Reduced Breast and Ovarian Cancer Through Targeted Genetic Testing: Estimates Using the NEEMO Microsimulation Model.

The effectiveness and cost-effectiveness of genetic testing for hereditary breast and ovarian cancer largely rely on the identification and clinical management of individuals with a pathogenic variant prior to developing cancer. Simulation modelling is commonly utilised to evaluate genetic testing strategies due to its ability to synthesise collections of data and extrapolate over long time periods and large populations. Existing genetic testing simulation models use simplifying assumptions for predictive genetic testing and risk management uptake, which could impact the reliability of their estimates.

Pharmacogenetic-guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC-PGx): A multicenter clinical trial.

PACIFIC-PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype-guided dosing on severe fluoropyrimidine (FP) and irinotecan-related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis).

Phenotype driven molecular genetic test recommendation for diagnosing pediatric rare disorders.

Patients with rare diseases often experience prolonged diagnostic delays. Ordering appropriate genetic tests is crucial yet challenging, especially for general pediatricians without genetic expertise. Recent American College of Medical Genetics (ACMG) guidelines embrace early use of exome sequencing (ES) or genome sequencing (GS) for conditions like congenital anomalies or developmental delays while still recommend gene panels for patients exhibiting strong manifestations of a specific disease.

Sleep restriction and age effects on distinct aspects of cognition in adolescents.

Insufficient sleep negatively impacts scholastic performance in children and adolescents. Here we use a dose-response time in bed (TIB) restriction study to evaluate associations between sleep loss and multiple aspects of cognition. We evaluated changes in cognitive measures across ages 10 to 23 years and determined whether the effects of sleep loss changed across this age range.

Outcomes from low-risk ductal carcinoma in situ: a systematic review and meta-analysis.

Purpose: The current standard of treatment for ductal carcinoma in situ (DCIS) is surgery with or without adjuvant radiotherapy. With a growing debate about overdiagnosis and overtreatment of low-risk DCIS, active surveillance is being explored in several ongoing trials. We conducted a systematic review and meta-analysis to evaluate the recurrence of low-risk DCIS under various treatment approaches.

Quantification of serovar Typhimurium Population Dynamics in Murine Infection Using a Highly Diverse Barcoded Library.

Murine models are often used to study the pathogenicity and dissemination of the enteric pathogen serovar Typhimurium. Here, we quantified Typhimurium population dynamics in mice using the STAMPR analytic pipeline and a highly diverse . Typhimurium barcoded library containing 55,000 unique strains distinguishable by genomic barcodes by enumerating .

Stromal lymphocytes are associated with upgrade of B3 breast lesions.

Various histopathological, clinical and imaging parameters have been evaluated to identify a subset of women diagnosed with lesions with uncertain malignant potential (B3 or BIRADS 3/4A lesions) who could safely be observed rather than being treated with surgical excision, with little impact on clinical practice. The primary reason for surgery is to rule out an upgrade to either ductal carcinoma in situ or invasive breast cancer, which occurs in up to 30% of patients. We hypothesised that the stromal immune microenvironment could indicate the presence of carcinoma associated with a ductal B3 lesion and that this could be detected in biopsies by counting lymphocytes as a predictive biomarker for upgrade.

Ethnic differences in time to surgery for women with early stage breast cancer in Aotearoa/New Zealand: a population-based study.

Background: This study evaluates whether there are ethnic differences in time to surgery in women with early-stage (1-3a) breast cancer in four NZ urban regions between 2000 and 2020 pre- and post- Faster Cancer Treatment (FCT) implementation, which was introduced to address inequities in cancer outcomes.

Methods: This retrospective analysis used (Breast Cancer Foundation National Register), a prospectively maintained database of breast cancers from 2000 to 2020. Women with stage 3b, 3c, metastatic or bilateral cancers were excluded.

pLxIS-containing domains are biochemically flexible regulators of interferons and metabolism.

Signal transduction proteins containing a pLxIS motif induce interferon (IFN) responses central to antiviral immunity. Apart from their established roles in activating the IFN regulator factor (IRF) transcription factors, the existence of additional pathways and functions associated with the pLxIS motif is unknown. Using a synthetic biology-based platform, we identified two orphan pLxIS-containing proteins that stimulate IFN responses independent of all known pattern-recognition receptor pathways.

Synthetic polymers: A global threat to aquatic benthic environments.

Finding time-efficient and cost-effective data collection methods is a challenge when addressing aquatic litter pollution on a global scale. In this study, we analysed data on aquatic benthic debris collected worldwide by volunteer scuba divers through the Dive Against Debris® citizen science initiative, examining its relationship with spatial and socio-economic factors. Plastic-dominated litter was found in both marine (64 %) and freshwater (48 %) environments, followed by metal and glass.

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.

Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).

Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes.

Inducible transposon mutagenesis for genome-scale forward genetics.

Transposon insertion sequencing (Tn-seq) is a powerful method for genome-scale functional genetics in bacteria. However, its effectiveness is often limited by a lack of mutant diversity, caused by either inefficient transposon delivery or stochastic loss of mutants due to population bottlenecks. Here, we introduce "InducTn-seq", which leverages inducible mutagenesis for temporal control of transposition.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10).

Ultrasmall and Highly Dispersed Pt Entities Deposited on Mesoporous N-doped Carbon Nanospheres by Pulsed CVD for Improved HER.

Vapor-based deposition techniques are emerging approaches for the design of carbon-supported metal powder electrocatalysts with tailored catalyst entities, sizes, and dispersions. Herein, a pulsed CVD (Pt-pCVD) approach is employed to deposit different Pt entities on mesoporous N-doped carbon (MPNC) nanospheres to design high-performance hydrogen evolution reaction (HER) electrocatalysts. The influence of consecutive precursor pulse number (50-250) and deposition temperature (225-300 °C) are investigated.

Exome sequencing identifies as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls.

Haploinsufficiency Contributes to the Development of Congenital Diaphragmatic Hernia.

encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of is associated with a neurodevelopmental disorder: autosomal dominant mental retardation with language impairment with or without autistic features. More recently, heterozygous variants have also been shown to cause a variety of structural birth defects including central nervous system (CNS) anomalies, congenital heart defects, congenital anomalies of the kidney and urinary tract, cryptorchidism, and hypospadias.

Ethnic inequities in use of breast conserving surgery and radiation therapy in Aotearoa/New Zealand: which factors contribute?

Purpose: Aotearoa/New Zealand (NZ) faces ethnic inequities with respect to breast cancer survival and treatment. This study establishes if there are ethnic differences in (i) type of surgery and (ii) receipt of radiotherapy (RT) following breast conserving surgery (BCS), among women with early-stage breast cancer in NZ.

Methods: This analysis used Te Rēhita Mata Ūtaetae (Breast Cancer Foundation National Register), a prospectively maintained database of breast cancers from 2000 to 2020.

Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.

Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females).

Does diabetes affect breast cancer survival?

Objectives: The objective of this study is to investigate the influence of diabetes on breast cancer-specific survival among women with breast cancer in Aotearoa/New Zealand.

Methods: This study included women diagnosed with invasive breast cancer between 2005 and 2020, with their information documented in the Te Rēhita Mate Ūtaetae-Breast Cancer Foundation National Register. Breast cancer survival curves for women with diabetes and those without diabetes were generated using the Kaplan-Meier method.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women.

A qualitative study exploring the challenges and enablers of pharmacists with a recent background in community pharmacy transitioning into primary care.

Background: Pharmacists are an increasing part of the primary care health care team in Scotland. Recruitment to this expanding sector has largely come from community pharmacy. However, it is unknown if these pharmacists have specific needs to perform their role within the primary care team.

Emergency Department Take-Home Naloxone Improves Access Compared with Pharmacy-Dispensed Naloxone.

Background: Opioid overdose is a major cause of mortality in the United States. In spite of efforts to increase naloxone availability, distribution to high-risk populations remains a challenge.

Objective: To assess the effects of multiple different naloxone distribution methods on patient obtainment of naloxone in the emergency department (ED) setting.