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Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71–88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

ObjectivesTo determine the prevalence and predictors of self-reported access to appropriate personal protective equipment (aPPE) for healthcare workers (HCWs) in the United Kingdom (UK) during the first UK national COVID-19 lockdown (March 2020) and at the time of questionnaire response (December 2020 – February 2021).DesignTwo cross sectional analyses using data from a questionnaire-based cohort study.SettingNationwide questionnaire from 4th December 2020 to 28th February 2021.ParticipantsA representative sample of HCWs or ancillary workers in a UK healthcare setting aged 16 or over, registered with one of seven main UK healthcare regulatory bodies.Main outcome measureBinary measure of self-reported aPPE (access all of the time vs access most of the time or less frequently) at two timepoints: the first national lockdown in the UK (primary analysis) and at the time of questionnaire response (secondary analysis).Results10,508 HCWs were included in the primary analysis, and 12,252 in the secondary analysis. 3702 (35.2%) of HCWs reported aPPE at all times in the primary analysis; 6806 (83.9%) reported aPPE at all times in the secondary analysis. After adjustment (for age, sex, ethnicity, migration status, occupation, aerosol generating procedure exposure, work sector, work region, working hours, night shift frequency and trust in employing organisation), older HCWs (per decade increase in age: aOR 1.2, 95% CI 1.16-1.26, pConclusionsWe found that only a third of HCWs in the UK reported aPPE at all times during the period of the first lockdown and that aPPE had improved later in the pandemic. We also identified key sociodemographic and occupational determinants of aPPE during the first UK lockdown, the majority of which have persisted since lockdown was eased. These findings have important public health implications for HCWs, particularly as cases of infection and long-COVID continue to rise in the UK.Trial registrationISRCTN 11811602What is already known on this topicAccess to personal protective equipment (PPE) is crucial to protect healthcare workers (HCWs) from infection. Limited data exist concerning the prevalence of, and factors relating to, PPE access for HCWs in the United Kingdom (UK) during the COVID-19 pandemic.What this study addsOnly a third of HCWs reported having access to appropriate PPE all of the time during the first UK national lockdown. Older HCWs, those working in Intensive Care Units and those who trusted their employing organisation to deal with concerns about unsafe clinical practice, were more likely to report access to adequate PPE. Those from Asian ethnic groups (compared to White ethnic groups) and those who saw a high number of COVID-19 were less likely to report access to adequate PPE. Our findings have important implications for the mental and physical health of HCWs working during the pandemic in the UK.

IntroductionThe COVID-19 pandemic has resulted in significant morbidity and mortality and devastated economies globally. Among groups at increased risk are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests that HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related outcomes. To date, there has been no large-scale analysis of these risks in UK HCWs or ancillary workers in healthcare settings, stratified by ethnicity or occupation, and adjusted for confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).Methods and analysisA baseline questionnaire will be administered to a national cohort of UK HCWs and ancillary workers in healthcare settings, and those registered with UK healthcare regulators, with follow-up questionnaires administered at 4 and 8 months. With consent, questionnaire data will be linked to health records with 25-year follow-up. Univariate associations between ethnicity and clinical COVID-19 outcomes, physical and mental health, and key confounders/explanatory variables will be tested. Multivariable analyses will test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables. We will model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.Ethics and disseminationThe study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk. We aim to manage the small risk of participant distress about questions on sensitive topics by clearly participant information that the questionnaire covers sensitive topics and there is no obligation to answer these or any other questions, and by providing support organisation links. Results will be disseminated with reports to Government and papers submitted to pre-print servers and peer reviewed journals.Trial registration numberISRCTN11811602; Pre-results.

IntroductionCOVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities.Methods and analysisThis study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes.Ethics and disseminationEthical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/).Trial registration numberISRCTN11811602.

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk. Tweetable abstract @ERSpublications click to tweet Heterozygosity for the SERPINA1 Z allele is associated with higher lung function in nonsmokers (but this advantage is abolished by smoking) as well as a variety of nonrespiratory diseases and traits, including liver-, heart- and bone-related conditions https://bit.ly/37XC0Yg Introduction Homozygosity for the SERPINA1 Z allele (rs28929474(T)) is the commonest cause of severe α1-antitrypsin deficiency (AATD) and is a well-established genetic risk factor for lung diseases such as chronic obstructive pulmonary disease (COPD). However, the health consequences of heterozygosity for the Z allele are not as well-understood [1]. Given that approximately one in 30 Europeans is heterozygous for the Z allele, the phenotypic consequences of carriage of this allele could have important public health implications. Some previous studies have sought to characterise the effect of Z allele heterozygosity on nonrespiratory traits, particularly liver diseases [2–6]. However, these have often been carried out in small sample sizes and/or clinical subgroups. The recent development of phenome-wide association studies (PheWASs) and the availability of the well-phenotyped UK Biobank population-based cohort provides a platform for systematic investigation of the effects of heterozygosity for the Z allele on nonrespiratory traits. PheWASs test the association between genetic variants and a large number of phenotypic traits, including diseases and their subtypes, and potential intermediate phenotypes [7]. This differs from genome-wide association studies, which test a large number of variants across the genome for association with only one trait. The effect of Z allele heterozygosity on lung function traits and lung disease has been the subject of many studies. Recent COPD case–control and family-based studies have shown reduced lung function and increased risk of COPD in heterozygous current and former smokers [8–11]. However, a population-based study demonstrated no significant reductions in lung function in heterozygous smokers, despite having greater numbers of heterozygous smokers compared to previous studies [12]. It also showed enhanced lung function in heterozygous individuals overall, partially explained by strong association of the Z allele with increased height. This discrepancy may be due, in part, to the fact that identifying and recruiting study participants based on their health status (as in case–control studies [8, 9]) or based on the health status of a family member [10, 11] can lead to causal estimates that are subject to ascertainment bias [13], whereas population-based studies [12, 14] overcome these biases. The effects of the Z allele on lung function in relation to smoking status therefore remain uncertain. Finally, despite evidence for sex-differential effects of Z allele homozygosity on lung function [15, 16], we are not aware of any studies that have compared the effect of Z allele heterozygosity on lung function in males versus females. We therefore systematically evaluated the effects of Z allele heterozygosity in the UK biobank population, which in total includes >18 000 Z allele heterozygotes. We aimed: 1) to undertake the most extensive PheWAS to date, including blood biomarkers, for Z allele heterozygosity and homozygosity to identify effects beyond the respiratory system; and 2) to fully define the effects of Z allele heterozygosity on lung function measures (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) in smokers and nonsmokers and in males and females.

IntroductionThe COVID-19 pandemic has resulted in significant morbidity and mortality, and has devastated economies in many countries. Amongst the groups identified as being at increased risk from COVID-19 are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related physical and mental health outcomes. To date there has been no large-scale analysis of these risks in UK healthcare workers or ancillary workers in healthcare settings, stratified by ethnicity or occupation type, and adjusted for potential confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).Methods and analysisA baseline questionnaire with follow-up questionnaires at 4 and 8 months will be administered to a national cohort of UK healthcare workers and ancillary workers in healthcare settings, and those registered with UK healthcare regulators. With consent, data will be linked to health records, and participants followed up for 25 years.Univariate associations between ethnicity and primary outcome measures (clinical COVID-19 outcomes, and physical and mental health) and key confounders/explanatory variables will be tested, followed by multivariable analyses to test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables, with interactions included as appropriate. Using follow-up data, multilevel models will be used to model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.Ethics and disseminationThe study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk to participants. We aim to manage the small risk of participant distress due to being asked questions on sensitive topics by clearly indicating on the participant information sheet that the questionnaire covers sensitive topics and that participants are under no obligation to answer these, or indeed any other, questions, and by providing links to support organisations. Results will be disseminated with reports to Government and papers uploaded to pre-print servers and submitted to peer reviewed journals.Registration detailsTrial ID: ISRCTN11811602STRENGTHS AND LIMITATIONS OF THIS STUDYNational, UK-wide, study, aiming to capture variety of healthcare worker job roles including ancillary workers in healthcare settings.Longitudinal study including three waves of questionnaire data collection, and linkage to administrative data over 25 years, with consent.Unique support from all major UK healthcare worker regulators, relevant healthcare worker organisations, and a Professional Expert Panel to increase participant uptake and the validity of findings.Potential for self-selection bias and low response rates, and the use of electronic invitations and online data collection makes it harder to reach ancillary workers without regular access to work email addresses.

To assess the cost effectiveness of buprenorphine versus methadone in the management of opioid use disorder (OUD) during pregnancy.We designed a decision-analytic model to evaluate the costs and outcomes associated with buprenorphine compared to methadone for pregnant people with OUD. We used a theoretical cohort of 22,400 pregnant people, which is an estimation of pregnancies affected by OUD per year in the United States. Outcomes included maternal retention in maintenance treatment, neonatal opioid withdrawal syndrome, preterm birth, fetal growth restriction, cerebral palsy, and maternal overdose in addition to cost and quality-adjusted life-years (QALYs). We used a willingness-to-pay threshold of $100,000/QALY. All model inputs were derived from the literature and varied in sensitivity analyses to assess the robustness of our baseline inputs.In our theoretical cohort, treatment of OUD with buprenorphine during pregnancy resulted in 2413 fewer cases of neonatal opioid withdrawal syndrome, 1089 fewer preterm births, 299 fewer cases of fetal growth restriction, 32 fewer stillbirths, and 13 fewer cases of cerebral palsy compared to methadone treatment. Despite lower rates of retention, buprenorphine treatment saved nearly 123 million healthcare dollars and resulted in 558 additional QALYs, making it the dominant strategy compared to methadone treatment. Our findings were robust over a wide range of assumptions.Our data suggest that buprenorphine should be considered a cost effective treatment option for OUD in pregnancy, as it is associated with improved neonatal outcomes compared to methadone despite the risk of treatment discontinuation.

Some individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.

BRCA1 or 2 mutations result in higher cancer risk for breast cancer (BC) and epithelial ovarian cancer (EOC) for carriers than exists in the general population. Optimal breast imaging surveillance in these patients has not been well defined. An Institutional Review Board-approved, multi-institutional retrospective chart review was performed. Patients diagnosed with BRCA-associated EOC between 1990-2015 were identified; demographic and clinical data were collected and analyzed. 192 BRCA mutation–positive patients with EOC were identified. 16/192 (8.3%) women were diagnosed with BC following EOC, at a median of 50 (range 5-327) months following EOC diagnosis and median age 59.5 (45-84) years. Breast cancer was most commonly detected on mammogram 7/16 (44%) or clinical exam 7/16 (44%). 2/16 (12.5%) had occult BC found during risk-reducing mastectomy. 14 (88%) had early-stage (0-2) disease. At mean follow-up of 8.1 years, 6 (37.5%) patients with BC following EOC had died due to EOC. The risk of BC diagnosis following EOC in BRCA mutation carriers is low; most of these BCs are early stage and diagnosed with mammography or physical exam. Overall, survival in BRCA mutation carriers is dominated by EOC-related mortality. Breast cancer surveillance in BRCA mutation carriers following EOC should prioritize nonsurgical strategies.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Using primary care electronic health records from UK Biobank and EXCEED studies, we defined MDD and TRD, providing an easily accessible approach to investigate their clinical and genetic characteristics.MDD defined from primary care records was compared with other measures of depression and validated using the MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least six weeks. Clinical-demographic characteristics, SNP-heritability and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases.In 230,096 and 8,926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD (2,430 and 159 cases), respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 72%-88% with other MDD definitions. In UKB, TRD and non-TRD heritability was comparable (h2SNP = 0.25 [SE=0.04] and 0.19 [SE=0.02], respectively). TRD was positively associated with the polygenic risk score (PRS) of attention deficit hyperactivity disorder and negatively associated with the PRS of intelligence compared to non-TRD. It was more strongly associated with unfavourable clinical-demographic variables than non-TRD.This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Background Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD. Methods We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium. Results In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001). Conclusion The healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.

BackgroundEosinophils are granulocytes associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled by interleukin-5: anti-interleukin-5 agents reduce asthma and COPD exacerbation frequency, and response correlates with baseline eosinophil counts. However, causal relationships between eosinophils and other respiratory phenotypes are less studied.MethodsWe investigated causality between eosinophils and: lung function, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), moderate-to-severe asthma, and respiratory infections. We performed Mendelian randomization (MR) using 151 genetic variants from genome-wide association studies of blood eosinophil counts in UK Biobank/INTERVAL, and respiratory data from UK Biobank, using MR methods relying on different assumptions for validity. Multivariable MR using eight blood cell type exposures was performed for outcomes showing evidence of causation by eosinophils.FindingsThere was evidence that higher eosinophils reduce FEV1/FVC and FEV1 (weighted median estimator, SD change FEV1/FVC per SD eosinophils: −0.054 [95%CI −0.078,−0.029]. There was also evidence that eosinophils cause ACO (weighted median OR 1.44 [95%CI 1.19,1.74]), and asthma (weighted median OR 1.50 [95%CI 1.23,1.83]). Multivariable MR for FEV1/FVC, FEV1, ACO and asthma suggested that eosinophils were the cell type with the most important effect. Causal estimates of individual variants were heterogeneous, which may arise from pleiotropy.InterpretationWe found evidence that eosinophils reduce lung function, and increase ACO and asthma risk, on average over the set of genetic variants studied. Eosinophils appear to be causal determinants of fixed airflow obstruction among individuals with features of both asthma and COPD.FundingWellcome, BHF, MRC, BBSRC CASE studentship with GSK, GSK/BLF.

Homozygosity for theSERPINA1Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear. We conducted the largest population-based study to date to determine Z allele effects on >2,400 phenotypes using the UK Biobank study (N>303,353). We detected strong associations between heterozygosity and non-respiratory phenotypes including increased height, increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher lung function in non-smokers, but smoking appears to abolish this protective effect. Individuals heterozygous for the Z allele may therefore have altered risk of smoking-induced lung disease and other, non-respiratory conditions.

Objectives: Mutations in BRCA1 and BRCA2 increase the risk of epithelial ovarian cancer (EOC). Emerging evidence suggests obesity may influence BRCA tumor biology; body mass index (BMI) appears to correlate with DNA damage in breast epithelium in BRCA women. We hypothesized that obesity negatively influences tumor biology in BRCA women with EOC, and sought to identify correlations with BMI and clinical outcomes in this population. Methods: We performed an IRB approved retrospective study. We identified patients with BRCA-associated EOC diagnosed between 1990-2015. All women underwent surgical resection with platinum-based chemotherapy. We abstracted clinical and pathologic data, and calculated BMI at the time of diagnosis. Obesity was examined per WHO criteria of normal weight, overweight, class I obesity, and class II obesity. We performed descriptive statistics with Kaplan-Meier, Cox Proportional Hazards Regression, and univariate analyses. Results: We identified 179 women meeting criteria. Most were BRCA1 (125, or 70%); 53 (30%) were BRCA2; and 1 had both a BRCA1 and BRCA2 mutation. The majority had stage III/IV disease (137, 77%) and grade 3 serous histology (168, 94%); 150 patients underwent optimal cytoreduction (87%). BMI was distributed throughout the WHO strata: 101 women had normal weight; 46 were overweight; 20 had class I obesity; 12 had class II obesity. Age, medical comorbidities, and rates of optimal surgical cytoreduction were similar among these groups. In a subcohort of patients with stage III/IV disease, we identified a significant trend between increased BMI strata and poor disease-free survival (35, 32, 25, and 13.5 months, p=0.003). This was also observed for overall disease-specific survival (132, 144, 112, and 72.5 months, p=0.0306). Multivariable analyses of the entire cohort confirmed that age (p=0.035), stage (p Download : Download high-res image (114KB) Download : Download full-size image Conclusions: We identified a significant and independent association between BMI and clinical outcome in BRCA positive women with EOC. Factors associated with obesity may negatively influence BRCA associated ovarian cancer biology, and suggest this may be a modifiable risk factor to target for therapy.

BACKGROUND: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined.OBJECTIVES: We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline.METHODS: We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts.RESULTS: The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts.CONCLUSIONS: Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

5565 Background: Patients with BRCA mutations are at increased risk of developing both breast (BC) and epithelial ovarian cancer (EOC). Optimal breast cancer surveillance guidelines for BRCA mutation carriers following EOC has not been defined due to high risk of EOC recurrence. The recent SOLO-1 trial demonstrated a survival benefit of olaparib maintenance therapy for newly diagnosed women with advanced stage EOC. Olaparib reduced the risk of disease-progression or death by 70% compared to placebo with a median progression-free survival (PFS) of 36 months. Methods: An IRB-approved, multi-institutional study retrospective chart review was performed. Patients had BRCA-associated EOC diagnosed between 1990-2015 without a history of prior BC or mastectomy. All women received combination chemotherapy for EOC. The observed breast cancer free survival was adjusted to reflect the enhanced 3-year PFS observed in olaparib-treated women from the SOLO-1 trial. Kaplan-Meier survival curves were performed. Results: 191 patients with BRCA-associated EOC were included (135 BRCA1, 55 BRCA2, 1 BRCA1 and BRCA2). Median age was 53 years. Most women had advanced stage, high-grade serous EOC (75%). The median overall survival was 7.7 years for BRCA 1, and 9.7 years for BRCA2 mutation carriers. Annual mammography and MRI were performed in 43% and 34% of women, respectively, with a median of 4 mammograms and 3 MRI per patient. 16 women (8.3%) were diagnosed with BC over a median follow up of 80 months: 7 (44%) DCIS and 9 (56%) invasive ductal carcinoma. 14 (88%) women had early stage (0-2) BC. 28 (15%) of women had risk-reducing mastectomy performed an average of 2.1 years following their EOC diagnosis. The incidence of BC increased from 5.6% to 11% at 5- and 10-years post EOC, and in the predicted model with olaparib, from 10% to 17% at 5- and 10-years, assuming olaparib does not impact breast cancer incidence. Conclusions: The risk of metachronous BC following BRCA-associated EOC increases over time. In the post SOLO trial era, BC surveillance strategies in women with EOC should be optimized to reflect improved outcome. [Table: see text]

BackgroundAntibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups.ObjectiveTo determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers.MethodsQuantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study).ResultsARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r2=0.23; pConclusionsARGs are highly prevalent in sputum, broadly in proportion to bacterial abundance in both healthy and COPD subjects. Thus, COPD appears to be an ARG reservoir due to high levels of bacterial colonisation.

EXCEED is a longitudinal population-based cohort which facilitates investigation of genetic, environmental and lifestyle-related determinants of a broad range of diseases and of multiple morbidity through data collected at baseline and via electronic healthcare record linkage. Recruitment has taken place in Leicester, Leicestershire and Rutland since 2013 and is ongoing, with 9,840 participants aged 30-69 to date. The population of Leicester is diverse and additional recruitment from the local South Asian community is ongoing. Participants have consented to follow-up for up to 25 years through electronic health records and additional bespoke data collection is planned. Data available includes baseline demographics, anthropometry, spirometry, lifestyle factors (smoking and alcohol use) and longitudinal health information from primary care records, with additional linkage to other EHR datasets planned. Patients have consented to be contacted for recall-by-genotype and recall-by-phenotype sub-studies, providing an important resource for precision medicine research. We welcome requests for collaboration and data access by contacting the study management team via exceed@le.ac.uk.

In Africa, the incidence of cancer is increasing rapidly and efforts to establish minimum services for the prevention and treatment of the disease still meet with enormous difficulties. The basic components of cancer control are especially inadequate in sub-Saharan Africa, where survival remains lower than in all other low-income countries. The main challenges stem from the scarcity or absence of cancer control programmes, qualified staff, diagnostic and treatment capacity, cancer care funding, and political commitment. Policies devised to overcome these problems include capacity building in health planning, provision of technical and fi nancial support to create sustainable national cancer control programmes, promotion of horizontal integration of cancer control programmes with other health services, establishment of regional referral centres, creation of telemedicine infrastructures, support of drug donation initiatives world wide, and establishment of international partnerships between national govern ments, non-governmental organisations, foundations, higher education institutions, associations of health-care professionals, and industry. In the past few years, these principles have been integrated into comprehensive strategic plans designed

After the usual house jobs, national service, and a brief period in general practice, Herbert Hugh John decided to specialise in public health. He held senior appointments in Oxford, Staffordshire, and Cleveland, before returning to London as the last holder of the historic office of medical officer of health, publishing papers on a wide range of subjects. …