COVID-19: time to rethink palliative care strategy in resource-poor settings

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Variation in the Commissioning of Semaglutide for the Treatment of Obesity and Overweight Across England: Results of Three Freedom of Information‐Based Mapping Exercises Across the 42 Integrated Care Boards of England

Obesity medications are recommended in England with legislation necessitating their availability. However, given the number of people who meet clinically approved eligibility criteria, funding these medications and associated support services may limit efficacy at a population health level. This study aimed to assess the commissioning and availability of services and obesity medications across England. Three sets of freedom of information requests were sent to the 42 ICBs in England by Sky News Ltd, The BMJ and the study investigators of this work with questions focused on commissioning of services and medication eligibility and prescription across England. The three data sets were combined to provide a narrative description to inform further development in obesity care. The availability of services across England was partial, and when services did exist, medication access was limited by funding and more restrictive eligibility criteria beyond those approved by the National Institute of Health and Care Excellence. Subsequently, very few patients receive NHS prescriptions even in areas where funding medications are reportedly available. The capacity of services to offer comprehensive care for patients to receive obesity medications is insufficient to meet current demand. Despite legislation for the delivery of obesity medications, these treatment options are not widely available on the NHS. There is insufficient service capacity to provide comprehensive care for eligible patients seeking obesity medications as a treatment option

40 days and 40 nights: Clinical characteristics of major trauma and orthopaedic injury comparing the incubation and lockdown phases of COVID-19 infection

Aims The first death in the UK caused by COVID-19 occurred on 5 March 2020. We aim to describe the clinical characteristics and outcomes of major trauma and orthopaedic patients admitted in the early COVID-19 era. Methods A prospective trauma registry was reviewed at a Level 1 Major Trauma Centre. We divided patients into Group A, 40 days prior to 5 March 2020, and into Group B, 40 days after. Results A total of 657 consecutive trauma and orthopaedic patients were identified with a mean age of 55 years (8 to 98; standard deviation (SD) 22.52) and 393 (59.8%) were males. In all, 344 (approximately 50%) of admissions were major trauma. Group A had 421 patients, decreasing to 236 patients in Group B (36%). Mechanism of injury (MOI) was commonly a fall in 351 (52.4%) patients, but road traffic accidents (RTAs) increased from 56 (13.3%) in group A to 51 (21.6%) in group B (p = 0.030). ICU admissions decreased from 26 (6.2%) in group A to 5 (2.1%) in group B. Overall, 39 patients tested positive for COVID-19 with mean age of 73 years (28 to 98; SD 17.99) and 22 (56.4%) males. Common symptoms were dyspnoea, dry cough, and pyrexia. Of these patients, 27 (69.2%) were nosocomial infections and two (5.1%) of these patients required intensive care unit (ICU) admission with 8/39 mortality (20.5%). Of the patients who died, 50% were older and had underlying comorbidities (hypertension and cardiovascular disease, dementia, arthritis). Conclusion Trauma admissions decreased in the lockdown phase with an increased incidence of RTAs. Nosocomial infection was common in 27 (69.2%) of those with COVID-19. Symptoms and comorbidities were consistent with previous reports with noted inclusion of dementia and arthritis. The mortality rate of trauma and COVID-19 was 20.5%, mainly in octogenarians, and COVID-19 surgical mortality was 15.4%

SARS-CoV-2 variants, spike mutations and immune escape.

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets

Folate hydrolase‐1 (FOLH1) is a novel target for antibody‐based brachytherapy in Merkel cell carcinoma

Backgrounds: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. Materials & methods: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. Results: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/- MCC had available survival data f or analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (- and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. Conclusions: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy o f FOLH1-targeted brachytherapy for MCC.VoRSUNY DownstateRadiation OncologyN/

From COVID-19 research to vaccine application: why might it take 17 months not 17 years and what are the wider lessons?

It is often said that it takes 17 years to move medical research from bench to bedside. In a coronavirus disease (COVID-19) world, such time-lags feel intolerable. In these extraordinary circumstances could years be made into months? If so, could those lessons be used to accelerate medical research when the crisis eases? To measure time-lags in health and biomedical research as well as to identify ways of reducing them, we developed and published (in 2015) a matrix consisting of overlapping tracks (or stages/phases) in the translation from discovery research to developed products, policies and practice. The matrix aids analysis by highlighting the time and actions required to develop research (and its translation) both (1) along each track and (2) from one track to another, e.g. from the discovery track to the research-in-humans track. We noted four main approaches to reducing time-lags, namely increasing resources, working in parallel, starting or working at risk, and improving processes. Examining these approaches alongside the matrix helps interpret the enormous global effort to develop a vaccine for the 2019 novel coronavirus SARS-CoV-2, the causative agent of COVID-19. Rapid progress in the discovery/basic and human research tracks is being made through a combination of large-scale funding, work being conducted in parallel (between different teams globally and through working in overlapping tracks), working at greater (but proportionate) risk to safety than usual, and adopting various new processes. The overlapping work of some of the teams involves continuing animal research whilst entering vaccine candidates into Phase I trials alongside planning their Phase II trials. The additional funding available helps to reduce some of the usual financial risks in moving so quickly. Going forward through the increasingly large human trials for safety, dosage and efficacy, it will be vital to overlap work in parallel in the often challenging public policy and clinical tracks. Thus, regulatory and reimbursement bodies are beginning and preparing rapid action to pull vaccines proving to be safe and effective through to extraordinarily rapid application to the general population. Monitoring the development of a COVID-19 vaccine using the matrix (modified as necessary) could help identify which of the approaches speeding development and deployment could be usefully applied more widely in the future.United Kingdom’s Medical Research Council grant MR/K014773/1 ‘Time Lags in the Translation of Medical Research: Developing a Case Study Approach to Achieve a Better Understanding’ from the MRC’s Economic Impact call from the Methodology Research Programme