Selective Effects of Substantia Nigra and Locus Coeruleus Degeneration on Cognition in Parkinson's Disease.

Background: The substantia nigra (SN) and locus coeruleus (LC) are among the first brain regions to degenerate in Parkinson's disease (PD). This has important implications for early cognitive deficits because these nuclei are sources of ascending neuromodulators (i.e.

WATCH: A Workflow to Assess Treatment Effect Heterogeneity in Drug Development for Clinical Trial Sponsors.

This article proposes a Workflow for Assessing Treatment effeCt Heterogeneity (WATCH) in clinical drug development targeted at clinical trial sponsors. WATCH is designed to address the challenges of investigating treatment effect heterogeneity (TEH) in randomized clinical trials, where sample size and multiplicity limit the reliability of findings. The proposed workflow includes four steps: analysis planning, initial data analysis and analysis dataset creation, TEH exploration, and multidisciplinary assessment.

A systematic study of CSTD-generated stress on different biomolecular modalities.

Although Closed System Transfer Devices (CSTDs) are used in oncology for dose preparation and administration, the impact of CSTDs on biologics and other non-small molecular modalities are not fully understood. We investigated particle formation when preparing and mock administering three experimental biologics (mAb, ADC, and fusion protein) using seven models of CSTDs. A wide range of visible and subvisible particle formation was observed among CSTD models.

Online unsupervised performance-based cognitive testing: A feasible and reliable approach to scalable cognitive phenotyping of Parkinson's patients.

Introduction: A better understanding of the heterogeneity in the cognitive and mood symptoms of Parkinson's disease will require research conducted in large samples of patients. Fully online and remote research assessments present interesting opportunities for scaling up research but the feasibility and reliability of remote and fully unsupervised performance-based cognitive testing in individuals with Parkinson's disease is unknown. This study aims to establish the feasibility and reliability of this testing modality in Parkinson's patients.

"Should I Let Them Know I Have This?": Multifaceted Genetic Discrimination and Limited Awareness of Legal Protections among Individuals with Hereditary Cancer Syndromes.

Introduction: Hereditary cancer syndromes (HCS), such as hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), represent approximately 10% of all cancers. Along with medical burdens associated with the genetic risk of developing cancer, many individuals face stigma and discrimination. Genetic discrimination refers to negative treatment, unfair profiling, or harm based on genetic characteristics, manifesting as "felt" stigma (ostracization without discriminatory acts) or "enacted" stigma (experiencing discriminatory acts).

Improving Access to Hereditary Testing in Pancreatic Ductal Carcinoma.

Purpose: Approximately 5%-10% of patients with pancreatic ductal adenocarcinoma (PDAC) have an inherited basis, yet uptake of genetic testing remains low and subject to disparities. This study compared two genetic testing pathways available to patients referred to a provincial cancer center, BC Cancer: a traditional hereditary cancer clinic-initiated testing (HCT) pathway and a new oncology clinic-initiated testing (OCT) pathway.

Methods: Study subjects were patients with confirmed PDAC referred for genetic testing through the HCT or OCT pathway between June 1, 2020, and February 1, 2022.

Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

Objectives: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada.

"I just wanted more": Hereditary cancer syndromes patients' perspectives on the utility of circulating tumour DNA testing for cancer screening.

Hereditary cancer syndromes (HCS) predispose individuals to a higher risk of developing multiple cancers. However, current screening strategies have limited ability to screen for all cancer risks. Circulating tumour DNA (ctDNA) detects DNA fragments shed by tumour cells in the bloodstream and can potentially detect cancers early.

New insights into the biology and development of lung cancer in never smokers-implications for early detection and treatment.

Lung cancer is the leading cause of cancer deaths worldwide. Despite never smokers comprising between 10 and 25% of all cases, lung cancer in never smokers (LCNS) is relatively under characterized from an etiological and biological perspective. The application of multi-omics techniques on large patient cohorts has significantly advanced the current understanding of LCNS tumor biology.

Beyond PACIFIC: Real-World Outcomes of Adjuvant Durvalumab According to Treatment Received and PD-L1 Expression.

Adjuvant durvalumab after chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). A post hoc exploratory analysis of PACIFIC revealed no OS benefit in the PD-L1 < 1% subgroup. This retrospective analysis assesses the real-world impact of durvalumab on OS according to PD-L1 tumor proportion score (TPS).

What competencies do European general practice trainees value the most? A prioritisation exercise using a Delphi-informed approach.

General Practice has changed over the past decade. Expansion of clinicians' roles may create uncertainty, stress, and overload - particular for those at the start of their career. The WONCA Europe network for medical education, EURACT, has published competency-based aims and requirements for speciality training in general practice.

Does the use of antipyretics prolong illness? A systematic review of the literature and meta-analysis on the effects of antipyretics in acute upper and lower respiratory tract infections.

Objective: Fever contributes to the inflammatory response; in some infections, antipyretics could prolong the illness. The objective of our study was to evaluate the impact of antipyretic treatments on the evolution of acute upper and lower respiratory tract infections (RTI).

Method: A systematic literature review of randomized controlled trials (RCTs) with meta-analysis was conducted.

Homologous recombination deficiency signatures in gastrointestinal and thoracic cancers correlate with platinum therapy duration.

There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores.

Defining the heterogeneity of unbalanced structural variation underlying breast cancer susceptibility by nanopore genome sequencing.

Germline structural variants (SVs) are challenging to resolve by conventional genetic testing assays. Long-read sequencing has improved the global characterization of SVs, but its sensitivity at cancer susceptibility loci has not been reported. Nanopore long-read genome sequencing was performed for nineteen individuals with pathogenic copy number alterations in BRCA1, BRCA2, CHEK2 and PALB2 identified by prior clinical testing.

Disparate Time-to-Treatment and Varied Incidence of Actionable Non-Small Cell Lung Cancer Molecular Alterations in British Columbia: A Historical Cohort Study.

Background: non-small cell lung cancer (NSCLC) outcomes remain suboptimal for early-stage disease despite emerging advances in systemic therapy for the peri-operative period. Next-generation sequencing (NGS) identifies driver mutations for which targeted therapies have been developed that improve survival. The BC lung cancer screening program, which was initiated in May 2022, is expected to identify people with early and late stages of NSCLC.

Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.

Introduction: Genetic testing for hereditary cancer syndromes (HCSs) can improve health outcomes through cancer risk mitigation strategies. Effective communication between tested individuals and their family members is key to reducing the hereditary cancer burden. Our objective was to develop a patient portal to improve familial communication for patients undergoing HCS genetic testing, followed by an early-phase evaluation.

Comparing algorithms for characterizing treatment effect heterogeneity in randomized trials.

The identification and estimation of heterogeneous treatment effects in biomedical clinical trials are challenging, because trials are typically planned to assess the treatment effect in the overall trial population. Nevertheless, the identification of how the treatment effect may vary across subgroups is of major importance for drug development. In this work, we review some existing simulation work and perform a simulation study to evaluate recent methods for identifying and estimating the heterogeneous treatments effects using various metrics and scenarios relevant for drug development.

Germline Testing and Somatic Tumor Testing for Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

Purpose: In 2020, ASCO recommended that all women with epithelial ovarian cancer have germline testing for mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing to determine eligibility for a poly (ADP-ribose) polymerase inhibitor. Consequently, the majority of patients with ovarian cancer will have both germline testing and somatic testing. An alternate strategy is tumor testing first and then germline testing if there is a PV in the tumor and/or significant family history.

Impact of a phone call with a medical student/general practitioner team on morbidity of chronic patients during the first French COVID-19 lockdown (COVIQuest): a cluster randomised trial.

Objectives: The first COVID-19 lockdown led to a significantly reduced access to healthcare, which may have increased decompensations in frail patients with chronic diseases, especially older patients living with a chronic cardiovascular disease (CVD) or a mental health disorder (MHD). The objective of COVIQuest was to evaluate whether a general practitioner (GP)-initiated phone call to patients with CVD and MHD during the COVID-19 lockdown could reduce the number of hospitalisation(s) over a 1-month period.

Design: This is a cluster randomised controlled trial.

Barriers and Facilitators to Participation in Health Screening: an Umbrella Review Across Conditions.

Screening is an essential prevention practice for a number of health conditions. However, screening coverage remains generally low. Studies that investigate determinants of screening participation are becoming more common, but oftentimes investigate screening for health conditions in an individualized rather than integrated fashion.

Comparison of 2-Weekly Versus 4-Weekly Durvalumab Consolidation for Locally Advanced NSCLC Treated With Chemoradiotherapy: A Brief Report.

Introduction: Durvalumab 10 mg/kg every 2 weeks for 1 year after chemoradiation has improved overall survival (OS) in unresectable stage III NSCLC. Subsequently, a 20 mg/kg 4-weekly regimen was approved. The study goal was to compare the efficacy and toxicity of the two regimens.

Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: A Reappraisal.

Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case-control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer.

Methods: A research questionnaire was administered every two years to collect information on exposures and disease.

"Game Changer": Health Professionals' Views on the Clinical Utility of Circulating Tumor DNA Testing in Hereditary Cancer Syndrome Management.

Background: We explored health professionals' views on the utility of circulating tumor DNA (ctDNA) testing in hereditary cancer syndrome (HCS) management.

Materials And Methods: A qualitative interpretive description study was conducted, using semi-structured interviews with professionals across Canada. Thematic analysis employing constant comparison was used for analysis.