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The effect of COVID rehabilitation for ongoing symptoms Post HOSPitalisation with COVID-19 (PHOSP-R): protocol for a randomised parallel group controlled trial on behalf of the PHOSP consortium.
INTRODUCTION: Many adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group. METHODS AND ANALYSIS: This is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue. The primary outcome is the Incremental Shuttle Walking Test following the eight week intervention phase. Secondary outcomes include measures of function, strength and subjective assessment of symptoms. Blood inflammatory markers and muscle biopsies are an exploratory outcome. The interventions last eight weeks and combine symptom-titrated exercise therapy, symptom management and education delivered either in a face-to-face setting or through a digital platform ( www.yourcovidrecovery.nhs.uk ). The proposed sample size is 159 participants, and data will be intention-to-treat analyses comparing rehabilitation (face-to-face or digital) to usual care. ETHICS AND DISSEMINATION: Ethical approval was gained as part of the PHOSP-COVID study by Yorkshire and the Humber Leeds West Research NHS Ethics Committee, and the study was prospectively registered on the ISRCTN trial registry (ISRCTN13293865). Results will be disseminated to stakeholders, including patients and members of the public, and published in appropriate journals. Strengths and limitations of this study • This protocol utilises two interventions to support those with ongoing symptoms of COVID-19 • This is a two-centre parallel-group randomised controlled trial • The protocol has been supported by patient and public involvement groups who identified treatments of symptoms and activity limitation as a top priority.
Epidemiology of acute flexor tendon injury and an analysis of outcomes – a study of 91,239 patients in England and Wales
The purpose of this study was to investigate the epidemiology of flexor tendon injuries and operative complications post-repair on a national scale. Using Hospital Episode Statistics data we identified a total of 91,239 patients in England who underwent a flexor tendon repair in the 20-year period between 1 April 1998 and 31 March 2018. Individuals were more likely to be male (74.6%) and of lower socioeconomic status. Median age was 31 years and patients had few medical comorbidities. After primary repair, 3.1% of patients required a revision repair within 90 days and 2.8% tenolysis within two years. Complications other than rupture, adhesions and wound site infection were rare. This study has shown that flexor tendon repair is primarily a procedure of working-age men, with rupture and adhesions the most common complication. The complication rate is less than previously reported in the literature. Level of evidence: III
Solution structure and synaptic analyses reveal determinants of bispecific T cell engager potency.
Bispecific T cell engagers (TcEs) link T cell receptors to tumor-associated antigens on cancer cells, forming cytotoxic immunological synapses (IS). Close membrane-to-membrane contact (≤13 nm) has been proposed as a key mechanism of TcE function. To investigate this and identify potential additional mechanisms, we compared four immunoglobulin G1-based (IgG1) TcE Formats (A-D) targeting CD3ε and Her2, designed to create varying intermembrane distances (A < B < C < D). Small-angle X-ray scattering (SAXS) and modeling of the conformational states of isolated TcEs and TcE-antigen complexes predicted close contacts (≤13 nm) for Formats A and B and far contacts (≥18 nm) for Formats C and D. In supported lipid bilayer (SLB) model interfaces, Formats A and B recruited, whereas Formats C and D repelled, CD2-CD58 interactions. Formats A and B also excluded bulky Quantum dots more effectively. SAXS also revealed that TcE-antigen complexes formed by Formats A and C were less flexible than complexes formed by Formats B and D. Functional data with Her2-expressing tumor cells showed cytotoxicity, surface marker expression, and cytokine release following the order A > B = C > D. In a minimal system for IS formation on SLBs, TcE performance followed the trend A = B = C > D. Addition of close contact requiring CD58 costimulation revealed phospholipase C-γ activation matching cytotoxicity with A > B = C > D. Our findings suggest that when adhesion is equivalent, TcE potency is determined by two parameters: contact distance and flexibility. Both the close/far-contact formation axis and the low/high flexibility axis significantly impact TcE potency, explaining the similar potency of Format B (close contact/high flexibility) and C (far contact/low flexibility).
Changes in hand function and health state utility after cubital tunnel release using the United Kingdom Hand Registry.
This study aimed to analyse and contrast changes in health-related quality of life (HR-QoL) and hand symptoms in the first 6 months after surgical treatment for primary cubital tunnel syndrome. Data originated from the United Kingdom Hand Registry. HR-QoL was assessed using the generic EuroQol five-dimensional assessment tool (EQ-5D-5L) and hand symptoms using the Patient Evaluation Measure (PEM). In total, 281 patients were included in the statistical analysis. Cubital tunnel release resulted in clinically relevant relief of hand symptoms. However, no improvement in HR-QoL was detected by the EQ-5D-5L. As a result, current health economic models, such as those used by the National Institute for Health Care Excellence (NICE) in the UK, might conclude that cubital tunnel release is not cost-effective. This discrepancy requires exploration, and hand-specific preference-based measures might be needed for value-based healthcare in hand surgery.Level of evidence: III.
CD4+ tissue-resident memory Th17 cells are a major source of IL-17A in Spondyloarthritis synovial tissue.
OBJECTIVES: Interleukin (IL)-17A is a key driver of spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with 2 forms of SpA, namely axial SpA (AxSpA) and psoriatic arthritis (PsA). METHODS: Synovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq; AxSpA, n = 5; PsA, n = 6) or spatial RNA profiling (PsA, n = 4). CellPhoneDB was used to infer cell-cell communication. Tissue-resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA, and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17. RESULTS: scRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of interleukin (IL)-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell-receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells. CONCLUSIONS: CD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator bromodomain-containing protein 1 (BRD1) contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission.
Effect of dietary fish oil on the sensitivity of hepatic lipid metabolism to regulation by insulin.
The contribution of dietary fat content and type to changes in the sensitivity of hepatic lipid metabolism to insulin was studied in primary hepatocyte cultures from donor rats maintained on a low-fat diet (LF), or on diets enriched in olive oil (OO) or fish oil (FO). The higher rate of fatty acid oxidation in hepatocytes from the FO-fed group was resistant to the inhibitory effects of insulin observed in hepatocytes from the other groups. Insulin stimulation of fatty acid incorporation into triglyceride (TG) was also less pronounced in hepatocytes from the FO-fed group than in those from the OO-fed group but there was no difference in the stimulatory effect of insulin on fatty acid incorporation into phospholipid (PL) in these two groups. In the case of fatty acid incorporation into both PL and TG, hepatocytes from the LF group were refractory to stimulation by insulin. At each concentration of insulin, hepatocytes from the FO-fed group secreted less very low density lipoprotein (VLDL) TG than those from the other groups. However, the absolute suppression of VLDL TG secretion by insulin was similar irrespective of the diet of the donor animals.We conclude that chronic consumption of a particular type of dietary fat does not affect the insulin sensitivity of the major pathways of hepatic lipid metabolism in a consistent manner.
US and European Patient and Health Care Professional Perspectives on Fatigue in Ulcerative Colitis and Crohn's Disease: Results From the Communicating Needs and Features of Inflammatory Bowel Disease Experiences Survey.
BACKGROUND: Fatigue is a burdensome symptom of Crohn's disease (CD) and ulcerative colitis (UC). The Communicating Needs and Features of Inflammatory Bowel Disease Experiences (CONFIDE) study investigated how patients and health care professionals (HCPs) in the United States (US) and Europe (France, Germany, Italy, Spain, and the United Kingdom) perceived the experiences and impact of CD/UC-related symptoms. METHODS: Online, quantitative, cross-sectional surveys were conducted separately among patients with moderate-to-severe CD/UC (defined based on previous treatment, steroid use, and/or hospitalization) and HCPs who treated patients with CD/UC. US and Europe data are presented as descriptive statistics. RESULTS: Surveys were completed by 215 US and 547 European patients with CD, 200 US and 556 European patients with UC, and 200 US and 503 European HCPs. Overall, 35.8% US and 34.2% European patients with CD and 27.5% US and 20.9% European patients with UC reported currently experiencing fatigue (in past month). Most of these patients reported severe fatigue and indicated that CD/UC negatively affected their sleep, energy levels, and quality of life (QoL). The majority of patients currently experiencing but not discussing fatigue with their HCPs at every appointment wished they discussed it more frequently. However, most HCPs reported proactively discussing fatigue at routine appointments. Approximately 20% patients with CD/UC reported declining participation in work/school, social activities, and sports/physical exercise, and avoiding sexual activities due to fatigue. CONCLUSIONS: US and European patients with CD/UC experienced severe burden of fatigue, which negatively affected their QoL. Assessing and discussing fatigue in routine appointments is critical for effectively managing this debilitating symptom.
Trends in Investigations for Suspected Head and Neck Carcinoma of the Unknown Primary: A HNCIG and IFHNOS International Survey of Practice
Background: The aim of this clinical survey was to assess variations in head and neck squamous cell carcinoma from an unknown primary (HNSCCUP) diagnostic practices across international centers. Methods: Clinical practice survey of experts nominated by Head and Neck Cancer International Group (HNCIG) and International Federation of Head and Neck Oncologic Societies (IFHNOS). Results: Responses were received from 48/49 (97.9%) participants. Outpatient laryngoscopy, CT, and 18-FDG-PETCT were used always or most of the time by 81.3%, 77.1%, and 79.2%, but only 50% regularly used MRI. Unilateral and bilateral tonsillectomy were frequently performed in 41.6% and 27.1% of unilateral nodal disease, and in 18.8% and 52.1% for bilateral disease. Ipsilateral Tongue Base Mucosectomy (TBM) was used always or most of the time in 12.5% of unilateral and 6.3% of bilateral HNSCCUP. Bilateral TBM was used in 10.4% for unilateral and 22.9% for bilateral cancers. Conclusions: While there is broad agreement regarding examination and cross-sectional imaging, there are considerable differences in the surgical strategies used to identify occult primaries.
Magnetic resonance enterography to predict subsequent disabling Crohn's disease in newly diagnosed patients (METRIC-EF)-multivariable prediction model, multicentre diagnostic inception cohort.
OBJECTIVES: Magnetic resonance enterography (MRE) is a first-line investigation to diagnose Crohn's disease (CD), but its role for prognostication is unknown. Accordingly, we assessed the predictive ability of prognostic models including MRE scores (MRE Global Score (MEGS), simplified MR Index of Activity (sMARIA), and Lémann index (LI)) against models using clinical predictors alone for the development of modified Beaugerie disabling CD (MBDD) within 5 years of diagnosis. METHODS: This was a multicentre, diagnostic inception cohort of patients with newly diagnosed CD across 9 UK hospitals, followed for 4 years or more. We censored development of MBDD ≤ 90 days from diagnosis, and used time-to-event models using Royston-Parmer flexible parametric models. RESULTS: We included 194 patients, median age 29, IQR 22-44 years, 52% female. Within 5 years of diagnosis, 42% (81/194) developed MBDD. In univariable analysis, initial steroid requirement was associated with increased risk of developing MBDD (HR 2.11 (95% CI 1.36, 3.26). The baseline clinical model had 49% (39, 60) sensitivity and 66% (57, 74) specificity for predicting the top 40% of patients with the greatest risk of developing MBDD, and 86% (77, 92) sensitivity and 35% (27, 45) specificity for predicting the development of MBDD in patients with an absolute risk of ≥ 10%. There was no significant difference in sensitivity when the MEGS, sMARIA, or LI were added to the baseline clinical model. CONCLUSIONS: Addition of MRE scores at diagnosis to a multivariable model comprising clinical predictors did not improve prediction of MBDD within 5 years of diagnosis. KEY POINTS: Question Magnetic resonance enterography (MRE) is important for diagnosing and monitoring Crohn's disease (CD), but primary research evaluating its prognostic role is lacking. Findings Adding MRE findings at diagnosis to a multivariable model comprising clinical predictors did not improve the prediction of disabling CD within 5 years of diagnosis. Clinical relevance When tested in a prospective, multicentre trial, current MRE activity and damage scores at diagnosis did not reliably predict whether patients would subsequently develop disabling CD. Notwithstanding this finding, MRE remains an essential tool for diagnosis and monitoring.
A literature review of the healthcare resource use and productivity burden of X-linked hypophosphataemia.
INTRODUCTION: X-linked hypophosphataemia (XLH) is a rare, genetic, renal phosphate wasting disorder that causes a lifelong rapid progression of morbidities, which are associated with substantial humanistic and economic burden. A structured literature review was carried out to identify publications reporting healthcare resource use and productivity impact of XLH to provide a comprehensive description of the burden. METHODS: Literature searches of the Embase®, Medline®, and EconLit electronic databases were carried out in August 2022 using free-text and subject heading search terms regarding XLH-related clinical morbidities and associated healthcare resource use, limited to English language records from 1992 onwards. RESULTS: After screening by pre-specified inclusion/exclusion criteria, 22 publications were selected for inclusion in the review. Use of conventional pharmacological therapy with oral phosphate and/or active vitamin D was reported in 15 publications, in up to 100% of paediatric patients and 75% of adults. Findings indicated that a high proportion of patients with XLH undergo orthopaedic procedures/surgeries, including a history of osteotomy in up to 25% of paediatric patients and 61% of adults, and a history of growth plate stapling in up to 63% of paediatric patients and 20% of adults. A high prevalence of fractures (in up to 61% of adults) and use of assistive mobility devices was also reported. The findings highlighted a substantial prevalence of morbidities, either due to persistently low phosphate levels or complications of conventional therapy, that had directly associated healthcare resource use, including dental problems, hearing problems, hyperparathyroidism, and nephrocalcinosis. Healthcare resource use and associated clinical events were generally found to be higher in adults compared with paediatric patients, which is consistent with the natural history of XLH as a progressive lifelong condition. Studies also highlighted the negative impact of XLH on school attendance and the ability to work. DISCUSSION: The results of this structured literature review emphasise the lifelong impact of XLH, showing that it is associated with a substantial economic burden, across many healthcare resource use categories including pharmacological therapy, management of pain and mobility, orthopaedic procedures, morbidities due to XLH or conventional therapy, and work/school productivity.
Developing a Standardised Dataset for Natural History Studies in Fibrous Dysplasia/McCune-Albright Syndrome.
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare and complex condition caused by somatic variants in the GNAS gene that lead to a wide clinical spectrum. The diagnostic process and therapeutic pathway vary per centre and therefore international harmonisation of data collection should be pursued. To understand the diagnostic pathways and clinical outcomes of patients with FD/MAS reported on an electronic-reporting tool (e-REC) across European centres to guide the develop a condition-specific module within the European Registries for Rare Endocrine and Bone conditions. Centres that reported new cases on e-REC between October 2019 and May 2021 were approached to complete a survey in May 2021. Fifty-eight cases were included. Median age at presentation was 20 years (range, 0, 72). Of the 58 included cases, the presentation type was isolated craniofacial FD in 19 (33%), monostotic FD in 15 (26%), polyostotic FD in 10 (17%), and MAS in 13 (13%). Standardised questionnaires to assess pain and quality of life were used routinely in 21/58 patients (36%). The majority of patients had more than one healthcare provider, with great diversity in the specialty of the coordinating physician. A standardised dataset module for FD/MAS was developed through collaboration with the FD/MAS study group, incorporating expert consensus and clinical insights. Key variables were identified to capture essential diagnostic, clinical, and patient-reported outcomes. The diagnostic path for patients with FD/MAS across European expert centres is variable. The outcomes of this study allowed the building of the first international FD/MAS-specific data collection.
Long-term adherence to anti-osteoporosis medication and determinants of adherence in the population-based screening trial ROSE.
UNLABELLED: Screening initiatives for osteoporosis must facilitate treatment of those at elevated fracture risk. In a randomized controlled trial of 24,229 women, those in the screening group with FRAX ≥ 15% were invited for DXA with AOM treatment offered as per national guidelines. Treatment initiation in the following year was 9.5 times higher compared with controls. PURPOSE: To determine if screened individuals have lower adherence to anti-osteoporotic medication (AOM) than unscreened and to examine determinants for low treatment adherence. METHOD: In 2010/2011, women aged 65-80 (N = 34,229) in the Region of Southern Denmark were invited to the risk-stratified osteoporosis strategy evaluation (ROSE) randomized study. Women in the screening group with moderate to high 10-year fracture risk (FRAX® ≥ 15%) were invited for dual-energy x-ray absorptiometry with AOM treatment as per national guidelines. Screened, controls, and an age-matched general population sample were compared for adherence to AOM using 10-year follow-up data on prescription and hospital records. RESULTS: Among ROSE participants with FRAX ≥ 15%, 5864 screened and 5790 controls were eligible for analysis, along with an equal number from the general population. AOM initiation in the first year was 9.5 times higher in screened compared to controls (HR 9.50, 7.16; 12.61). There was no difference in implementation assessed as medication possession ratio. The 5-year persistence rates were similar in screened and controls (51-52%), but lower in the general population (44%). FRAX risk factors partly influenced AOM initiation in the screened, with different patterns in other groups. Immobilization, comorbidities, and co-medications were key determinants of discontinuation in both the short and long term. CONCLUSION: The ROSE screening programme significantly increased treatment initiation in postmenopausal women. Screened women showed similar treatment adherence levels to non-screened once they started medication. However, frail women were more prone to treatment discontinuation, highlighting the need for targeted support in this subgroup. TRIAL REGISTRATION: The original ROSE trial is registered at ClinicalTrials.gov (NCT01388244). The study protocol has been published in Rubin et al. The risk-stratified osteoporosis strategy evaluation study (ROSE): a randomized prospective population-based study. Design and baseline characteristics. Calcif Tissue Int. 2015;96(2):167-79.