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Innovative and easy-to-implement strategies are needed to improve the pathogenicity assessment of rare germline missense variants. Somatic cancer driver mutations identified through large-scale tumor sequencing studies often impact genes that are also associated with rare Mendelian disorders. The use of cancer mutation data to aid in the interpretation of germline missense variants, regardless of whether the gene is associated with a hereditary cancer predisposition syndrome or a non-cancer-related developmental disorder, has not been systematically assessed. We extracted putative cancer driver missense mutations from the Cancer Hotspots database and annotated them as germline variants, including presence/absence and classification in ClinVar. We trained two supervised learning models (logistic regression and random forest) to predict variant classifications of germline missense variants in ClinVar using Cancer Hotspot data (training dataset). The performance of each model was evaluated with an independent test dataset generated in part from searching public and private genome-wide sequencing datasets from ~1.5 million individuals. Of the 2,447 cancer mutations, 691 corresponding germline variants had been previously classified in ClinVar: 426 (61.6%) as likely pathogenic/pathogenic, 261 (37.8%) as uncertain significance, and 4 (0.6%) as likely benign/benign. The odds ratio for a likely pathogenic/pathogenic classification in ClinVar was 28.3 (95% confidence interval: 24.2-33.1, p < 0.001), compared with all other germline missense variants in the same 216 genes. Both supervised learning models showed high correlation with pathogenicity assessments in the training dataset. There was high area under precision-recall curve values (0.847 and 0.829) and area under the receiver-operating characteristic curve values (0.821 and 0.774) for logistic regression and random forest models, respectively, when applied to the test dataset. With the use of cancer and germline datasets and supervised learning techniques, our study shows that cancer mutation data can be leveraged to improve the interpretation of germline missense variation potentially causing rare Mendelian disorders.

Objective While researchers are crucial to the successful delivery of implementation trials, their perspectives are rarely captured in the evaluation of these trials. This qualitative study aimed to capture the experiences of a small research team coordinating a large, multisite implementation trial (the Hide and Seek Project) in the Australian healthcare setting.Design A qualitative approach was used, whereby members of the Hide and Seek Project research team were invited to take part in semistructured focus groups led by an external facilitator. The focus group guide was developed to explore the experiences of the research team (including challenges and lessons learnt) as they moved through key study activities. Focus groups were transcribed verbatim and analysed using an inductive thematic approach. Barriers and facilitators identified within themes were deductively coded to domains of the updated Consolidated Framework for Implementation Research.Setting Participants were recruited from a research organisation based in Sydney, Australia.Participants A total of seven researcher and administering institution participants took part in four focus groups.Results Analysis highlighted the following themes: navigating bureaucracy, distinguishing implementation trials from clinical trials, the impact of COVID-19, balancing rigour and pragmatism in implementation trials, data access and complexity of analysis, and key learnings and future directions (subthemes: building relationships with ethics committees, communicating implementation concepts, streamlining of the implementation and research approach).Conclusions Findings highlight the need for streamlining current administrative and ethical review processes, as well as procedures that allow greater flexibility for researchers to respond to challenges as they arise. Lessons learnt by the Hide and Seek Project team hold potential relevance for fellow researchers involved in coordinating implementation trials across diverse contexts.

Summary: Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Review of Holly Taylor Coolman, _Parenting: The Complex and Beautiful Vocation of Raising Children_

Summary: MGA (OMIM: 616061) encodes a dual-specificity transcription factor that regulates the expression of Max-network and T-box family target genes, important in embryogenesis. Previous studies have linked MGA to various phenotypes, including neurodevelopmental disorders, congenital heart disease, and early-onset Parkinson’s disease. Here, we describe the clinical phenotype of individuals with de novo, heterozygous predicted loss-of-function variants in MGA, suggesting a unique disorder involving both neurodevelopmental and congenital anomalies. In addition to developmental delays, certain congenital anomalies were present in all individuals in this cohort including cardiac anomalies, male genital malformations, and craniofacial dysmorphisms. Additional findings seen in multiple individuals in this cohort include hypotonia, abnormal brain imaging, hearing loss, sleep dysfunction, urinary issues, skeletal abnormalities, and feeding difficulties. These findings provide support for MGA as a gene intolerant to protein truncation with a broad phenotypic spectrum.

When Russia invaded Ukraine in 2022, some of the timeliest intelligence was provided not by intelligence agencies, but by private actors. Open-source intelligence is an increasing focus in intelligence studies; however, little systematic attention has been paid to the vendors that collect, analyze, and operationalize intelligence outside of classified national security environments. This research addresses this gap through a new dataset that seeks to capture the expanding array of intelligence providers that serve the private sector. This paper examines how vendors apply intelligence tradecraft to support corporate risk mitigation, including travel security, executive protection, and geopolitical risk analysis. [ABSTRACT FROM AUTHOR]

Innovative and easy-to-implement strategies are needed to improve the pathogenicity assessment of rare germline missense variants. Somatic cancer driver mutations identified through large-scale tumor sequencing studies often impact genes that are also associated with rare Mendelian disorders. The use of cancer mutation data to aid in the interpretation of germline missense variants, regardless of whether the gene is associated with a hereditary cancer predisposition syndrome or a non-cancer-related developmental disorder, has not been systematically assessed. We extracted putative cancer driver missense mutations from the Cancer Hotspots database and annotated them as germline variants, including presence/absence and classification in ClinVar. We trained two supervised learning models (logistic regression and random forest) to predict variant classifications of germline missense variants in ClinVar using Cancer Hotspot data (training dataset). The performance of each model was evaluated with an independent test dataset generated in part from searching public and private genome-wide sequencing datasets from ~1.5 million individuals. Of the 2,447 cancer mutations, 691 corresponding germline variants had been previously classified in ClinVar: 426 (61.6%) as likely pathogenic/pathogenic, 261 (37.8%) as uncertain significance, and 4 (0.6%) as likely benign/benign. The odds ratio for a likely pathogenic/pathogenic classification in ClinVar was 28.3 (95% confidence interval: 24.2–33.1, p < 0.001), compared with all other germline missense variants in the same 216 genes. Both supervised learning models showed high correlation with pathogenicity assessments in the training dataset. There was high area under precision-recall curve values (0.847 and 0.829) and area under the receiver-operating characteristic curve values (0.821 and 0.774) for logistic regression and random forest models, respectively, when applied to the test dataset. With the use of cancer and germline datasets and supervised learning techniques, our study shows that cancer mutation data can be leveraged to improve the interpretation of germline missense variation potentially causing rare Mendelian disorders. Author summary: Our study introduces an approach to improve the interpretation of rare genetic variation, specifically missense variants that can alter proteins and cause disease. We found that published evidence from somatic cancer sequencing studies may be relevant to understanding the impact of the same variant in the context of rare inherited (Mendelian) disorders. By using widely available datasets, we noted that many cancer driver mutations have also been observed as rare germline variants associated with inherited disorders. This intersection led us to employ machine learning techniques to assess how cancer mutation data can predict the pathogenicity of germline variants. We trained machine learning models and tested them on a separate dataset curated by searching public and private genome-wide sequencing data from over a million participants. Our models were able to successfully identify pathogenic genetic changes, demonstrating strong performance in predicting disease-causing variants. This study highlights that cancer mutation data can enhance the interpretation of rare missense variants, aiding in the diagnosis and understanding of rare diseases. Integrating this approach into current genetic classification frameworks could be beneficial, and opens new avenues for leveraging existing cancer research to benefit broader genetic research and diagnostics for rare genetic conditions. [ABSTRACT FROM AUTHOR]

Objective To explore the clinical relevance and assay sensitivity of using personalized outcomes using data from a randomized clinical trial (RCT) in people with chemotherapy-induced peripheral neuropathy (CIPN). Design This study is a secondary analysis that leveraged data from a RCT of transcutaneous electrical stimulation for CIPN to test whether personalized outcomes could minimize potential floor effects and increase the assay sensitivity of pain clinical trials (ie, ability to detect a true treatment effect). Setting Participants were recruited for a RCT from community oncology clinics in the United States. Participants Adults with CIPN (N  = 72) who reported on average ≥4 intensity (measured via a 7-day baseline diary) for at least 1 of the following pain qualities: hot/burning pain, sharp/shooting pain, and/or cramping. Methods Personalized outcomes were defined based on participants' unique presentation of pain qualities at baseline, measured via 0-10 numeric rating scales (NRS), or ranking of the distress caused by the pain qualities. Analysis of covariance models estimated the treatment effect as measured by personalized and non-personalized outcomes. Results The adjusted mean difference between groups was higher using personalized outcomes (ie, 1.21-1.25 NRS points) compared to a non-personalized outcome (ie, 0.97 NRS points), although the standardized effect sizes were similar between outcomes (0.49-0.54). Conclusions These results suggest that personalized pain quality outcomes could minimize floor effects, while providing similar assay sensitivity to non-personalized pain quality outcomes. Personalized outcomes better reflect an individual's unique experience, inherently providing more clinically relevant estimates of treatment effects. Personalized outcomes may be advantageous, particularly for clinical trials in populations with high inter-individual variability in pain qualities. [ABSTRACT FROM AUTHOR]

Rationale: Although many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient nonimaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. Objectives: Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung samples. Methods: Using RNA-sequencing data from 446 samples in the Lung Tissue Research Consortium and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of chest computed tomography–quantified emphysema. We also leveraged publicly available lung single-cell RNA-sequencing data to identify cell types showing chronic obstructive pulmonary disease–associated differential expression of the emphysema pathways found in the bulk analyses. Measurements and Main Results: In the bulk lung RNA-sequencing analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared differentially expressed genes and biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and distinct pathway activities were observed among various macrophage subpopulations. Conclusions: This study identified emphysema-related changes in gene expression and alternative splicing, cell type–specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung. [ABSTRACT FROM AUTHOR]

Aim: To assess student nurses understanding and skills in the application of antimicrobial stewardship knowledge to practice. Design: Quantitative. Methods: Cross‐sectional survey. Results: Five hundred and twenty three student nurses responded across 23 UK universities. Although students felt prepared in competencies in infection prevention and control, patient‐centred care and interprofessional collaborative practice, they felt less prepared in competencies in which microbiological knowledge, prescribing and its effect on antimicrobial stewardship is required. Problem‐based learning, activities in the clinical setting and face‐to‐face teaching were identified as the preferred modes of education delivery. Those who had shared antimicrobial stewardship teaching with students from other professions reported the benefits to include a broader understanding of antimicrobial stewardship, an understanding of the roles of others in antimicrobial stewardship and improved interprofessional working. Conclusion: There are gaps in student nurses' knowledge of the basic sciences associated with the antimicrobial stewardship activities in which nurses are involved, and a need to strengthen knowledge in pre‐registration nurse education programmes pertaining to antimicrobial management, specifically microbiology and antimicrobial regimes and effects on antimicrobial stewardship. Infection prevention and control, patient‐centred care and interprofessional collaborative practice are areas of antimicrobial stewardship in which student nurses feel prepared. Interprofessional education would help nurses and other members of the antimicrobial stewardship team clarify the role nurses can play in antimicrobial stewardship and therefore maximize their contribution to antimicrobial stewardship and antimicrobial management. Implications for the Profession: There is a need to strengthen knowledge from the basic sciences, specifically pertaining to antimicrobial management, in pre‐registration nurse education programmes. Patient or Public Contribution: No patient or public contribution. Impact: What Problem Did the Study Address?: Nurses must protect health through understanding and applying antimicrobial stewardship knowledge and skills (Nursing and Midwifery Council 2018); however, there is no research available that has investigated nurses understanding and skills of the basic sciences associated with the antimicrobial stewardship activities in which they are involved. What Were the Main Findings?: There are gaps in student nurses' knowledge of the basic sciences (specifically microbiology and prescribing) associated with the antimicrobial stewardship activities in which nurses are involved. Problem‐based learning, and activities in the clinical setting, were reported as useful teaching methods, whereas online learning, was seen as less useful. Where and on Whom Will the Research Have an Impact?: Pre‐registration nurse education programmes. Reporting Method: The relevant reporting method has been adhered to, that is, STROBE. [ABSTRACT FROM AUTHOR]

This study investigated the benefits and challenges of intergenerational tutoring in a post-pandemic context. We explored how the benefits of intergenerational tutoring vary among subgroups of volunteers—first-time tutors, male tutors, tutors who are caregivers, and tutors with moderate or severe loneliness. Older adult tutors (N = 319) were surveyed before and after the 2021–2022 school year, and the data were analyzed with structural equation multivariate regression and thematic analysis. Results indicated that while public health measures like mask-wearing posed challenges for some tutors, there were positive outcomes for tutors, especially first-time tutors, who experienced more health and well-being benefits, and tutors who are caregivers, who experienced improved civic attitudes towards public education. These results can help programs attract subgroups of volunteers who are likely to benefit the most, as well as attend to the unique challenges of pandemic-related policies. [ABSTRACT FROM AUTHOR]

The article "Parenting: The Complex and Beautiful Vocation of Raising Children" discusses the evolving field of moral theology, with a focus on parenting as a crucial aspect of ecclesiological and moral importance. The author, Holly Taylor Coolman, combines her experience as a parent with her expertise as a theologian to provide insights accessible to non-academics of any Christian denomination. Coolman's book emphasizes the communal aspect of parenting, highlighting the importance of support networks for parents and children to thrive. The text also explores the challenges parents may face in finding a supportive community and offers perspectives on embracing suffering and seeking supernatural support in times of need. [Extracted from the article]

Scholarship is an important topic for the continuation of the discipline of nursing. Nursing Science Quarterly has asked Dr. John R. Phillips, a notable Rogerian scholar, to comment on nursing scholarship. Dr. Phillips is introduced here. [ABSTRACT FROM AUTHOR]

Significant sex-specific differences exist in heart failure with preserved ejection fraction (HFpEF). In particular, sub-analyses of key trials suggest a preferential benefit of specific HFpEF therapies in women. This work investigated potential differential treatment effects between women and men in the PARAGLIDE-HF (Prospective Comparison of ARNI with ARB given following Stabilization in Decompensated HFpEF) trial. We hypothesized that there would be no significant difference in treatment effect among women versus men in this high-risk population with LVEF>40%. In this pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGLIDE-HF trial. The primary endpoint was time-average proportional change in amino terminal pro-B type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. We also examined secondary outcomes and tolerability among women and men. Overall, 224 men (48%) and 242 women (52%) were randomized. Women had significantly higher LVEF, worse renal function, and less comorbid atrial fibrillation and coronary artery disease than men. In the overall study population, time-averaged reduction in NT-proBNP was significantly greater for Sacubitril-Valsartan (Sac/Val) than Valsartan (ratio of change 0.85; 95% CI:0.73-0.999). When examined according to sex, time-averaged reduction in NT-proBNP was numerically greater with Sac/Val than Valsartan in both men (ratio of change 0.84; 95% CI:0.67-1.05) and women (ratio of change 0.86; 95% CI:0.69-1.070), especially those with LVEF≤60% (ratio of change 0.75; 95% CI:0.59-0.96 for men; ratio of change 0.79; 95% CI:0.60-1.05 for women), with no significant differential treatment effect based on sex (P for interaction in overall sample=0.91, Figure 1). Similarly, the secondary hierarchical endpoint favored Sac/Val over Valsartan in both men and women but was not statistically significant (Figure 2). With regards to tolerability, study drug dosage levels were similar between Sac/Val and Valsartan across men and women. Likewise, there were no sex-specific differences in the incidence of adverse events. The efficacy, safety and tolerability of Sac/Val versus Valsartan were similar in both men and women in the PARAGLIDE-HF trial. [ABSTRACT FROM AUTHOR]