Advancing Principled Pharmacoepidemiologic Research to Support Regulatory and Healthcare Decision Making: The Era of Real-World Evidence.

A compilation of factors over the past decade-including the availability of increasingly large and rich healthcare datasets, advanced technologies to extract unstructured information from health records and digital sources, advancement of principled study design and analytic methods to emulate clinical trials, and frameworks to support transparent study conduct-has ushered in a new era of real-world evidence (RWE). This review article describes the evolution of the RWE era, including pharmacoepidemiologic methods designed to support causal inferences regarding treatment effects, the role of regulators and other health authorities in establishing distributed real-world data networks enabling analytics at scale, and the many global guidance documents on principled methods of producing RWE. This article also highlights the growing opportunity for RWE to support decision making by regulators, health technology assessment groups, clinicians, patients, and other stakeholders and provides examples of influential RWE studies.

Goliath clades and tracking of clonal dynamics show three phases of UV-induced skin carcinogenesis.

While the genetic paradigm of cancer etiology has proven powerful, it remains incomplete as evidenced by the widening spectrum of non-cancer cell-autonomous "hallmarks" of cancer. Studies have demonstrated the commonplace presence of high oncogenic mutational burdens in homeostatically-stable epithelia. Hence, the presence of driver mutations alone does not result in cancer.

Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib.

Background: The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability.

Patients And Methods: Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology.

A multitiered analysis platform for genome sequencing: Design and initial findings of the Australian Genomics Cardiovascular Disorders Flagship.

Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD).

Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS.

Evolutionary rescue model informs strategies for driving cancer cell populations to extinction.

Cancers exhibit a remarkable ability to develop resistance to a range of treatments, often resulting in relapse following first-line therapies and significantly worse outcomes for subsequent treatments. While our understanding of the mechanisms and dynamics of the emergence of resistance during cancer therapy continues to advance, questions remain about how to minimize the probability that resistance will evolve, thereby improving long-term patient outcomes. Here, we present an evolutionary simulation model of a clonal population of cells that can acquire resistance mutations to one or more treatments.

Airway total bacterial density, microbiota community composition and relationship with clinical parameters in bronchiectasis.

Background And Objective: This study explored the relationship between total bacterial density, airway microbiota composition and clinical parameters in bronchiectasis. We determined changes with time during clinical stability and following antibiotic treatment of a pulmonary exacerbation.

Methods: We conducted a multicentre longitudinal cohort study of UK participants with CT confirmed bronchiectasis.

: an underestimated pathogen in brain infection?

is an oral commensal organism belonging to the group (SAG). causes periodontitis as well as invasive, pyogenic infection of the central nervous system, pleural space or liver. Compared with other SAG organisms, has a higher mortality as well as a predilection for intracranial infection, suggesting it is likely to possess virulence factors that mediate specific interactions with the host resulting in bacteria reaching the brain.

Naturally acquired adaptive immunity to is impaired in rheumatoid arthritis patients.

Objectives: Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by . Why RA is associated with increased susceptibility to is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289  protein antigens using a novel protein array.

1-year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study.

Background: In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge.

Methods: Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium).

Development of an automated 3D high content cell screening platform for organoid phenotyping.

The use of organoid models in biomedical research has grown substantially since their inception. As they gain popularity among scientists seeking more complex and biologically relevant systems, there is a direct need to expand and clarify potential uses of such systems in diverse experimental contexts. Herein we outline a high-content screening (HCS) platform that allows researchers to screen drugs or other compounds against three-dimensional (3D) cell culture systems in a multi-well format (384-well).

Utilizing a Data-Driven Approach to Address Social Vulnerability in Outpatient Dialysis: A Quality Improvement Project.

Through a quality improvement project, we developed an initiative that leveraged patient- and community-level data to address health disparities and social vulnerability among patients receiving outpatient dialysis, including both incenter and home modalities. Using the Area Deprivation Index, we identified patients living in areas with the highest levels of deprivation and developed targeted interventions to help address adverse social determinants of health to improve patient health outcomes. Our quality improvement project demonstrates the potential of data-driven ap - proaches to identify and address health disparities in outpatient dialysis, and highlights the importance of addressing social determinants of health in improving patient outcomes.

Site-Specific Antibody Prodrugs via -Arylation: a Bioconjugation Approach Toward Masked Tyrosine Analogues.

The utility of antibody therapeutics is hampered by potential cross-reactivity with healthy tissue. Over the past decade, significant advances have been made in the design of activatable antibodies, which increase, or create altogether, the therapeutic window of a parent antibody. Of these, antibody prodrugs (pro-antibodies) are masked antibodies that have advanced the most for therapeutic use.

Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease.

Background: Persistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis.

The Intersection of Chronic Kidney Disease and Depression.

Chronic kidney disease (CKD) and depression often coexist, resulting in a complex interaction that can be detrimental to patient outcomes. This article examines the reciprocal association between CKD and depression, with a focus on the increased incidence of depression and the harmful effects of depressive symptoms among patients with CKD. Next, it investigates the role CKD plays as a risk factor for the onset and worsening of depression because symptoms of depression may interfere with the progression of CKD.

Brief Educational Workshops in Secondary Schools Trial (BESST trial), a school-based cluster randomised controlled trial of the DISCOVER workshop for 16-18-year-olds: recruitment and baseline characteristics.

Background: The Brief Educational Workshops in Secondary Schools Trial (BESST) is an England-wide school-based cluster randomised controlled trial assessing the clinical and cost-effectiveness of an open-access psychological workshop programme (DISCOVER) for 16-18-year-olds. This baseline paper describes the self-referral and other recruitment processes used in this study and the baseline characteristics of the enrolled schools and participants.

Method: We enrolled 900 participants from 57 Secondary schools across England from 4th October 2021 to 10th November 2022.