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The Aspirin Esomeprazole Chemoprevention Trial (AspECT) is to our knowledge one of the largest cancer prevention trials using aspirin and acid suppression in the world. In total 2557 patients with a common precancerous change in their oesophagus, called Barrett’s oesophagus, were followed up for an average of 9 years resulting in over 20,000 life-years of follow up. After informed written consent, patients were randomly allocated to four different combinations; Low acid suppression alone, High acid suppression alone, low acid suppression with 300mg aspirin and high acid suppression with 300mg aspirin. We wanted to see if we could prevent progression to local cancer/cancer in-situ (high grade dysplasia), invasive cancer or prevent death by all causes both cancer and non-cancer.
Metabolomics data for 'Glycogen synthase kinase-3 is essential for Treg development and function'
Underlying data for LC-MS experiment in Figure 4.
Progressive resistance and flexibility exercises versus usual care advice for improving pain and function after distal radius fracture in adults aged 50 years or over : protocol for the WISE randomized superiority trial.
AIMS: Distal radius fractures are very common injuries; the majority affect females aged 50 years or over. Most patients experience pain and stiffness in their wrist and upper limb weakness, making activities of daily living difficult. The aim of the WISE (Wrist Injury Strengthening Exercise) trial is to assess the effectiveness of a flexibility and resistance exercise programme for the upper limb compared with usual care advice after distal radius fracture. METHODS: This is a multicentre, parallel-group, superiority, individually randomized controlled trial. We aim to recruit 588 participants aged 50 years and older with a distal radius fracture treated surgically or non-surgically from at least 15 UK NHS hospitals. Participants will be randomized 1:1 using a web-based service to usual care advice plus a therapist-supervised exercise programme (three one-to-one therapy sessions of tailored advice and prescribed home exercise over 12 weeks) or usual care advice only. The primary outcome is participant-reported wrist-related pain and function six months after randomization, measured by the Patient-Rated Wrist Evaluation. Secondary outcomes at three and six months measure health-related quality of life, pain, physical function, self-efficacy, exercise adherence, grip strength, complications, and resource use. CONCLUSION: This study will assess whether a therapist-supervised exercise programme is more clinically effective than usual care advice for people aged 50 years and older after distal radius fracture. At the time of submission, the trial is currently completing recruitment; follow-up will be completed in 2025 (ISRCTN registry identifier: ISRCTN78953418).
Regulation of pulmonary plasma cell responses during secondary infection with influenza virus.
During secondary infection with influenza virus, plasma cells (PCs) develop within the lung, providing a local source of antibodies. However, the site and mechanisms that regulate this process are poorly defined. Here, we show that while circulating memory B cells entered the lung during rechallenge and were activated within inducible bronchus-associated lymphoid tissues (iBALTs), resident memory B (BRM) cells responded earlier, and their activation occurred in a different niche: directly near infected alveoli. This process required NK cells but was largely independent of CD4 and CD8 T cells. Innate stimuli induced by virus-like particles containing ssRNA triggered BRM cell differentiation in the absence of cognate antigen, suggesting a low threshold of activation. In contrast, expansion of PCs in iBALTs took longer to develop and was critically dependent on CD4 T cells. Our work demonstrates that spatially distinct mechanisms evolved to support pulmonary secondary PC responses, and it reveals a specialized function for BRM cells as guardians of the alveoli.
What Do Scientists Mean When They Talk About Research Animals "Volunteering"?
This paper examines discourses around "volunteering" in animal research. Through a qualitative textual analysis of the scientific literature using animals in behavioral and psychological research, we demonstrate that "voluntary" and related terms are used by scientists in a variety of distinct ways, which carry a range of ethical and political connotations. While any reference to volunteering might be assumed to imply free, unconstrained, and unpaid participation in an activity, in the animal research literature the term is often used simply to signal a lack of physical restraint, even though other human-imposed constraints are at play. Though truly voluntary behavior may be impossible, we nevertheless argue that there is a case for seeing use of the language of volunteering as an ethical or political move in which scientists aim to highlight a goal of minimizing human control, promoting animal welfare, or representing their research as ethically acceptable.
Development of START-EDI guidelines for reporting equality, diversity and inclusion in research: a study protocol.
INTRODUCTION: Acknowledging equality, diversity and inclusion (EDI) in research is not only a moral imperative but also an important step in avoiding bias and ensuring generalisability of results. This protocol describes the development of STAndards for ReporTing EDI (START-EDI) in research, which will provide a set of minimum standards to help researchers improve their consistency, completeness and transparency in EDI reporting. We anticipate that these guidelines will benefit authors, reviewers, editors, funding organisations, healthcare providers, patients and the public. METHODS AND ANALYSIS: To create START-EDI reporting guidelines, the following five stages are proposed: (i) establish a diverse, multidisciplinary Steering Committee that will lead and coordinate guideline development; (ii) a systematic review to identify the essential principles and methodological approaches for EDI to generate preliminary checklist items; (iii) conduct an international Delphi process to reach a consensus on the checklist items; (iv) finalise the reporting guidelines and create a separate explanation and elaboration document; and (v) broad dissemination and implementation of START-EDI guidelines. We will work with patient and public involvement representatives and under-served groups in research throughout the project stages. ETHICS AND DISSEMINATION: The study has received ethical approval from the Imperial College London Research Ethics Committee (study ID: 7592283). The reporting guidelines will be published in open access peer-reviewed publications and presented in international conferences, and disseminated through community networks and forums. TRIAL REGISTRATION NUMBER: The project is pre-registered within the Open Science Framework (https://osf.io/8udbq/) and the Enhancing the Quality and Transparency of Health Research Network.
Proactive and integrated consultation-liaison psychiatry for older medical inpatients: A mixed methods description of training, care provided and clinician experience in the HOME study.
OBJECTIVES: To describe the practical experience of delivering a proactive and integrated consultation-liaison (C-L) psychiatry service model (PICLP). PICLP is designed for older medical inpatients and is explicitly biopsychosocial and discharge-focused. In this paper we report: (a) observations on the training of 15 clinicians (seven senior C-L psychiatrists and eight assisting clinicians) to deliver PICLP; (b) the care they provided to 1359 patients; (c) their experiences of working in this new way. METHOD: A mixed methods observational study using quantitative and qualitative data, collected prospectively over two years as part of The HOME Study (a randomized trial comparing PICLP with usual care). RESULTS: The clinicians were successfully trained to deliver PICLP according to the service manual. They proactively assessed all patients and found that most had multiple biopsychosocial problems impeding their timely discharge from hospital. They integrated with ward teams to provide a range of interventions aimed at addressing these problems. Delivering PICLP took a modest amount of clinical time, and the clinicians experienced it as both clinically valuable and professionally rewarding. CONCLUSION: The experience of delivering PICLP highlights the special role that C-L psychiatry clinicians, working in a proactive and integrated way, can play in medical care.
Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago.
BACKGROUND: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. METHODS: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. RESULTS: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P
When research animals become pets and pets become research animals: care, death, and animal classification.
This paper explores what happens to care, and decisions about ending and extending life, when research animals become pets and pets become research animals. To do this, we draw on in-depth qualitative research on (i) rehoming of laboratory animals, (ii) veterinary clinical research, and (iii) the role of the Named Veterinary Surgeon (NVS) in UK animal research. We begin by exploring how (in theory and practice) the ethical, affective, and practical elements of care are split in the research laboratory. We then investigate arguments for and against ending and extending animal life via clinical research and rehoming, highlighting how these activities bring norms and dilemmas around animal death in the laboratory and veterinary clinic to the fore. We conclude by demonstrating the value of investigating borders between animal categories for understanding dilemmas around care and death, and for contributing to emerging literatures within geography around animal care, death, and categorisation. Key contributions of our work include highlighting: how care roles can be split; the importance of considering speculative and in-practice elements of care; the context-dependency and multiplicity of practices of killing in the veterinary clinic and laboratory; and the flexibility and changing nature of animal categories.
Prediction and characterisation of the human B cell response to a heterologous two-dose Ebola vaccine.
Ebola virus disease (EVD) outbreaks are increasing, posing significant threats to affected communities. Effective outbreak management depends on protecting frontline health workers, a key focus of EVD vaccination strategies. IgG specific to the viral glycoprotein serves as the correlate of protection for recent vaccine licensures. Using advanced cellular and transcriptomic analyses, we examined B cell responses to the Ad26.ZEBOV, MVA-BN-Filo EVD vaccine. Our findings reveal robust plasma cell and lasting B cell memory responses post-vaccination. Machine-learning models trained on blood gene expression predicted antibody response magnitude. Notably, we identified a unique B cell receptor CDRH3 sequence post-vaccination resembling known Orthoebolavirus zairense (EBOV) glycoprotein-binding antibodies. Single-cell analyses further detailed changes in plasma cell frequency, subclass usage, and CDRH3 properties. These results highlight the predictive power of early immune responses, captured through systems immunology, in shaping vaccine-induced B cell immunity.
Reverse Shoulder Arthroplasty for Acute Trauma vs Trauma Sequalae following failed conservative management: A cohort study using data from the National Joint Registry and Hospital Episode Statistics for England.
INTRODUCTION: While the majority of proximal humerus fractures (PHFs) can be managed conservatively, for some, particularly complex 3- or 4-part fractures, management is controversial. The decision-making process can be challenging, especially in older patients when considering whether secondary surgery for failed non operative management comes with more risk than acute surgical treatment. There is limited evidence in the literature that compares the outcomes of patients having an acute reverse shoulder arthroplasty (rTSA) for trauma against those having an rTSA for trauma sequalae following failed previous conservative management. This study aims to use the National Joint Registry (NJR) and Hospital Episode Statistics (HES) for England to compare outcomes of rTSA for acute trauma against those of rTSA for trauma sequalae following failed conservative management. METHODS: NJR data from April 2012 to March 2022 was linked to HES. All patients undergoing an rTSA for acute or trauma sequalae were included. Primary outcome was revision. Secondary outcomes were non revision re-operation, mortality, medical complications within 30 & 90 days of primary procedure and length of stay. RESULTS: In the propensity matched cohorts, there were 2488 patients in the acute trauma group and 1267 patients in the trauma sequalae group. rTSA for trauma sequalae had a higher cumulative revision rate at 1,3,5,7 and 10 years and statistically significant increased risk in overall revision (HR of 2.44 (1.68-3.55 p<0.001) in comparison to acute trauma rTSA. There was no statistical difference in incidence of non-revision re-operation (p=0.17). At one year the mortality rate was 4.11% (3.38-5.00) for acute trauma and 3.07% (2.23-4.23) for trauma sequalae and this was not statistically different (HR 0.74 (0.51-1.09) p=0.13). In the acute trauma group, there was a statistically significant increase in medical complications at 30 & 90 days post procedure as well as length of stay (p<0.001). CONCLUSION: Based on this national joint registry analysis, patients are twice as likely to require a revision surgery if they undergo rTSA after conservative management has failed, compared to those who receive the procedure immediately following a proximal humerus fracture. While this may inform decision making and the consent process, given some of the limitations around registry analysis, the findings underline the importance of well-designed prospective trials in establishing the optimal timing of surgery. LEVEL OF EVIDENCE: Level III; Retrospective Cohort Comparison using Large Database; Treatment Study.
Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States.
PURPOSE: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. PATIENTS AND METHODS: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE. RESULTS: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09-0.13%) in Canada to 1.01% (0.97-1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21-0.26%) in Canada to 0.84% (0.80-0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06-0.07%) in England to 1.04% (1.01-1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24-0.26%) in England to 1.02% (0.99-1.04%) in the US. CONCLUSION: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.
Chromatin-focused genetic and chemical screens identify BRPF1 as a targetable vulnerability in Taxol-resistant triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is a particularly aggressive and frequently recurring form of breast cancer, where chemotherapy is the primary treatment approach. Unfortunately, the development of resistance to chemotherapy poses a considerable challenge, restricting the already limited therapeutic alternatives for recurrent cases. Here, we generated two Taxol-resistant TNBC cell lines with a dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited reduced growth rates, altered morphology and evasion of apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in these resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted chromatin-focused genetic and chemical screens and pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) as a novel regulator of Taxol resistance. Knockout of BRPF1, the reader protein in the MOZ-MORF histone acetyltransferase complex, but not the other complex members, sensitized resistant cells to Taxol. In addition, BRPF1 inhibitors, PFI-4 and OF-1, in combination with Taxol significantly reduced cell viability. Transcriptome analysis upon BRPF1 loss or inhibition revealed a negative impact on ribosome biogenesis-related gene sets, resulting in a global decrease in protein translation in Taxol-resistant cells. CUT&RUN-qPCR analysis demonstrated that BRPF1 directly binds to the ABCB1 promoter, enhancing its expression toward inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. Our findings uncover a comprehensive molecular framework, highlighting the pivotal role of epigenetic reader protein BRPF1 in Taxol resistance and providing potential avenues for therapeutic intervention in TNBC.
Incidence of post-acute COVID-19 symptoms across healthcare settings in seven countries: an international retrospective cohort study using routinely-collected data.
BACKGROUND: The World Health Organisation (WHO) has identified a range of symptomatic manifestations to aid in the clinical diagnosis of post-COVID conditions, herein referred to as post-acute COVID-19 symptoms. We conducted an international network cohort study to estimate the burden of these symptoms in North American, European, and Asian populations. METHODS: A federated analysis was conducted including 10 databases from the United Kingdom, Netherlands, Norway, Estonia, Spain, France, South Korea, and the United States, between September 1st 2020 and latest data availability (which varied from December 31st 2021 to February 28th 2023), covering primary and secondary care, nationwide registries, and claims data, all mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM). We defined two cohorts for the main analyses: a SARS-CoV-2 infection cohort [positive polymerase chain reaction (PCR) or rapid lateral flow test (LFT) result or clinical COVID-19 diagnosis] and a general population cohort. Individuals with less than 365 days of prior history or 120 days of follow-up were excluded. We estimated incidence rates (IRs) of the 25 WHO-proposed post-acute COVID-19 symptoms, considering symptoms that occurred ≥90 and ≤365 days after index date, excluding individuals with the respective symptoms 180 days prior to the index event. Stratified analyses were conducted by age and sex. Incidence rate ratios (IRRs) were calculated comparing rates in the infected cohort versus the general population. Results from the different databases were combined using random-effects meta-analyses. FINDINGS: 3,019,408 individuals were included in the infection cohort. 1,585,160 of them were female and 1,434,248 of them male. 929,351,505 individuals were included in the general population group. 461,195,036 of them were female and 466,022,004 of them male. The 1-year IR of any post-acute COVID-19 symptom in the COVID-19 infection cohort varied significantly across databases, from 4.4 (95% CI 3.8-5.1) per 100 person-years to 103.9 (95% CI 103.2-104.7). The five most common symptoms were joint pain (from 1.6 (95% CI 1.3-1.9) to 14.3 (95% CI 14.1-14.6)), abdominal pain (from 0.3 (95% CI 0.1-0.5) to 9.9 (95% CI 9.7-10.1)), gastrointestinal issues (from 0.6 (95% CI 0.4-0.9) to 13.3 (95% CI 13.1-13.6)), cough (from 0.3 (95% CI 0.2-0.5) to 9.1 (95% CI 8.9-9.3)), and anxiety (from 0.8 (95% CI 0.6-1.2) to 11.4 (95% CI 11.2-11.6)); whereas muscle spasms (from 0.01 (95% CI 0.008-0.2) to 1.7 (95% CI 1.6-1.8)), pins and needles (from 0.05 (95% CI 0.03-0.0.9) to 1.5 (95% CI 1.4-1.6)), memory issues (from 0.03 (95% CI 0.02-0.06) to 0.8 (95% CI 0.7-0.8)), cognitive dysfunction (from 0.007 (95% CI 0.004-0.01) to 0.6 (95% CI 0.4-0.8)), and altered smell and/or taste (from 0.04 (95% CI 0.03-0.04) to 0.7 (95% CI 0.6-0.8)) were least common. Incidence rates of any post-acute COVID-19 symptoms generally increased with age, with certain symptoms peaking in middle-aged adults (anxiety, depressive disorders, headache, altered smell and taste) and others in pre-school children (gastrointestinal issues and cough). Females had higher incidence rates for most symptoms. Based on the random-effects model, the infected cohort had a higher incidence of any post-acute COVID-19 symptom than the general population, with a meta-analytic incidence rate ratio (meta-IRR) of 1.4 (1-2). A similar pattern was seen for all individual symptoms. The highest meta-IRRs were depressive disorder, 2.6 (1.7-3.9); anxiety, 2.3 (1.4-3.8); allergy, 2.1 (1.7-2.8) and sleep disorders, 2.1 (1.5-2.6). The meta-IRR for altered smell and/or taste was 1.9 (1.3-2.8). INTERPRETATION: Post-acute COVID-19 symptoms, as listed by the WHO, were commonly observed following COVID-19 infection. However, even after standardising research methods, there was significant heterogeneity in the incidence rates from different healthcare settings and geographical locations. This is the first international study of the epidemiology of post-acute COVID-19 symptoms using the WHO-listed symptoms. Its findings contibute to understand the epidemiology of this condition from a multinational approach. Limitations of this study include the lack of consensus of the post-acute COVID-19 definition, as well as the difficulty to capture the impact on daily life of the post-acute COVID-19 symptoms in the available datasets. FUNDING: This work has been funded by the European Health Data Evidence Network (EHDEN) through an Evidence Generation Fund Grant and by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC).