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The Centre for Evidence-Based Medicine (CEBM) at Oxford University develops, promotes and disseminates better evidence for health care.
When I use a word . . . Medical blue plaques-the Peckham Experiment
The Pioneer Health Centre in Peckham, also known as the Peckham Centre, running what became known at the Peckham Experiment, was founded in 1926 by two doctors, Innes Pearse (1889-1978) and her colleague George Scott Williamson (1884-1953). It closed down in 1929 and reopened in 1935 in new purpose-built premises. Families paid a shilling a week for membership, which gave them free medical consultations of various sorts and access to a wide variety of recreations, but no medical treatment. The purpose was to observe how their health progressed and to discover what factors were involved in good health and wellbeing. After closing down again during World War II the centre reopened, but was forced to close again in 1950, this time for good, because of lack of funds, due to a complex range of factors. In a 1938 publication, the founders stressed that health and wellbeing were not synonymous; health, they wrote, operates with a cumulative deposit account and wellbeing on a diminishing current account. Two blue plaques commemorate the Pioneer Health Centre: an English Heritage blue plaque at 142 Queen's Road, Peckham, London SE15, the site of the centre's original building, and a plaque put up by the London Borough of Southwark at the site of the second building, now converted to a block of flats, and situated round the corner from the Queen's Road premises, in Frobisher Place, St Mary's Road, Peckham.
Virtual follow-up care among breast and prostate cancer patients during and beyond the COVID-19 pandemic: Association with distress
BACKGROUND: The purpose of this study was to investigate associations between self-reported distress (anxiety/depression) and satisfaction with and desire for virtual follow-up (VFU) care among cancer patients during and beyond the COVID-19 pandemic. METHODS: Breast and prostate cancer patients receiving VFU at an urban cancer centre in Toronto, Canada completed an online survey on their sociodemographic, clinical, and technology, characteristics and experience with and views on VFU. EQ5D-5 L was used to assess distress. Statistical models adjusted for age, gender, education, income and Internet confidence. RESULTS: Of 352 participants, average age was 65 years, 48% were women,79% were within 5 years of treatment completion, 84% had college/university education and 74% were confident Internet users. Nearly, all (98%) had a virtual visit via phone and 22% had a virtual visit via video. The majority of patients (86%) were satisfied with VFU and 70% agreed that they would like VFU options after the COVID-19 pandemic. Participants who reported distress and who were not confident using the Internet for health purposes were significantly less likely to be satisfied with VFU (OR = 0.4; 95% CI: 0.2-0.8 and OR = 0.19; 95% CI: 0.09-0.38, respectively) and were less likely to desire VFU option after the COVID-19 pandemic (OR = 0.49; 95% CI: 0.30-0.82 and OR = 0.41; 95% CI: 0.23-0.70, respectively). CONCLUSIONS: The majority of respondents were satisfied with VFU and would like VFU options after the COVID-19 pandemic. Future research should determine how to optimize VFU options for cancer patients who are distressed and who are less confident using virtual care technology.
Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.
BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 μg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).
A Prognostic Model for Critically Ill Children in Locations With Emerging Critical Care Capacity
OBJECTIVES: To develop a clinical prediction model to risk stratify children admitted to PICUs in locations with limited resources, and compare performance of the model to nine existing pediatric severity scores. DESIGN: Retrospective, single-center, cohort study. SETTING: PICU of a pediatric hospital in Siem Reap, northern Cambodia. PATIENTS: Children between 28 days and 16 years old admitted nonelectively to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data recorded at the time of PICU admission were collected. The primary outcome was death during PICU admission. One thousand five hundred fifty consecutive non-elective PICU admissions were included, of which 97 died (6.3%). Most existing severity scores achieved comparable discrimination (area under the receiver operating characteristic curves [AUCs], 0.71-0.76) but only three scores demonstrated moderate diagnostic utility for triaging admissions into high- and low-risk groups (positive likelihood ratios [PLRs], 2.65-2.97 and negative likelihood ratios [NLRs], 0.40-0.46). The newly derived model outperformed all existing severity scores (AUC, 0.84; 95% CI, 0.80-0.88; p < 0.001). Using one particular threshold, the model classified 13.0% of admissions as high risk, among which probability of mortality was almost ten-fold greater than admissions triaged as low-risk (PLR, 5.75; 95% CI, 4.57-7.23 and NLR, 0.47; 95% CI, 0.37-0.59). Decision curve analyses indicated that the model would be superior to all existing severity scores and could provide utility across the range of clinically plausible decision thresholds. CONCLUSIONS: Existing pediatric severity scores have limited potential as risk stratification tools in resource-constrained PICUs. If validated, our prediction model would be a readily implementable mechanism to support triage of critically ill children at admission to PICU and could provide value across a variety of contexts where resource prioritization is important.
A Comparison of Signals of Designated Medical Events and Non-designated Medical Events: Results from a Scoping Review.
INTRODUCTION AND OBJECTIVE: The European Medicines Agency (EMA) maintains a list of designated medical events (DMEs), events that are inherently serious and are prioritized for signal detection, irrespective of statistical criteria. We have analysed the results of our previously published scoping review to determine whether DME signals differ from those of other adverse events in terms of time to communication and characteristics of supporting reports of suspected adverse drug reactions. METHODS: For all signals, we obtained the launch year of medicinal products from textbooks or regulatory agencies, extracted the year of the first report in VigiBase and calculated the interval between the first report and communication (time to communication, TTC). We further retrieved the average completeness (via vigiGrade) of the reports in each case series in the years before the communication. We categorised as DME signals those concerning an event in the EMA's list. We described the two groups of signals using medians and interquartile ranges (IQR) and compared them using the Brunner-Munzel test, calculating 95% confidence intervals (95% CI) and P values. RESULTS: Of 4520 signals, 919 concerned DMEs and 3601 concerned non-DMEs. Signals of DMEs were supported by a median of 15 reports (IQR 6-38 reports) with a completeness score of 0.52 (IQR 0.43-0.62) and signals of non-DMEs by 20 reports (IQR 6-84 reports) with a completeness score of 0.46 (IQR 0.38-0.56). The probability that a random DME signal was supported by fewer reports than non-DME signals was 0.56 (95% CI 0.54-0.58, P < 0.001) and that of one having lower average completeness was 0.39 (95% CI 0.36-0.41, P < 0.001). The median TTCs of DME and non-DME signals did not differ (10 years), but the TTC was as low as 2 years when signals (irrespective of classification) were supported by reports whose average completeness was > 0.80. CONCLUSIONS: Signals of designated medical events were supported by fewer reports and higher completeness scores than signals of other adverse events. Although statistically significant, the differences in effect sizes between the two groups were small. This suggests that listing certain adverse events as DMEs is not having the expected effect of encouraging a focus on reports of the types of suspected adverse reactions that deserve special attention. Further enhancing the completeness of the reports of suspected adverse drug reactions supporting signals of designated medical events might shorten their time to communication and reduce the number of reports required to support them.
Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
AbstractViral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031
Integrated palliative care in oncology: a protocol for a realist synthesis.
INTRODUCTION: Emerging evidence suggests improved quality of life, reduced symptom burden and lower health services costs when integrated palliative care and cancer care are implemented. Integrated palliative care aims to achieve care continuity by integrating organisational, administrative and clinical services involved in patient care networks. However, integrated palliative care for cancer is not common practice. This project, therefore, aims to understand how integrated palliative care and cancer care works in different healthcare settings (inpatient/outpatient), and for which groups of people (at what stage of the cancer journey), so we can develop guidance for optimal delivery. METHODS AND ANALYSIS: We will conduct a realist synthesis to develop a programme theory of how integrated palliative care in cancer works, for whom and in what contexts to achieve improved symptom management and quality of life for patients and their families.This realist synthesis will follow the five stages outlined by Pawson: (1) locating existing theories, (2) searching for evidence, (3) article selection, (4) extracting and organising data and (5) synthesising the evidence and drawing conclusions. We will work closely with our expert stakeholder group, which includes health and social care professionals providing palliative care and oncology; management and policy groups and members of the public and patients. We will adhere to RAMESES quality standards for undertaking a realist synthesis. ETHICS AND DISSEMINATION: Ethics approval for this project is not required.The realist synthesis will develop a programme theory that provides clarity on the optimal delivery of palliative care for adults with cancer. We will use the programme theory to coproduce guidance and user-friendly outputs, working with stakeholders to inform delivery of best practice. Findings will inform further research in integrated palliative care and cancer. Stakeholder engagement will assist in the dissemination of our findings. PROSPERO REGISTRATION NUMBER: CRD42023389791.
Defining success in adult obesity management: A systematic review and framework synthesis of clinical practice guidelines
Obesity is a chronic and complex disease affecting millions of people worldwide. Currently, there is no standard definition of success for the management of obesity. We set out to complete a synthesis of clinical practice guidelines for obesity management for adult populations, aiming to provide both a quantitative descriptive and qualitative analysis of definitions of success in clinical practice guidelines. An electronic search retrieved 4477 references. Sixteen clinical practice guidelines were included after screening and full-text review. We coded definitions of success 147 times across the included guidelines. No standard or explicit definition of success was identified in the guidelines but rather success was implicitly defined. We developed three themes describing how success was defined in the clinical practice guidelines: Knowledge-based decision making; management of expectations; and the perception of control. The review reinforced that success is an inherently subjective and complex concept. Defining success is limited by existing studies that focus on weight loss and would benefit from additional research on different outcomes. Equally, the relationship between people living with obesity and their clinicians should be further explored to understand how defining success is controlled, discussed and framed in a clinical setting.
Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage
Background: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. Methods: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. Results: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. Conclusions: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.
When I use a word . . . Medicines regulation-diethylene glycol.
In 1937, when diethylene glycol was used as a solvent in the preparation of a medicinal product, an elixir of sulfanilamide, resulting in deaths, public outcry hastened the promulgation of an act that had been in preparation in the USA for several years, but which had met with opposition from pharmaceutical companies. The 1938 Food, Drug, and Cosmetics Act, as it was known, gave greater powers to the then recently formed Food and Drug Administration (FDA) in regulating the contents of medicinal formulations. Nevertheless, although similar regulatory systems have since been established around the world, episodes of poisoning with diethylene glycol in pharmaceutical formulations, whether deliberately included adulteration or as a contaminant, continue to be reported, generally in developing countries, usually affecting children, and often causing deaths.
Disparities in COVID-19 Mortality Amongst the Immunosuppressed: A Systematic Review and Meta-analysis for Enhanced Disease Surveillance.
BACKGROUND: Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. METHODS: We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent controls. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. FINDINGS: We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. INTERPRETATION: Excess COVID-associated mortality among the immunosuppressed compared to immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission. FUNDING: Supported by EMIS Health and the UK Medical Research Council. Grant number: MR/R015708/1.