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Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Abstract Background As precision medicine advances, polygenic scores (PGS) have become increasingly important for clinical risk assessment. Many methods have been developed to create polygenic models with increased accuracy for risk prediction. Our select and shrink with summary statistics (S4) PGS method has previously been shown to accurately predict the polygenic risk of epithelial ovarian cancer. Here, we applied S4 PGS to 12 phenotypes for UK Biobank participants, and compared it with the LDpred2 and a combined S4 + LDpred2 method. Results The S4 + LDpred2 method provided overall improved PGS accuracy across a variety of phenotypes for UK Biobank participants. Additionally, the S4 + LDpred2 method had the best estimated PGS accuracy in Finnish and Japanese populations. We also addressed the challenge of limited genotype level data by developing the PGS models using only GWAS summary statistics. Conclusions Taken together, the S4 + LDpred2 method represents an improvement in overall PGS accuracy across multiple phenotypes and populations.

Abstract Background People with severe COVID anxiety have poor mental health and impaired functioning, but the course of severe COVID anxiety is unknown and the quality of evidence on the acceptability and impact of psychological interventions is low. Methods A quantitative cohort study with a nested feasibility trial. Potential participants aged 18 and over, living in the UK with severe COVID anxiety, were recruited online and from primary care services. We examined levels of COVID anxiety in the six months after recruitment, and factors that influenced this, using linear regression. Those scoring above 20 on the short Health Anxiety Inventory were invited to participate in a feasibility trial of remotely delivered Cognitive Behavioural Therapy for Health Anxiety (CBT-HA). Exclusion criteria were recent COVID-19, current self-isolation, or current receipt of psychological treatment. Key outcomes for the feasibility trial were the level of uptake of CBT-HA and the rate of follow-up. Results 204 (70.2%) of 285 people who took part in the cohort study completed the six month follow-up, for whom levels of COVID anxiety fell from 12.4 at baseline to 6.8 at six months (difference = -5.5, 95% CI = -6.0 to -4.9). Reductions in COVID anxiety were lower among older people, those living with a vulnerable person, those with lower baseline COVID anxiety, and those with higher levels of generalised anxiety and health anxiety at baseline. 36 (90%) of 40 participants enrolled in the nested feasibility trial were followed up at six months. 17 (80.9%) of 21 people in the active arm of the trial received four or more sessions of CBT-HA. We found improved mental health and social functioning among those in the active, but not the control arm of the trial (Mean difference in total score on the Work and Social Adjustment Scale between baseline and follow up, was 9.7 (95% CI = 5.8–13.6) among those in the active, and 1.0 (95% C.I. = -4.6 to 6.6) among those in the control arm of the trial. Conclusions While the mental health of people with severe COVID anxiety appears to improve over time, many continue to experience high levels of anxiety and poor social functioning. Health anxiety is highly prevalent among people with severe COVID anxiety and may provide a target for psychological treatment. Trial registration Retrospectively registered at ISRCTN14973494 on 09/09/2021.

Abstract Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10−8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Objective Fluoropyrimidine chemotherapy is a first-line treatment for many gastrointestinal (GI) cancers, however, cardiotoxicity concerns may limit administration in patients with pre-existing cardiovascular disease (CVD). This study investigated the association of pre-existing CVD with use of fluoropyrimidine chemotherapy in tumour-eligible GI cancer patients.Methods and analysis National cancer registry data from the Virtual Cardio-Oncology Research Initiative from England between 2014 and 2018 was used to identify GI cancer patients eligible to receive fluoropyrimidine chemotherapy. Linkage to Hospital Episode Statistics and CVD registry data were used to ascertain prior CVD and outcomes. Primary outcome was first administration of fluoropyrimidine chemotherapy following cancer diagnosis. Cox proportional hazard models determined HR and 95% CIs for the association between initiation of fluoropyrimidine treatment and prior CVD.Results 112 726 eligible patients were identified (median age 71 years (IQR 62–80), 39.7% female). 33 026 (29.3%) had pre-existing CVD. 73 392 (65.1%) patients had a diagnosis of colorectal, 23 208 (20.6%) oesophageal, 14 788 (13.1%) gastric and 1338 (1.2%) small bowel cancer. Individuals with pre-existing CVD had a 27% reduced rate of receiving fluoropyrimidine chemotherapy (HR, 0.73; 95% CI 0.70 to 0.75) on multivariable analysis. Significantly reduced rates of fluoropyrimidine administration were found across all subtypes of pre-existing CVD.Conclusions GI cancer patients with all types of pre-existing CVD are less likely to receive fluoropyrimidine chemotherapy despite eligibility. This suggests widespread caution regarding administration of fluoropyrimidines across this population; further research is needed to assess whether such conservatism is justified.

BackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P

Abstract Little is known about the prevalence of Conduct Disorder (CD) and symptoms of CD in high risk psychosis persons at both clinical and community populations in LMICs and in particular Kenya. This study aimed to document (1) the prevalence of CD diagnosis and symptoms in youth who screened positive for psychosis and (2) the associated mental disorders and substance use in the same cohort in LMIC. The sample size was 536 students who had screened positive on the Washington Early Recognition Center Affectivity and Psychosis (WERCAP) from a population of 9,742 high school, college and university students, but had not converted to a psychotic disorder. We collected data on socio-demographic characteristics and used the following tools: Economic indicators tool; the Diagnostic Interview Schedule (DIS) tool for DSM-5 diagnosis; World Health Organization (WHO) Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Basic descriptive statistics, chi-square test, Fisher's exact test, Pearson correlation and Poisson regression were conducted. Five percent (5%) of the respondents met the criteria for DSM-5 CD. Indeterminate CD comprised 10.1%. Male gender, all substances except hallucinogens lifetime, obsessive compulsive disorder, psychosis, agoraphobia, social phobia, drug abuse/dependence, antisocial personality disorder, oppositional defiant disorder, suicidality, WERCAP screen for bipolar disorder and WERCAP screen for schizophrenia were significantly (p

In post-compulsory initial teacher education (ITE) in the UK, mentors are purported to play a critical role in shaping trainee teachers' professional development through the provision of regular, constructive and purposeful feedback on their mentee's teaching practices. However, the complexity of mentoring feedback practices -- socially, spatially and temporally -- situated within programmatical and institutional architectures and in the turbulent landscape of Further Education (FE), is often underestimated. Using the theory of practice architectures, this single-site case study attempts to untangle this complexity as it explores how mentoring feedback practices were realised on one post-compulsory ITE programme, examining the processes, arrangements and artefacts which enabled and constrained their enactment. The site ontological approach also examines the dynamic unfolding of mentoring feedback practices in response to these institutional conditions in time and space, concluding that their trajectory largely depends on the 'stickiness' of their relationship and congruence with other organisational practices and concerns.

People with intellectual disabilities (ID) are vulnerable to multiple long-term conditions (MLTC). However, in the UK, there are no individual strategies tailored for them. This study synthesised evidence on prevalence of MLTC in people with ID alongside risk factors, outcomes and preventative strategies. The scoping review used the tool Abstrackr to search retrieved articles from three bibliographic databases. Of 933 articles initially screened and further identified, 20 papers met our inclusion criteria. Our findings revealed significant data on prevalence of MLTC in people with ID across the studies, but very limited data on clusters or patterns of co-occurrence in this population. The majority of papers explored risk factors and strategies for prevention of MLTC, but far fewer compared outcomes by MLTC. The identified gaps in the literature indicate the need for further research to identify clusters of MLTC and tailored prevention strategies to reduce poor outcomes in this population.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Abstract Background Patient and Public Involvement and Engagement (PPIE) is important to all aspects of health research. However, there are few examples of successful PPIE in statistical methodology research. One of the reasons for this relates to challenges in the identification of individuals interested in statistical methodology research projects, and ambiguities over the importance of PPIE to these projects. Methods This project was conducted between August 2022 and August 2023. The aim is to report the process of the development of an accessible animation to describe what statistical methodology is and the importance of PPIE in statistical methodology research projects. For this, we combined storyboarding and scriptwriting with feedback from PPIE members and researchers. Results After three stages that incorporated feedback from the relevant stakeholders, we produced a final animation about PPIE in statistical methodology. The resulting animation used minimal text, simple animation techniques and was of short duration (

Abstract Background Life expectancy is a simple measure of assessing health differences between two or more populations but current life expectancy calculations are not reliable for small populations. A potential solution to this is to borrow strength from larger populations from the same source, but this has not formally been investigated. Methods Using data on 451,222 individuals from the Clinical Practice Research Datalink on the presence/absence of intellectual disability and type 2 diabetes mellitus, we compared stratified and combined flexible parametric models, and Chiang’s methods, for calculating life expectancy. Confidence intervals were calculated using the Delta method, Chiang’s adjusted life table approach and bootstrapping. Results The flexible parametric models allowed calculation of life expectancy by exact age and beyond traditional life expectancy age thresholds. The combined model that fit age interaction effects as a spline term provided less bias and greater statistical precision for small covariate subgroups by borrowing strength from the larger subgroups. However, careful consideration of the distribution of events in the smallest group was needed. Conclusions Life expectancy is a simple measure to compare health differences between populations. The use of combined flexible parametric methods to calculate life expectancy in small samples has shown promising results by allowing life expectancy to be modelled by exact age, greater statistical precision, less bias and prediction of different covariate patterns without stratification. We recommend further investigation of their application for both policymakers and researchers.

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value

BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

The fiftieth anniversary of the Royal College of Psychiatrists, and the publication of a detailed multidisciplinary social history of British psychiatry and mental health in recent decades have offered an opportunity to take a helicopter view and reflect on the relation between psychiatry and changing British society. We argue that the time has come to move on from the rhetoric of deinstitutionalisation and community mental healthcare to lead public debate and advocacy for the needs of the mentally ill in the new era of ‘meta-community psychiatry and mental healthcare’. We need to respond effectively to the increasing awareness of mental health problems across society, aiming for a pluralist, integrated and well-funded reform led by joint professional and patient interests which could be unstoppable if we all work together.

Increasing linguistic diversity creates a need to construct early learning environments as spaces where children’s whole multilingual repertoires are represented. The purpose of these spaces is to support the crossing of linguistic boundaries during collaborative, play-based activities. In Finland, the language policies of the National Core Curriculum for Early Childhood Education and Care have been changed to promote multilingualism. This study focuses on data provided by early childhood education and care (ECEC) staff, documenting changing language policies in learning environments through the management of space and practice. The study analyzes what ECEC staff (N = 81 participant groups) report on constructing multilingual learning environments and what type of barriers and enablers are described as present in such environments. Theoretically, the analysis draws on pedagogical translanguaging. The data were collected using the LangPeda tool, and the participant groups’ textual documents were scrutinized via qualitative content analysis. The findings suggested that although most of the groups’ textual documents reflected either pre-planned or spontaneous pedagogical translanguaging, not all the groups were eager to change their monolingual practices. Linguistic hierarchies were found, and the development of children’s linguistic repertoires appeared to be hindered by misconceived understanding of language learning. Enabling pedagogical translanguaging to become part of ECEC institutions’ (spatial) practices requires sufficient resources, materials, and systematic education for ECEC staff.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P

This paper explores the potential of a new source of fly ash, deposited on the site of a coal-fired power plant in Ireland dating from 1985 to 1995, as a cement replacement material. A series of X-ray diffraction (XRD) analyses on binder samples with cement replacement levels of 0, 10, 25 and 35% was undertaken to determine the fly ash’s mineralogical composition and to determine its suitability as a supplemental cementitious material (SCM). The XRD results reveal a unique mineral composition with promising characteristics for enhancing the strength and durability of concrete. The experimental results were used to calibrate a thermodynamic model to predict changing phase assemblage and hydration behaviour over time and per replacement level. Thermodynamic models have been shown to give credible predictions of the long-term performance of cements, including SCMs. The initial experimental results’ thermodynamic modelling demonstrates the feasibility of this fly ash source as a sustainable alternative to traditional cement, paving the way for more eco-friendly construction. Ash deposits dating from 1995 to 2005 and from 2005 to the present will be presented in subsequent publications.

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

The present research utilized the resistance spot welding process on stainless steel and low carbon steel. The diameters of joint and nugget, microstructure and shearing strength of joints were examined. When increasing the welding current, welding time or clamping force, the diameters of welding joints and nuggets became larger due to the higher heat input and normal load. The shearing strength of joints increased and then decreased with increasing welding current or welding time and decreased with increasing clamping force. For the metallurgical evaluation, it was found that there were five regions around the joint, which consisted of the nugget (austenite and martensite with dendritic structures), coarse heat-affected zone (martensite and pro-eutectoid ferrite), fine heat-affected zone (ferrite and pearlite), base material (ferrite and pearlite) for low carbon steel, and base material (austenite) for stainless steel. In orthogonal tests, it was found that the welding current had the most significant influences on shearing strength, and then welding time and clamping force. Finally, an artificial neural network was established to predict the shearing strength of joints under various welding conditions. The results showed that the shearing strengths predicted by the artificial neural network had good correlation with experimental values. A shearing strength higher than 10000 N could be achieved when welding current was higher than 12.5 kA and welding time was longer than 85 ms. The artificial neural network model has applicable values for predicting the shearing strengths of joints between dissimilar steel plates.

The high kaolinite content of metakaolin makes it valuable to other industries, thereby affecting its availability and affordability for the production of limestone calcined clay cement (LC3). This work presents a study on the potential utilization of low-grade clay in place of pure metakaolin in the preparation of LC3 for mortar formulations. CEM I was partially substituted with calcined clay and limestone by 20, 30, 40, and 50 wt.%. The weight ratio of calcined clay and limestone was maintained at 2:1 for all mixes and the water-to-binder ratio was 0.48. X-ray diffraction (XRD), thermogravimetric analysis (TGA), and isothermal conduction calorimetry were used to study the hydration process and products after 28 days. Mechanical and durability assessments of the LC3 mortar specimens were conducted. LC3 specimens (marked LC20%, LC30%, LC40%, and LC50%) trailed the control sample by 1.2%, 4%, 9.8%, and 18%, respectively, at 28 days and 1.6%, 2.3%, 3.6%, and 5.5%, respectively, at 91 days. The optimum replacement of OPC clinker, calcined clay, and limestone was 20% (LC20%).

Secondary school, age range 11-14, technology and engineering education in England has been delivered mainly within Design and Technology (D&T). This inadvertently makes D&T teachers responsible for pupils' engineering education and motivation. This paper analyses D&T teachers' (N = 33) technology subject knowledge through self-assessment competency questionnaires, before and after developing a Science, Technology, Engineering and Mathematics (STEM)-focused project of their choice for their classroom. Participants were least confident in teaching the areas of technology that required mathematics and scientific knowledge. The results analyse a suggested misalignment between teachers' Creative Arts background subject knowledge compared to the technology subject knowledge required for engineering education. Suggested causes of this issue are Initial Teacher Training standards and curriculum flexibility, not teacher capability. The paper concludes that teachers have been unaware of some elements of STEM education and that continuing professional development interventions are required to assist teachers and improve their engineering knowledge in order to better equip their pupils for engineering.

Abstract: Purpose: The known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results: The odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ObjectiveGenome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.MethodsGenotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.ResultsAt chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Introduction Some people are so anxious about COVID-19 that it impairs their functioning. However, little is known about the course of severe COVID-19 anxiety or what can be done to help people who experience it.Methods and analysis Cohort study with a nested feasibility trial with follow-up at 3 and 6 months. We recruited 306 people who were aged 18 and over, lived in the UK and had severe COVID-19 anxiety (indicated by a score of 9 or more on the Coronavirus Anxiety Scale (CAS)). To take part in the nested feasibility trial, participants also had to have a score of 20 or more on the Short Health Anxiety Inventory. We excluded people from the trial if they had had COVID-19 within the previous 4 weeks, if they were currently self-isolating or if they were already receiving psychological treatment.We publicised the study nationally through adverts, social media and posts on message boards. We also recruited participants via clinicians working in primary and secondary care NHS services in London. All those in the active arm will be offered 5–10 sessions of remotely delivered modified cognitive–behavioural therapy for health anxiety (CBT-HA). We will examine the proportion of participants who remain above threshold on the CAS at 3 and 6 months and factors that influence levels of COVID-19 anxiety over 6 months using mixed effects logistic regression. The key feasibility metrics for the nested trial are the level of uptake of CBT-HA and the rate of follow-up.Ethics and dissemination Approved by Leicester Central Research Ethics Committee (reference: 20/EM/0238). The results of the study will be published in peer-reviewed scientific journals.Trial registration number ISRCTN14973494.

Background: There is a need to systematically compare and contrast mortality predictors and disparities in people with intellectual disabilities (ID) for global prevention strategy development. Method: Bibliographic databases and grey literature were searched using systematic review methodology and the machine learning tool "Abstrackr." Results: Fifty-four relevant articles and reports published from 2010 to 2019 were identified. Nearly all (n = 53) were from high-income countries. Mortality disparities were apparent and consistent across countries and publication years, with no evidence of a decrease over time. People with ID can still expect to live 12-23 years less than the general population and are particularly vulnerable to deaths from respiratory infections and epilepsy. Conclusions: Both population and individual-level approaches to prevention are indicated to tackle the continuing mortality disparities in people with ID, including consideration of reasonable adjustments in general population efforts to reduce health inequalities.

Abstract Background Immortal time bias is common in observational studies but is typically described for pharmacoepidemiology studies where there is a delay between cohort entry and treatment initiation. Methods This study used the Clinical Practice Research Datalink (CPRD) and linked national mortality data in England from 2000 to 2019 to investigate immortal time bias for a specific life-long condition, intellectual disability. Life expectancy (Chiang’s abridged life table approach) was compared for 33,867 exposed and 980,586 unexposed individuals aged 10+ years using five methods: (1) treating immortal time as observation time; (2) excluding time before date of first exposure diagnosis; (3) matching cohort entry to first exposure diagnosis; (4) excluding time before proxy date of inputting first exposure diagnosis (by the physician); and (5) treating exposure as a time-dependent measure. Results When not considered in the design or analysis (Method 1), immortal time bias led to disproportionately high life expectancy for the exposed population during the first calendar period (additional years expected to live: 2000–2004: 65.6 [95% CI: 63.6,67.6]) compared to the later calendar periods (2005–2009: 59.9 [58.8,60.9]; 2010–2014: 58.0 [57.1,58.9]; 2015–2019: 58.2 [56.8,59.7]). Date of entry of diagnosis (Method 4) was unreliable in this CPRD cohort. The final methods (Method 2, 3 and 5) appeared to solve the main theoretical problem but residual bias may have remained. Conclusions We conclude that immortal time bias is a significant issue for studies of life-long conditions that use electronic health record data and requires careful consideration of how clinical diagnoses are entered onto electronic health record systems.

The use of compacted bentonites in radioactive waste repository barriers is a relevant application of geoenvironmental engineering. The on-site structural characteristics of the bentonites determine the performance and integrity of the barrier. The present work addresses the adaptation of the standardized sand equivalent shaking method for the controlled disaggregation of Wyoming bentonite specimens prepared at low, medium, and high compaction. The evolution of the macrostructural units’ size distribution was determined by sieving at different shaking times. The stability of the compacted material increases with dry density. However, if enough energy is applied in the disaggregation process, the size distribution of the macrostructural units after disaggregation has the same characteristics as that of the uncompacted starting material, regardless of the applied degree of compaction. Since the disaggregation rate is a function of the aggregation level (compaction), it follows that compaction energy is not only spent on reducing porosity but also on generating more stable macrostructural units. These findings pave the way for future research with different materials and test conditions (compaction, moisture, etc.). In addition, the proposed shaking method is adaptable and could also be used in other sectors, such as agriculture, to determine the structural stability of natural soils.