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Earlier this year, when the world was somewhat uncertain, a few nurses within NDORMS received a calling. The Oxford Vaccine Group (OVG) were looking for help with a Covid Vaccine Trial. Six NDORMS nurses stepped up to join the fight against coronavirus.
Feasibility assessment of radiolabeled FAPI-04 for diagnostic and therapeutic use in rheumatoid arthritis.
OBJECTIVE: Fibroblast activation protein alpha (FAPα) plays a key role in cartilage degradation, inflammation, and bone erosion, particularly in rheumatoid arthritis (RA) where fibroblast-like synoviocytes in synovial tissue show elevated FAPα expression. This study explored radiolabeled FAP inhibitors for arthritis diagnosis and therapy. DESIGN: We used the radiotracer 68Ga-FAPI-04 for PET/CT imaging to predict collagen-induced arthritis (CIA) onset. Weekly scans quantified tracer uptake via SUV values, correlating results with disease scores and incidence. For therapeutic evaluation, 177Lu-FAPI-04 targeted FAPα-expressing cells, and arthritis scores of treated CIA mice were compared with untreated controls using one-way ANOVA. RESULTS: CIA mice with elevated SUV one week post-booster immunization had a 94.6 % arthritis incidence. SUV correlated with arthritis severity, reflecting increased FAPα expression. Treatment with 177Lu-FAPI-04 reduced arthritis scores by 64 % compared to controls (p
Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): a randomized controlled trial.
BACKGROUND AND AIMS: Barrett's esophagus (BE) is a precursor lesion for esophageal adenocarcinoma (EA). Surveillance endoscopy aims to detect early malignant progression: though widely practised it has not previously been tested in a randomized trial. METHODS: BOSS was a randomized controlled trial at 109 centres in the UK. Patients with BE were randomized to two-yearly surveillance endoscopy or 'at need' endoscopy, offered only for symptoms. Follow up was a minimum of 10 years. The primary outcome was overall survival in the intention-to-treat population. Secondary outcomes included cancer-specific survival; time to diagnosis of EA; stage of EA at diagnosis; frequency of endoscopy and serious adverse events related to interventions. RESULTS: 3453 patients were recruited. 1733 patients were randomized to surveillance and 1719 to 'at need' endoscopy. Median follow up time was 12·8 years for the primary outcome. There was no evidence of a difference in overall survival between surveillance (333 deaths in 1733 patients) versus 'at need' arms (356 deaths in 1719 patients), hazard ratio 0·95 (95% CI 0·82-1·10), stratified log-rank p=0·503). There was no evidence of a difference for surveillance versus 'at need' endoscopy in cancer-specific survival (108 vs. 106 deaths from any cancer, HR 1·01 (95% CI 0·77-1·33), p=0·926), time to diagnosis of EA (40 vs. 31 patients had a diagnosis of EA, HR 1·32 (95% CI 0·82-2·11), p=0·254), or cancer stage at diagnosis. 8 (0·46%) surveillance patients and 7 (0·41%) 'at need' patients reported serious adverse events. CONCLUSION: Surveillance did not improve overall survival or cancer-specific survival. 'At need' endoscopy may be a safe alternative for low-risk patients.
Effect of intra-articular corticosteroid injections for knee osteoarthritis on the rates of subsequent knee replacement and post-operative outcomes: a national cohort study of England.
BACKGROUND: Intra-articular corticosteroid injection (IACI) is an established treatment option for uncontrolled pain in osteoarthritis. There is a lack of longer-term follow-up in most studies of the effects of IACI, meaning there is scarcity of data on the impact of IACI on the subsequent need for joint replacement. Our aim was to assess the effect of IACI for knee osteoarthritis on the subsequent incidence of knee replacement surgery and on associated post-operative outcomes. METHODS: We conducted a cohort study of knee osteoarthritis patients registered in the Clinical Practice Research Datalink (CPRD) GOLD database with an incident diagnosis between 2005 and 2019. Exposure was single or repeated IACI use, analysed separately. The primary outcome was knee replacement during 1-year and 5-year follow-ups. Secondary outcomes included post-operative patient-reported outcome measures and adverse events. Primary analyses used general practitioner practice preference for IACI as an instrumental variable given this methodology can account for strong and unmeasured confounding. Secondary analyses used propensity score matching, accounting for measured covariates only. RESULTS: During 1-year follow-up, 1628/33,357 (4.9%) knee osteoarthritis patients underwent knee replacement, for which single IACI was associated with lower risk, which persisted to 5-year follow-up (incidence rate ratio: 0.52 [0.36, 0.77]). Conversely, in secondary propensity score analyses no association was found between IACI use and knee replacement rate at 1-year follow-up, and an estimated increased rate of knee replacement at 5-year follow-up. Use of IACI pre-joint replacement was not associated with any adverse post-operative outcomes, for example, 1-year complication rates (per 100 person-years) following knee replacement were 4.6 (3.8, 5.8), 4.0 (2.7, 6.0) and 5.0 (3.1, 8.1) among patients with no, single and repeat pre-joint replacement IACI use, respectively. CONCLUSIONS: Findings from our main analysis suggest that short-term pain reduction following IACI for knee osteoarthritis may translate to lower rates of knee replacement over 5 years follow-up, although contradictory associations were observed in secondary analyses which likely reflected residual confounding by indication. Reassuringly, IACI use before knee replacement was not associated with post-operative adverse outcomes.
British Elbow and Shoulder Society patient care pathway: Frozen shoulder
Background Current guidelines from the British Elbow and Shoulder Society (BESS) were published in 2015 for managing frozen shoulders in the primary and secondary care setting. Updated guidelines have been developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Methods A multi-disciplinary BESS Working Group defined key management questions based on agreed outcome measures and time points. A literature search, conducted up to March 2023 following PRISMA guidelines, identified randomised controlled trials, systematic reviews, and meta-analyses. Quality assessments were performed using the GRADE Decision Framework, considering bias, imprecision, indirectness, and inconsistency. Data were extracted for meta-analysis. In the absence of high-quality trials, narrative reviews were created. Results Consensus opinions produced statements based on the quality and volume of evidence and the magnitude of desirable and undesirable effects. These statements form a comprehensive framework for managing frozen shoulder. Discussion This updated guideline provides evidence-based guidance for managing frozen shoulder and identifies key areas for future research.
SPIRIT 2025 statement: Updated guideline for protocols of randomised trials.
IMPORTANCE: The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. OBJECTIVE: To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. DESIGN: We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. FINDINGS: Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. CONCLUSIONS AND RELEVANCE: Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.
SPIRIT 2025 statement: updated guideline for protocols of randomized trials.
The protocol of a randomized trial is the foundation for study planning, conduct, reporting and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Here, we aimed to systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomized trial. We completed a scoping review and developed a project-specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrollment, interventions and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators and other reviewers.
SPIRIT 2025 statement: updated guideline for protocols of randomised trials.
IMPORTANCE: The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. OBJECTIVE: To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. DESIGN: We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. FINDINGS: Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. CONCLUSIONS AND RELEVANCE: Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.
The impact of complications on quality of life and mortality after hip fracture
Aims: Complications are to be key drivers of poorer outcome but there is limited information on how they influence quality of life (QoL) after hip fracture. The aim of this study was to investigate the relationship between complications, QoL, and mortality after hip fracture. Methods: The World Hip Trauma Evaluation (WHiTE) study is a multi-centre, prospective cohort study that collected data from patients ≥60 years who received operative treatment for their hip fracture. Patients were followed up for 120 days after surgery. The primary and secondary outcomes were health-related QoL (EQ-5D-5L) and mortality, respectively. Linear and logistic regression models were fitted to assess the relationship between complications, EQ-5D-5L, and mortality. Results: Among 24,523 patients with a hip fracture, the mean differences in EQ-5D-5L in patients who had surgery-specific complications were: prosthesis dislocation -0.14 (95% CI: - 0.20 to -0.08); fixation failure 0.00 (95% CI: -0.15 to 0.14); peri-prosthetic or peri-implant fracture -0.08 (95% CI: -0.18 to 0.02); re-operation for any indication -0.09 (95% CI: -0.14 to -0.05); surgical site infection (SSI) -0.06 (95% CI: -0.10 to -0.01); and deep SSI -0.13 (95% CI: -0.20 to -0.07). The mean differences in EQ-5D-5L for the general complications were: acute kidney injury -0.05 (95% CI: -0.07 to -0.02); blood transfusion -0.01 (95% CI: -0.03 to 0.01); lower respiratory tract infection -0.07 (95% CI: -0.09 to -0.05); urinary tract infection 0.01 (95% CI: -0.01 to 0.03); cerebrovascular accident (CVA) -0.17 (95% CI: -0.25 to -0.09); myocardial infarction (MI) -0.14 (95% CI: -0.20 to -0.08); and venous thromboembolism 0.03 (95% CI: -0.02 to 0.08). Conclusions: We observed worse health-related QoL in patients who had a complication after hip fracture. Those who underwent revision surgery or had a prosthesis dislocation or deep SSI experienced similar levels of disability to those with a CVA or MI.
Autoimmunity in inflammatory bowel disease: a holobiont perspective
Adaptive immunity towards self-antigens (autoimmunity) and intestinal commensal microbiota is a key feature of inflammatory bowel disease (IBD). Considering mucosal adaptive immunity from a holobiont perspective, where the host and its microbiome form a single physiological unit, emphasises the challenge of avoiding damaging responses to self-antigen and symbiotic microbial communities in the gut while protecting against potential pathogens. Intestinal tolerance mechanisms prevent maladaptive T and B cell responses to microbial, environmental, and self-antigens, which drive inflammation. We discuss the spectrum of antimicrobial and autoantibody responses and highlight mechanisms by which common IBD-associated adaptive immune responses contribute to disease.
A Single-Domain VNAR Nanobody Binds with High-Affinity and Selectivity to the Heparin Pentasaccharide Fondaparinux
Glycosaminoglycans (GAGs) are key ligands for proteins involved in physiological and pathological processes. Specific GAG-binding patterns are rarely identified, with the heparin pentasaccharide as an Antithrombin-III ligand being the best characterized. Generating glycan-specific antibodies is difficult due to their size, pattern dispersion, and flexibility. Single-domain variable new antigen receptors (VNAR nanobodies) from nurse sharks are highly soluble, stable, and versatile. Their unique properties suggest advantages over conventional antibodies, particularly for challenging biotherapeutic targets. Here we have used VNAR semi-synthetic phage libraries to select high-affinity fondaparinux-binding VNARs that did not show cross-reactivity with other GAG species. Competition ELISA and surface plasmon resonance identified a single fondaparinux-selective VNAR clone. This VNAR exhibited an extraordinarily stable protein fold: the beta-strands are stabilized by a robust hydrophobic network, as revealed by heteronuclear NMR. Docking fondaparinux to the VNAR structure revealed a large contact surface area between the CDR3 loop of the antibody and the glycan. Fusing the VNAR with a human Fc domain resulted in a stable product with a high affinity for fondaparinux (Kd = 9.3 × 10−8 M) that could efficiently discriminate between fondaparinux and other glycosaminoglycans. This novel glycan-targeting screening technology represents a promising therapeutic strategy for addressing GAG-related diseases.
Prevalence & Risk Factors of Post-traumatic Stress Disorder in Patients with Lower Limb Fractures in South Africa.
BACKGROUND: Fractures occur at disproportionately higher rates in low-income and middle-income countries (LMIC) and commonly occur following a traumatic event. The association between suffering from a fracture and the development of psychological symptoms is under-reported. The aim of this study was to investigate the prevalence and risk factors of developing post-traumatic stress disorder (PTSD) among patients following lower limb trauma in South Africa. METHODS: The study was undertaken from September 2017 to December 2018 and included a cohort of 260 patients with lower limb long bone fractures. Patients were screened using the Primary Care PTSD (PC-PTSD-5) screening tool, which is a gold standard measure to identify patients at risk of PTSD in the civilian population. Within this cohort, high-risk patients were assessed with the PTSD checklist (PCL-C), which is a standardized questionnaire scale to indicate if an individual may have PTSD. RESULTS: There were 254 patients in the final cohort analysis with ages ranging from 18 to 71 years, and 75.6% (192/254) of the cohort were male patients. Femoral fractures were found in 51.6% (131/254) of patients while tibial fractures were found in 48.4% (123/254). The rate of PTSD within the study population was found to be 7.1% (18/254), and the risk of developing PTSD was 13.4% (34/254). We did not identify any risk factors, including open fractures, high-injury severity, and complication such as nonunion, for the development of PTSD. CONCLUSIONS: This study found the rate of PTSD to be lower compared with that in high-income countries, but still higher than the general population in South Africa. Our study indicates that screening for PTSD in patients with lower limb trauma in LMICs could be beneficial. Early identification of patients at risk of developing PTSD would enable appropriate resources, support, and treatment to be provided. LEVEL OF EVIDENCE: Level II. See Instructions for Authors for a complete description of levels of evidence.
Social contact and the perceived impact of social distancing on health outcomes during the COVID-19 pandemic among community dwelling older adults taking part in the OPAL cohort study.
BACKGROUND: During the COVID-19 pandemic, social distancing and reduced social contact may have affected older adults' health. OBJECTIVES: To evaluate the perceived impact of social distancing on older adults' health and explore the association between social contact and health outcomes. DESIGN: Cross-sectional and longitudinal analyses of the OPAL cohort study. SUBJECTS: Community dwelling older adults. METHODS: We sent questionnaires to participants of an existing cohort study (n = 4328). Questions included the amount and type of social contact, and how often they went outside. Participants rated the impact of social distancing on their health. Sociodemographic factors and quality of life were available from previous questionnaires. We examined quality of life prior to and during the pandemic and explored the cross-sectional relationship between social contact and health using logistic regression. RESULTS: There were 3856/4328 (89%) questionnaires returned. EQ-5D scores changed little compared to pre-pandemic scores but 25% of participants reported their overall health had worsened. The telephone was the most used method of contact (78%). Video calls were used least with 35% of participants not using them or having no access to them. 13% of respondents never went outside. Lower levels of contact were associated with increased risk of reporting worse health (Odds ratio (OR) 1.04 (95% CI 1.01-1.08)). Those experiencing financial strain and who spent less time outside experienced the largest increase in risk of reporting perceived worsened overall health. Those reporting a strain to get by financially were 4 times more likely to report worsened health than those who described themselves as quite comfortably off (OR 4.00 (95% CI 1.86-8.16)). Participants who reported never going outside were twice as likely to report worsened health compared to those who went outside daily (OR 2.00 (95% CI 1.57-2.54)). CONCLUSIONS: Less contact with other people was associated with perceived worsening in overall health. Although many older people reported using online technology, such as video calls, a substantial proportion were not using them. Older people facing financial strain were more likely to report worsened health, highlighting the impact of social inequalities during the pandemic. Going outside less was also associated with perceived worsened health.
Resilience of the acute sector in recovery from COVID-19 pressures.
The COVID-19 pandemic had a profound impact on the management and delivery of acute healthcare. To tackle the pandemic, hospitals redesigned their organisational models to provide a rapid increase in acute care assessment and treatment capacity for patients with COVID-19 whilst also trying to maintain delivery of care for patients with non-COVID-19 healthcare needs. This capacity to adjust and recover after COVID-19 might be shaped by both measures taken by acute hospitals and wider hospital pre-pandemic characteristics. The aim of this study is to examine how hospital characteristics in acute care are associated with recovery of elective activity after the height of the COVID-19 pandemic compared to pre-pandemic levels. Using patient-level data from Hospital Episode Statistics aggregated at monthly-trust level for all English National Health Service (NHS) acute hospital trusts in 2019 and 2021, we estimate the associations between hospital recovery rate and hospital pre-pandemic characteristics by employing linear regressions of the proportional change over time in elective activity against a set of explanatory variables related to supply factors (e.g., hospital size, workforce, type of hospital, regional location), demand factors (e.g., population need, patient case-mix) and time factors. On average, English NHS acute hospital trusts did not fully recover from the COVID-19 pandemic in 2021. The results show that the explanatory variables are not systematically associated with hospital recovery rate, excepting regional differences. Hospital trusts not located in London, especially in the North of England, are associated with a lower recovery (less resilience) of total elective activity and orthopaedic and vascular surgical elective activity. The implication for policy development is that the evolution of hospital recovery rates in elective activity varied across English regions, especially for high-volume and high-risk elective specialties, with better recovery in London than elsewhere.