Value-Based Healthcare in Practice: IDEATE, a Collaboration to Design and Test an Outcomes-Based Agreement for a Medicine in Wales.

Objective: To develop a sustainable, scalable methodology for the design of outcome-based agreements (OBAs) that works on the ground and dynamically overcomes historical challenges.

Methods: Project IDEATE co-created solutions to known (and emergent) challenges via iterative workshops and real-world data analysis to develop and refine a hypothetical model for an OBA in a trusted research environment. A cross-disciplinary collaboration between National Health Service (NHS) Wales, industry and academia was developed.

Clinical outcomes following acute sore throat assessment at community pharmacy versus general practice: a retrospective, longitudinal, data linkage study.

Background: To date, no research has compared longer-term outcomes (antibiotic provision; re-consultations; hospital admissions for quinsy; cost-effectiveness) following presentation with acute sore throat at general practice (GP) versus newer, pharmacy-led services.

Methods: A retrospective, longitudinal cohort study of sore throat consultations between 1 November 2018 and 28 February 2020 either with the Wales pharmacy-led sore throat test and treat (STTT) service or with a healthcare professional at GP. Individual-level pharmacy consultation data from the national Choose Pharmacy IT application were securely uploaded to the Secure Anonymised Information Linkage Databank and linked to routinely collected, anonymized, population-scale, individual-level, anonymized health and administrative data.

Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: A retrospective cohort study.

Objective: To compare the effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab with no treatment in preventing hospital admission or death in higher-risk patients infected with SARS-CoV-2 in the community.

Design: Retrospective cohort study of non-hospitalized adult patients with COVID-19 using the Secure Anonymised Information Linkage (SAIL) Databank.

Setting: A real-world cohort study was conducted within the SAIL Databank (a secure trusted research environment containing anonymised, individual, population-scale electronic health record (EHR) data) for the population of Wales, UK.

Developing a population data science approach to assess increased risk of COVID-19 associated with attending large events.

Introduction: In summer 2021, as rates of COVID-19 decreased and social restrictions were relaxed, live entertainment and sporting events were resumed. In order to inform policy on the safe re-introduction of spectator events, a number of test events were organised in Wales, ranging in setting, size and audience.

Objectives: To design and test a method to assess whether test events were associated with an increase in risk of confirmed COVID-19, in order to inform policy.

Digital Approaches to Music-Making for People With Dementia in Response to the COVID-19 Pandemic: Current Practice and Recommendations.

Before COVID-19, dementia singing groups and choirs flourished, providing activity, cognitive stimulation, and social support for thousands of people with dementia in the UK. Interactive music provides one of the most effective psychosocial interventions for people with dementia; it can allay agitation and promote wellbeing. Since COVID-19 has halted the delivery of in-person musical activities, it is important for the welfare of people with dementia and their carers to investigate what alternatives to live music making exist, how these alternatives are delivered and how their accessibility can be expanded.

Understanding and responding to COVID-19 in Wales: protocol for a privacy-protecting data platform for enhanced epidemiology and evaluation of interventions.

Introduction: The emergence of the novel respiratory SARS-CoV-2 and subsequent COVID-19 pandemic have required rapid assimilation of population-level data to understand and control the spread of infection in the general and vulnerable populations. Rapid analyses are needed to inform policy development and target interventions to at-risk groups to prevent serious health outcomes. We aim to provide an accessible research platform to determine demographic, socioeconomic and clinical risk factors for infection, morbidity and mortality of COVID-19, to measure the impact of COVID-19 on healthcare utilisation and long-term health, and to enable the evaluation of natural experiments of policy interventions.

Exploring the association of the discharge medicines review with patient hospital readmissions through national routine data linkage in Wales: a retrospective cohort study.

Objective: To evaluate the association of the discharge medicines review (DMR) community pharmacy service with hospital readmissions through linking National Health Service data sets.

Design: Retrospective cohort study.

Setting: All hospitals and 703 community pharmacies across Wales.

Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap.

Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis.

Effects and costs of implementing predictive risk stratification in primary care: a randomised stepped wedge trial.

Aim: We evaluated the introduction of a predictive risk stratification model (PRISM) into primary care. Contemporaneously National Health Service (NHS) Wales introduced Quality and Outcomes Framework payments to general practices to focus care on those at highest risk of emergency admission to hospital. The aim of this study was to evaluate the costs and effects of introducing PRISM into primary care.

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis.

Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL.

Karyopherin Alpha Proteins Regulate Oligodendrocyte Differentiation.

Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination.

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation.

Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage.

Oligodendrocytes derive from progenitors (OPCs) through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing, and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPCs, yet genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice.

Relapses in multiple sclerosis: Relationship to disability.

Multiple sclerosis (MS) is a recurrent inflammatory disease of the central nervous system, which ultimately causes substantial disability in many patients. A key clinical feature of this disease is the occurrence of relapses, consisting of episodes of neurological dysfunction followed by periods of remission. This review considers in detail the importance of the occurrence of relapses to the ultimate course of MS and the impact of relap setreatment (both acutely and prophylactically) on the long-term outcome for individuals.

Bevacizumab is safe in acute relapses of neuromyelitis optica.

Objectives: Neuromyelitis optica (NMO) is a relapsing autoimmune disease targeting the spinal cord and optic nerve leading to paralysis and blindness. Current treatment for acute NMO attacks is immunosuppression with high-dose corticosteroids and/or plasmapheresis. Preclinical animal studies suggest that bevacizumab might be beneficial in limiting the extent of inflammation during a NMO relapse by reducing the disruption of the blood-brain barrier.

Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain.

Alterations in the structure and organization of the aging central nervous system (CNS), and associated functional deficits, result in cognitive decline and increase susceptibility to neurodegeneration. Age-related changes to the neurovascular unit (NVU), and their consequences for cerebrovascular function, are implicated as driving cognitive impairment during aging as well as in neurodegenerative disease. The molecular events underlying these effects are incompletely characterized.

Prevalence of defined ultrasound findings of unknown significance at the second trimester fetal anomaly scan and their association with adverse pregnancy outcomes: the Welsh study of mothers and babies population-based cohort.

Objective: The aim of this article was to estimate the population prevalence of seven defined ultrasound findings of uncertain significance ('markers') in the second trimester and the associated risk of adverse pregnancy outcomes.

Method: A prospective record-linked cohort study of 30 078 pregnant women who had second trimester anomaly scans between July 2008 and March 2011 in Wales was conducted.

Results: The prevalence of markers ranged from 43.

Update on biomarkers in neuromyelitis optica.

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO.

Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder.

Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field.

Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption.

SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB.

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination.

In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination.