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Enjoyment in primary physical education (PE) is a key factor in increasing children's physical activity engagement in PE and leisure time. While existing PE research has largely focused on a motivational PE climate and meaningful experiences in PE, research on children's perceptions of enjoyable teaching practices (TPs) in PE is limited. Therefore, this study aimed to explore primary school children's perspectives on TPs that foster PE enjoyment. In addition, we observed to what extent these TPs were applied in daily PE practice. Four focus groups with 10- to 12-year-old children (12 boys, 12 girls) from four primary schools were formed and inductive analysis resulted in 32 child-identified TPs categorized into 10 dimensions. Thirty-one PE lessons taught by 19 different PE teachers (11 generalists, 8 PE specialists) were recorded and coded using the child-identified TPs. Teachers regularly performed a substantial number of these TPs during their PE lessons. However, TPs such as the use of cooperative learning, instructional methods to promote children's (social) learning process, an emphasis on children's individual improvements, and consciously grouping were rarely observed. Moreover, PE specialists showed TPs supporting exploratory learning and children's individual learning processes more frequently than generalists. In addition, PE specialists provided challenging, differentiated tasks with a creative use of equipment more often than generalists. Including children's perspectives contributes to a comprehensive understanding of PE enjoyment and TPs that can promote enjoyable PE experiences. Children's voices need to be heard continuously by PE teachers to ensure enjoyable PE experiences for all children.

Purpose CHEK2 c.1100delC is associated with an increased breast cancer risk in women. While this variant is prevalent in the Netherlands (1% in the general population), knowledge of aetiology and prognosis of breast cancer and other tumours in CHEK2 c.1100delC carriers is lacking. The nationwide HEreditary Breast and Ovarian cancer study the Netherlands (Hebon) cohort aims to answer study questions in families with an increased risk of breast cancer and ovarian cancer. While initially focusing on BRCA1/2-variant families, Hebon gradually expanded to include pathogenic variants in other genes associated with breast and/or ovarian cancer over time. This provides an excellent setting to establish a cohort to ultimately study the impact of CHEK2 c.1100delC on cancer risk prediction and surveillance, breast cancer treatment and prognosis.Participants We invited all heterozygous and homozygous CHEK2 c.1100delC indexes and tested female relatives. 1802 women were included, of whom 1374 were heterozygotes and 938 were breast cancer cases. Pedigrees were collected from all clinical genetic departments. Furthermore, participants completed a detailed questionnaire on hormonal and lifestyle factors, family history, cancer diagnosis and treatment.Findings to date Mean age at study inclusion was 53 years. Linkage with the Netherlands Cancer Registry showed a younger age at diagnosis in homozygotes (mean age 41.7 years) and heterozygotes (47.9 years) than non-carriers (51.2 years). Furthermore, carriers were more often diagnosed with grade 2, oestrogen receptor-positive breast cancer and more often developed contralateral breast cancer than non-carriers. Most women consumed alcohol regularly and about half never smoked.Future plans Further data linkages with the Netherlands Cancer Registry will allow prospective follow-up and breast cancer risk assessment in unaffected women at the time of genetic testing, risk of contralateral breast cancer and survival in patients with breast cancer. Also, linkage with the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) allows us to retrieve tumour samples to study tumourigenesis.

Objective To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit.Design Individual participant data meta-analysis.Data sources Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset.Eligibility criteria for selecting studies Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model.Results The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, −18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of −22.3 g (Allen cohort), −33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (−154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making.Conclusions The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required.Trial registration PROSPERO CRD42019135045

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 This paper explores the institutional mainstreaming of nature-based solutions (NBS) to advance a process-based understanding about how to strategically develop the governance capacities needed for systemic, localised and inclusive NBS. To this end, it reports how policy officers in ten European cities have started to mainstream NBS by interacting with and changing incumbent governance arrangements when experimenting with novel governance processes and mechanisms to plan, deliver and steward NBS. Based on these activities of the policy officers, the analysis identifies three strategies, associated stepping stones and changes in governance conditions, to mainstream NBS in governance capacities: institutionalising (a) a systems’ approach to link NBS to policies, regulations, and departments across goals and sectors, (b) inclusive collaborations for localised and inclusive interventions, and (c) reflexivity and learning about how NBS interact with the (institutional, ecological, social, etc.) contexts and create impacts. The strategies illustrate institutional entrepreneurship in interacting with incumbent governance contexts, and how starting from NBS as a type of systemic innovation can promote broader shifts in urban governance arrangements.

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families.In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups.The surveillance advice was reclassified in 20 (34.5%) heterozygotes and 21 (35.6%) non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 11 (20.0%) heterozygotes and 8 (15.1%) non-carriers; and a sub-analysis showed that adding breast density on top shifted another 9 (23.1%) heterozygotes and 5 (27.8%) non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance.The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

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

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

Objective: The primary objective of this study is to establish maternal reference values of anti‐Müllerian hormone (AMH) in a fertile multi-ethnic urban pregnant population and to evaluate the effect of gestational age. The secondary objective of this study is to explore the association between AMH and placental biomarkers. Design: This study was embedded in the Generation R Study, an ongoing population-based prospective cohort study from early pregnancy onwards. Setting: City of Rotterdam, the Netherlands, out of hospital setting. Patients: In 5806 women, serum AMH levels were determined in early pregnancy (median 13.5 weeks; 95% range 10.5–17.2). Intervention(s): None. Main outcome measures: Maternal AMH levels in early pregnancy and its association with placental biomarkers, including human chorionic gonadotrophin (hCG), soluble fms-like tyrosine kinase-1 (sFLT), and placental growth factor (PLGF). Results: A nomogram of AMH in early pregnancy was developed. Serum AMH levels showed a decline with advancing gestational age. Higher AMH levels were associated with a higher level of the placental biomarkers hCG and sFLT in early pregnancy. This last association was predominantly mediated by hCG. AMH levels were negatively associated with PLGF levels. Conclusion: In this large study, we show that AMH levels in early pregnancy decrease with advancing gestational age. The association between AMH and the placental biomarkers hCG, sFLT, and PLGF suggests a better placental development with lower vascular resistance in mothers with higher AMH levels. Hence, AMH might be useful in predicting adverse pregnancy outcomes due to impaired placental development.

Purpose: Visual cues from a speaker's face may benefit perceptual adaptation to degraded speech, but current evidence is limited. We aimed to replicate results from previous studies to establish the extent to which visual speech cues can lead to greater adaptation over time, extending existing results to a real-time adaptation paradigm (i.e., without a separate training period). A second aim was to investigate whether eye gaze patterns toward the speaker's mouth were related to better perception, hypothesizing that listeners who looked more at the speaker's mouth would show greater adaptation. Method: A group of listeners (n = 30) was presented with 90 noise-vocoded sentences in audiovisual format, whereas a control group (n = 29) was presented with the audio signal only. Recognition accuracy was measured throughout and eye tracking was used to measure fixations toward the speaker's eyes and mouth in the audiovisual group. Results: Previous studies were partially replicated: The audiovisual group had better recognition throughout and adapted slightly more rapidly, but both groups showed an equal amount of improvement overall. Longer fixations on the speaker's mouth in the audiovisual group were related to better overall accuracy. An exploratory analysis further demonstrated that the duration of fixations to the speaker's mouth decreased over time. Conclusions: The results suggest that visual cues may not benefit adaptation to degraded speech as much as previously thought. Longer fixations on a speaker's mouth may play a role in successfully decoding visual speech cues; however, this will need to be confirmed in future research to fully understand how patterns of eye gaze are related to audiovisual speech recognition.

Purpose: This study first aimed to establish whether viewing specific parts of the speaker's face (eyes or mouth), compared to viewing the whole face, affected adaptation to distorted noise-vocoded sentences. Second, this study also aimed to replicate results on processing of distorted speech from lab-based experiments in an online setup. Method: We monitored recognition accuracy online while participants were listening to noise-vocoded sentences. We first established if participants were able to perceive and adapt to audiovisual four-band noise-vocoded sentences when the entire moving face was visible (AV Full). Four further groups were then tested: a group in which participants viewed the moving lower part of the speaker's face (AV Mouth), a group in which participants only see the moving upper part of the face (AV Eyes), a group in which participants could not see the moving lower or upper face (AV Blocked), and a group in which participants saw an image of a still face (AV Still). Results: Participants repeated around 40% of the key words correctly and adapted during the experiment, but only when the moving mouth was visible. In contrast, performance was at floor level, and no adaptation took place, in conditions when the moving mouth was occluded. Conclusions: The results show the importance of being able to observe relevant visual speech information from the speaker's mouth region, but not the eyes/upper face region, when listening and adapting to distorted sentences online. Second, the results also demonstrated that it is feasible to run speech perception and adaptation studies online, but that not all findings reported for lab studies replicate.

BackgroundHeight and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.MethodsWe applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.ResultsObserved height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction

BackgroundBRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.MethodsWe used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.ResultsObserved height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.ConclusionHeight is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

Abstract Background The impact and costs associated with work-related sprains and strains in New Zealand and globally are substantial and a major occupational and public health burden. In New Zealand around one-third of all sprains and strains workers compensation (ACC) claims (2019) are for back injuries, but shoulder and arm injuries are increasing at a faster rate than other sprain and strain injuries (ACC, 2020). A need exists for a change to current approaches to sprains and strains prevention, to more effectively manage this significant and persistent problem in workplaces. Designing out hazards is one of the most effective means of preventing occupational injuries and illnesses. This paper outlines the study protocol of the surveillance, management and prevention programme and describes the utilisation of prevention through design principles in the prevention of work-related sprains and strains in agriculture/horticulture/food production in the Hawkes Bay region of New Zealand. Methods This is a prospective mixed methods study incorporating the collection of quantitative data to describe the epidemiology of work related sprains and strains injuries presenting to the regional health centre (Hastings Health Centre) over a period of 24 months and qualitative data from participants presenting at the health centre to identify high risk industry sectors/ occupations/ workplaces and tasks and design, develop and apply prevention through design principles/ solutions/interventions to critical features of the work and work environment and undertake an outcome evaluation during the last 6 months of the project. Discussion The purpose of this project is to establish an epidemiological surveillance programme to assess the incidence and prevalence of work-related sprains and strains according to age, sex, industry sector and occupation to target efforts to prevent work-related sprains and strains, by applying prevention through design (PtD) principles in selected workplaces in agriculture. The collection of more detailed case, occupational and work history data from a sample of patients presenting at the HHC clinic will identify high risk industry sectors/occupations/workplaces and tasks. Assessment techniques will include comprehensive design, design thinking and human factors/ergonomics methodologies through co-design and participatory ergonomics techniques. The PtD solutions/ interventions implemented will be evaluated using a quasi-experimental design consisting of a pre-test/ post-test with-in subjects design with control groups that do not receive the intervention.

Abstract Background Maternal lipid levels in early pregnancy are associated with maternal health and foetal growth. It is however unclear if maternal lipids in early pregnancy can be used to predict childhood lipid levels. The aim of this study is to assess the association between maternal and offspring childhood lipid levels, and to investigate the influence of maternal BMI and diet on these associations. Methods This study included 2692 women participating in the Generation R study, an ongoing population-based prospective cohort study from early life onwards. Women with an expected delivery date between 2002 and 2006 living in Rotterdam, the Netherlands were included. Total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-c) were measured in early pregnancy (median 13.2 weeks [90% range 10.6; 17.1]). Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Corresponding lipid measurements were determined in 2692 children at the age of 6 (median 6.0 years [90% range 5.7; 7.5]) and 1673 children 10 years (median 9.7 years [90% range 9.5; 10.3]). Multivariate linear regression analysis was used to examine the association between maternal lipid levels in early pregnancy and the corresponding childhood lipid measurements at the ages of 6 and 10 years while adjusting for confounders. Results Maternal lipid levels in early pregnancy are positively associated with corresponding childhood lipid levels 6 and 10 years after pregnancy, independent of maternal body mass index and diet. Conclusions Maternal lipid levels in early pregnancy may provide an insight to the lipid profile of children years later. Gestational lipid levels may therefore be used as an early predictor of children’s long-term health. Monitoring of these gestational lipid levels may give a window-of-opportunity to start early interventions to decrease offspring’s lipid levels and possibly diminish their cardiovascular risk later in life. Future studies are warranted to investigate the genetic contribution on maternal lipid levels in pregnancy and lipid levels of their offspring years later.

Robotic-assisted laparoscopic nephroureterectomy (NU) became the gold standard in the treatment of upper tract urothelial cancer (UTUC). Usually, a transabdominal approach is used. However, this approach is flawed because of the problematic range of motion and conflicting instruments, especially during the preparation of the ureter orifice in the deep pelvis. We have recently published a novel approach for nephrectomy and partial nephrectomy using the transabdominal lumbar approach (TALA). Using the DaVinci Xi system's rotation possibility, we modified TALA for NU. This includes an un- and redocking step with a 180° rotation of the robot before the dissection of the distal ureter. We have analysed the outcome of all consecutive patients who underwent DRONE at our institution. Between June 2022 and September 2024, we performed Drone on 14 patients and analysed the outcome of 13 patients (10 male/3 female, aged 55–86). The median Operation time was 226 min (158–361). Rotation time was 9 min (6–15). Median blood loss was 100 ml (0–400). Median length of stay was 6 days (5–13). Two patients had Clavien–Dindo complication (CDC) grade 2 complications, and one patient required open revision due to postoperative bleeding and intensive care corresponding to a CDC grade 4a. Our first promising report reveals that the DRONE technique is feasible and safe. The rotation step only took a few minutes and, therefore, seems straightforward. We believe that DRONE facilitates robotic NU by enhancing the range of motion and reducing instrument conflicts. [ABSTRACT FROM AUTHOR]

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.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Abstract Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early‐onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre‐screen for other PHTS features or direct germline testing. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST) and Crh+ neurons in this region play a key role in chronic ethanol‐induced increases in volitional intake, hypothesized to be driven by emergent negative affective behaviors. Excitatory N‐methyl‐d‐aspartate receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. Specifically, GluN2D subunit‐containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. Methods: Male and female mice underwent a home cage chronic drinking forced abstinence model (CDFA) to assess the impact of 1 day or 2 weeks of ethanol abstinence on BNST synaptic transmission and BNST Grin gene expression. Constitutive and conditional BNST GluN2D knockout mice were used to assess the impact of GluN2D deletion on continuous access ethanol intake as well as negative affect behaviors, using the open field, elevated zero maze, and forced swim tasks. Results: We report here that excitatory transmission undergoes time‐dependent upregulation in BNST Crh+ cells. Further, knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in the dBNST or dBNST Crh+ neurons. Finally, we find that deletion of GluN2D fails to alter negative affect in ethanol‐naïve female mice. Conclusions: These data suggest a role for BNST GluN2D‐containing NMDARs in ethanol drinking but not ethanol abstinence, highlighting sex differences and behavioral specificity. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior. [ABSTRACT FROM AUTHOR]