESULTS: Following analysis and interpretation of observations, interviews and informal conversations, the following themes were developed where either successfully achieved or missed opportunities for person-centred moments were observed: 1) considering the setting, 2) listening to and implementing resident choice, 3) enabling residents to help/care for themselves and others, 4) providing individualised care in a communal setting, and 5) knowing the person in the past and present. Residents experienced moments of participatory choice, interaction, independence and dignity, but opportunities for these were often missed due to organisational or policy constraints. CONCLUSIONS: There are opportunities for person-centred moments during the mealtime, some of which are taken and some missed. This largely depended on the setting observed, which includes the overall environment (size of dining area, seating arrangements etc.) and allocation of staff resources, and the level of resident involvement in mealtimes, from preparation to the actual activity.

Diverse mutational landscapes in human lymphocytes.

The lymphocyte genome is prone to many threats, including programmed mutation during differentiation1, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.

Clonal dynamics of haematopoiesis across the human lifespan.

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

Navigating the LGB Data Landscape: A Review of Appropriate Secondary Data Sources for Sexuality and Substance Use Research in the UK.

Research has found that sexual minority individuals are more likely to experience health inequalities and have higher rates of substance use compared with their heterosexual counterparts. This association between sexuality and health outcomes is increasingly being explored using quantitative methodologies within the context of public health, psychology and health geography. Much of this research, however, has relied on primary data, despite the wide availability of secondary sources, mainly survey data, collecting information on sexuality and different types of health outcomes and health risk behaviours, such as substance use. This study reviewed recent surveys in the UK that are appropriate for exploring topics related to LGB populations and substance use behaviours. We carried out a narrative review of secondary data sources in the UK to assess the accessibility and suitability of secondary sources for sexuality and substance use research. We identified eight cross-sectional and two longitudinal surveys that contained both sexuality and substance use data. We summarised the possible applications of each survey and the scope of questions within sexuality and substance use research that could be addressed by each survey. The identification of appropriate surveys in this review can allow researchers to extend the use of secondary data sources in the UK to examine substance use inequalities between sexuality groups, further advancing this key topic.

Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts.

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.

Somatic mutation landscapes at single-molecule resolution.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Trends in smoking prevalence over time and space: A comparison between sexual minority and heterosexual populations.

Research has suggested that lesbian, gay and bisexual (LGB) individuals are more likely to smoke tobacco than heterosexual individuals, but specific geographic patterns have not been examined frequently. We analysed change in smoking prevalence over time across Great Britain for LGB and heterosexual populations, comparing models for men and women. Smoking prevalence remained greater for sexual minority (SM) women over time than for other groups. Across Great Britain, decreases in smoking prevalence in urban areas were more pronounced for SM men compared with SM women. Future anti-smoking policies should consider sexuality and its association with place to eradicate smoking inequalities.

A relational ethic of rural home support on two Gulf Island communities, 1978-2018.

Since their widespread establishment in the 1970s, home support services across Canada have been subject to shifting state logics, policies, and funding models. The impacts and responses of local actors differ across historical, socio-cultural, and geographical settings. This paper traces the development and evolution of a small home support society on two rural islands off the coast of British Columbia, Canada. Using historical and current data sources, we demonstrate that local actors have consistently engaged a relational ethic that challenges neo-liberal discourses and practices. Our central thesis is that the islands' distinct social, cultural, and rural features set the context for particular constructions of relational care. We identify three themes central to a relational ethic of home support on two rural islands: the strength of intergenerational connections, community-embedded relationships, and care as compassionate civic engagement. Within each theme, we consider how shifting policy structures inform changes over time in the nature and delivery of home support. To conclude, we elaborate on the conditions that allow for relational care to flourish in a particular rural context, and on the potential relevance to other settings.

Multiple Sources of the Outbreak of Legionnaires' Disease in Genesee County, Michigan, in 2014 and 2015.

BACKGROUND: A community-wide outbreak of Legionnaires' disease (LD) occurred in Genesee County, Michigan, in 2014 and 2015. Previous reports about the outbreak are conflicting and have associated the outbreak with a change of water source in the city of Flint and, alternatively, to a Flint hospital. OBJECTIVE: The objective of this investigation was to independently identify relevant sources of Legionella pneumophila that likely resulted in the outbreak. METHODS: An independent, retrospective investigation of the outbreak was conducted, making use of public health, health care, and environmental data and whole-genome multilocus sequence typing (wgMLST) of clinical and environmental isolates. RESULTS: Strong evidence was found for a hospital-associated outbreak in both 2014 and 2015: a) 49% of cases had prior exposure to Flint hospital A, significantly higher than expected from Medicare admissions; b) hospital plumbing contained high levels of L. pneumophila; c) Legionella control measures in hospital plumbing aligned with subsidence of hospital A-associated cases; and d) wgMLST showed Legionella isolates from cases exposed to hospital A and from hospital plumbing to be highly similar. Multivariate analysis showed an increased risk of LD in 2014 for people residing in a home that received Flint water or was located in proximity to several Flint cooling towers. DISCUSSION: This is the first LD outbreak in the United States with evidence for three sources (in 2014): a) exposure to hospital A, b) receiving Flint water at home, and c) residential proximity to cooling towers; however, for 2015, evidence points to hospital A only. Each source could be associated with only a proportion of cases. A focus on a single source may have delayed recognition and remediation of other significant sources of L. pneumophila. https://doi.org/10.1289/EHP5663.

Differential pathways into smoking among sexual orientation and social class groups in England: A structural equation model.

PURPOSE: Previous research has shown that lesbian, gay and bisexual (LGB) populations smoke more than their heterosexual counterparts. Little is known about the pathways into smoking among LGB populations in England relative to the lower social class populations that are the focus of the current Tobacco Control Plan (TCP). METHODS: Using the 2013/2014 waves of the Health Survey for England (HSE), we created a structural equation model to analyze pathways and interactions between sexual orientation, social class, and the number of cigarettes smoked daily. The path analysis assessed whether three intervening factors-age of initiation, mental wellbeing score, and exposure to smoke-are implicated similarly in smoking among LGB and lower social class populations, and whether interaction between sexual orientation and class is further associated with smoking. RESULTS: Bivariate analysis showed that LGB-identified individuals and individuals in lower occupational classes smoke more cigarettes daily, respectively, than heterosexual individuals and those in professional/managerial-class populations. Path analysis showed that the number of cigarettes smoked daily was mediated by age of initiation, mental wellbeing score and weekly exposure to smoke among routine and manual workers; by mental wellbeing score and exposure to smoke among intermediate class workers, and by mental wellbeing score in the LGB population. Interactions between sexual orientation and social class were not significant. CONCLUSIONS: The differential nature of pathways into smoking for lower social classes and LGB populations in England suggests the need for tailored prevention and cessation efforts, with programming for LGB populations focused on the distinct stressors they face.