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BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

In this study, we examined college and career readiness (CCR) support for students with and without disabilities using data from the National Longitudinal Transition Study 2012. We selected variables relevant to CCR and focused on the interaction of disability, race and ethnicity, and household income across a range of disability categories, including those on individualized education programs and 504 plans, as well as for those without disabilities. Overall, we analyzed 19 groups of students representing these intersectional characteristics. Our findings show significant differences among the groups with regard to receiving the CCR supports: help with college applications, course-taking advice, interpretation of college admissions exam scores, and arranging college visits. Results show students of color without disabilities from low-income households were 2 times more likely to receive certain CCR supports. In contrast, across all study outcomes, students with disabilities showed different patterns than their counterparts without disabilities and were at a clear disadvantage with regard to access to CCR supports. Findings suggest disparities in schoolwide CCR supports for those with disabilities, which are more pronounced for students of color with disabilities. Implications for secondary transition educators and school counselors are discussed.

In this preregistered study, we confirmed a transition-planning construct and determined its relationship with an established economic-hardship construct using parent- and youth-reported data from the National Longitudinal Transition Study 2012 and following established quality indicators of preregistered secondary data analyses studies. Transition planning was made up of seven items relevant to individualized education program (IEP) meeting participation. We examined measurement invariance on the basis of disability category and race/ethnicity as well as the intersection of these student characteristics in order to make unbiased group comparisons on key latent parameters. Contrary to our hypotheses, there was no meaningful correlation between transition planning and economic hardship. Moreover, we were unable to establish measurement invariance of transition planning because the item "youth's role in IEP meeting" functioned differently on the basis of disability category. Implications for practice are discussed regarding how decisions about IEP meeting participation are made, by whom and why, and whether evidence-based practices are effectively disseminated. Future research should ensure adequate sampling plans for national survey attempts in order to conduct an in-depth examination based on intersectional student characteristics.

Independent living skills (ILS) are crucial for the post-school success of students with disabilities. In this systematic literature review, we examined ILS interventions for secondary and postsecondary education students with intellectual disability or autism ranging from ages 13-24 years. Forty-two articles met the inclusion criteria and were examined. Findings indicated the most frequent intervention method used was prompting followed by video modeling/prompting. Technology was the most frequent modality used to deliver interventions. The most common types of ILS taught to students were cooking and cleaning. Implications for policy and practice include educators evaluating the range of ILS taught to students. Implications for future research include an emphasis on further developing technological interventions that expand to a wider variety of skills.

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Abstract Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008—0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring.

Abstract Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip. Regression analyses of paired tumour and adjacent benign samples identified 2,386 significant dmCpGs (Bonferroni p

The purpose of the current study was to conceptually replicate a multi-indicator construct of economic hardship in a national sample of adolescents with and without disabilities (N = 9,230). Using data from the National Longitudinal Transition Study 2012 (NLTS2012), the latent construct economic hardship was confirmed from six theoretically relevant indicators: household income, parent education level, parent employment status, one- or two-parent household, household internet access, and participation in government-assisted social programs (e.g., Supplemental Security Income benefits, Supplemental Nutrition Assistance Program, Temporary Assistance for Needy Families). In addition, we examined group differences on the latent mean of economic hardship based on disability category, race and ethnicity, and school and family factors. Mean differences showed significantly lower economic hardship for youth on 504 plans, youth with autism, and for White non-Hispanic youth; whereas there was significantly greater hardship for youth with intellectual disability and youth with emotional disturbance and among youth of color. The implications of the replicated and expanded findings for adolescents with and without disabilities are discussed.

Previous research reported differences in student self-determination based on disability status. Specifically, students without disabilities consistently self-report higher self-determination compared with their peers with disabilities, suggesting differential opportunities and supports for self-determination exist within school contexts. To further examine potential differences in student self-determination, the present study examined the impact of an evidence-based practice designed to promote student self-determination, the "Self-Determined Learning Model of Instruction" (SDLMI), on student self-determination outcomes when implemented in inclusive, secondary core content classrooms as a universal (i.e., Tier 1) support across an academic year. Findings suggested a relatively small change in overall self-determination during the first year of a multiyear study, but consistent patterns across students with and without disabilities. Implications for research and practice are discussed.

BackgroundThe role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.MethodsLOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source.ResultsLOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes.ConclusionsLOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

PurposeA polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.MethodsWomen with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.ResultsThe PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.ConclusionAn increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.

In this study, we estimated the cost of implementing the Self-Determined Learning Model of Instruction (SDLMI), an evidence-based practice in secondary transition, at scale in 17 U.S. school districts to enhance self-determination and transition goal attainment outcomes among 340 transition-age adolescents with intellectual disability. An advantage of the SDLMI is that it can be overlaid upon any curriculum and, therefore, can minimize opportunity costs for self-determination instruction. Using the ingredients method, the current study: (a) identified and described the essential ingredients of SDLMI implementation in typical high school settings, (b) assigned and described the cost of needed ingredients, and (c) calculated a generalizable estimate of the average cost of using the SDLMI with 340 students for one school year across 17 school districts to be $40,221.26 (or $118.30 per student). We discuss how decision-makers considering using the SDLMI in their context can minimize costs while maximizing effects on transition goal attainment outcomes. Several implications of these findings for the field of transition are also described.

Secondary data analyses occur when new analyses are proposed for existing data. Although they are prevalent in special education research, there is little guidance on how to prepare secondary data analyses studies. Preregistration of secondary data analyses studies provides a nice opportunity and structure for fellow researchers to share innovative questions and analytic approaches to existing data sets as well as increase transparency. In this manuscript, we (a) describe quality indicators of secondary data analyses consistent with open science practices and (b) provide applied examples of these indicators from a sampling of published studies based on two iterations of data from the National Longitudinal Transition Study (NLTS2 and NLTS2012) with the overall goals to provide guidance to authors and peer reviewers and promote collaboration among fellow researchers engaged in secondary analyses for a range of purposes.

Abstract Research into relationships between victim-generated content, abuse received, and observer characteristics when considering Twitter abuse has been limited to male victims. We evaluated participant perceptions of female celebrity victims and abuse received on Twitter. We used a 3 (Initial Tweet Valence; negative, neutral, positive) × 2 (Abuse Volume; low, high) repeated measures design and online survey method. Participants were shown tweets generated by six female celebrities, counterbalanced such that each participant saw each celebrity in one Valence-Volume condition. Stimuli were presented across six ‘lists’ such that celebrity ‘victims’ could be rotated across Valence-Volume pairings. Participants rated—per target stimulus—the level of blame attributable to the victim and the perceived severity of the incident. Furthermore, participants were asked to complete a Dark Tetrad scale—measuring their Machiavellianism, Narcissism, Psychopathy, and Sadism. Analyses determined that victim-blaming was influenced by victim Initial Tweet Valence (greater victim-blaming associated with more-negative content) and observer Machiavellianism. Perceived severity was influenced by victim Initial Tweet Valence, Volume of Abuse received, and observer Machiavellianism. Results were consistent with previous research involving male celebrity victims. Further research is needed to understand the contributions of participants’ hostile and benevolent sexism, as well as the role of victim attractiveness.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

A major instructional focus of interventions designed to promote self-determination, such as the Self-Determined Learning Model of Instruction (SDLMI), is to engage students in learning to set their goals, identify action plans, and evaluate their performances. However, little is known about how students define their goal attainment outcomes, or the degree to which students and teachers agree on the attainment of goals set using the SDLMI in inclusive general education classes. This study examined the relation between student and teacher ratings of goal attainment during the first semester of a longitudinal, cluster randomized controlled trial of the SDLMI, as well as the impact of student disability status and teacher supports for implementing the SDLMI (i.e., online resources vs. online resources + in-person coaching) on goal attainment. Findings suggested the feasibility of engaging students with and without disabilities in rating their goal attainment process during SDLMI in secondary schools, with kappa analysis indicating that, when credit is given for at least partial agreement between students and teachers, there is a fair amount of interrater agreement using conventional interpretation criteria. Importantly, however, conclusions drawn about the impact of student (i.e., disability status) and teacher factors (i.e., teacher implementation supports) on goal attainment outcomes are impacted by whether student or teaching ratings of goal attainment are utilized as the outcome measure. Implications for future research and practice are described. [For the Grantee Submission, see ED607065.]

BackgroundGenome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.MethodsAnalyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.ResultsAssuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

BackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

ABSTRACT Fimbriae are essential virulence factors for many bacterial pathogens. Fimbriae are extracellular structures that attach bacteria to surfaces. Thus, fimbriae mediate a critical step required for any pathogen to establish infection by anchoring a bacterium to host tissue. The human pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7encodes 16 fimbriae that may be important for EHEC to initiate infection and allow for productive expression of virulence traits important in later stages of infection, including a type III secretion system (T3SS) and Shiga toxin; however, the roles of most EHEC fimbriae are largely uncharacterized. Here, we provide evidence that two EHEC fimbriae, Yad and Yeh, modulate expression of diverse genes including genes encoding T3SS and Shiga toxin and that these fimbriae are required for robust colonization of the gastrointestinal tract. These findings reveal a significant and previously unappreciated role for fimbriae in bacterial pathogenesis as important determinants of virulence gene expression.IMPORTANCEFimbriae are extracellular proteinaceous structures whose defining role is to anchor bacteria to surfaces. This is a fundamental step for bacterial pathogens to establish infection in a host. Here, we show that the contributions of fimbriae to pathogenesis are more complex. Specifically, we demonstrate that fimbriae influence expression of virulence traits essential for disease progression in the intestinal pathogen enterohemorrhagic Escherichia coli. Gram-positive and Gram-negative bacteria express multiple fimbriae; therefore, these findings may have broad implications for understanding how pathogens use fimbriae, beyond adhesion, to initiate infection and coordinate gene expression, which ultimately results in disease.

Internet technology has changed the way we interact, and online communication has become increasingly common. There is a need to know more about how individuals present and behave online. The study examined relationships between perfectionism (self-oriented, socially prescribed, other-oriented), online self-presentation types (idealised self, multiple selves and consistent self), cyberbullying experiences (victimisation and perpetration) and psychological outcomes (rumination and depressive symptoms). An online questionnaire measuring these variables was completed by 139 general population adults (91.2 % from the UK, 73 % female; age range 17–70 years; Mean = 33.32 SD = 13.76). Regression analysis showed a role of self-oriented and socially prescribed perfectionism in idealised self and multiple selves online presentation. Further, self-presentation was related to individuals’ likelihood to engage in cyberbullying as a perpetrator. Finally, self-presentation and cyberbullying perpetration were predictive of rumination and depressive symptoms. The findings provide insight into adults’ online behaviour and related outcomes thus contributing to our understanding of the psychology within online interactions.

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

ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

BackgroundPredict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).MethodThe prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.ResultsHaving a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.ConclusionThe inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.

We develop and demonstrate a fully real-space perspective on high harmonic generation (HHG) in crystals. Due to the Wannier-Stark localization induced on subcycle timescales in the presence of a strong field, real-space descriptions are natural for strongly driven solids. Our approach allows us to address the origin of the extremely short dephasing times, which appear necessary for agreement between experimental HHG measurements and theoretical calculations generally performed in reciprocal space. We develop a physically transparent model of real-space dephasing which relates its rate to the distance between different sites in a laser-driven lattice. Our approach leads to well-structured high harmonic spectra at the microscopic level, reproduces the results of macroscopic propagation, and demonstrates that the requirement for ultrafast dephasing times stems from the need for suppressing recombination events with large electron-hole separations during radiative recombination.

BackgroundThe use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.MethodsWe conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.ResultsThe use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P

The purpose of this study was to establish construct validity of a college and career readiness measure using a sample of youth with (n = 356) and without (n = 1,599) disabilities from five high schools across three U.S. states. We established content validity through expert item review, structural validity through initial field-testing, and convergent validity by correlating domain scores with school academic and behavioral data. A four-factor measurement model emerged representing the domains Ownership of Learning, Academic Engagement and Processes, Interpersonal Engagement, and Career Development. Domain scores were significantly correlated with achievement, college admission exam scores, and attendance. Implications for research and practice with an emphasis on transition service delivery via multi-tiered systems of support are discussed.

While peer mentor programs for students with disabilities in higher education are increasing in prevalence, the research examining the effectiveness of these programs remains limited. In this study, the effect of one college peer mentoring program on academic performance at a small, private four-year university was examined. The sample was drawn from all students registered with the Office of Disability Services (n = 287), some of whom participated in a peer mentoring intervention as well as a comparison group comprised of non-participants. In light of the observational nature of the data, propensity score weighting and matching were used to adjust for possible confounding variables and to explore robustness to different methodological approaches. Logistic and linear regression methods were used to examine the effect of peer mentoring on academic probation status and grade point average (GPA), respectively, while incorporating propensity score-based adjustments. There were no significant differences between the intervention and comparison groups for either outcome; however, intervention group students had a statistically significantly higher number of accommodations available to them. The study illustrates that extant data, when used in conjunction with appropriate statistical adjustments, is a viable alternative to randomized studies. Implications for higher education researchers and practitioners are discussed, including suggestions to collect various types of non-academic data (e.g., satisfaction, well-being, self-determination surveys) as well as examine structural factors of the program (e.g., mentor-mentee relationships, mentor training) in order to better understand the possible benefits of peer mentor programs and the need for collaborative partnerships between disability services, student affairs, researchers, and institutional research staff.