Search results
Found 30669 matches for
A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.
Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.
Sexual dimorphisms in fat distribution: investigating oestradiol’s depot-specific effects on preadipocyte and macrophage interactions
Fat distribution is a key regulator of cardiometabolic disease risk, with biological females typically favouring fat storage in the gluteofemoral region, while males tend to store fat around the abdomen. Accumulation of gluteofemoral adiposity, particularly through hyperplastic expansion, is metabolically favourable and is thought to be promoted by the sex hormone oestradiol in females. Alterations in oestradiol concentrations, such as those occurring at menopause or during oestradiol therapy, are associated with shifts in fat distribution and subsequent changes in cardiometabolic risk. However, the mechanisms underlying these oestradiol-induced changes remain poorly understood and are complicated by the controversial literature surrounding the effects of oestradiol on adipose tissue expansion. Given the documented role of oestradiol in modulating the inflammatory phenotypes of other cells within the adipose tissue stromovascular fraction (SVF), particularly macrophages, it is essential to investigate how oestradiol may influence signalling between adipocytes and macrophages to promote depot-specific changes in adipose expansion, favouring gluteofemoral adipose tissue growth and abdominal adipose tissue regression. This thesis aimed to first characterize the depot-specific SVF population landscape using single-cell RNA sequencing (scRNASeq) on paired abdominal and gluteal adipose tissue biopsies. It then assessed oestradiol signalling in abdominal and gluteal preadipocytes using in-vitro models, and established an in-vitro co-culture system between preadipocytes and macrophages. This system facilitated the identification of oestradiol-primed communication signals that may modulate depot-specific expansion through RNA sequencing approaches. The results reveal unique transcriptional landscapes of abdominal and gluteal adipose tissue SVF and demonstrate that preadipocyte responses to oestradiol are highly depot-specific. Additionally, this work identified a range of candidate signals exchanged between preadipocytes and macrophages that may contribute to oestradiol-primed, depots-specific adipose tissue expansion. Future research should aim to functionally test these signals using the in-vitro systems developed here.
Resistance to immunomodulatory drugs in multiple myeloma: the cereblon pathway and beyond
Acquired resistance to immunomodulatory drugs (IMiD) remains a significant unmet need in the treatment landscape of multiple myeloma (MM). The cereblon (CRBN) pathway-dependent mechanisms are known to be vital contributors to IMiD resistance; however, they may account for only a small proportion. Recent research has unveiled additional mechanisms of acquired IMiD resistance that are independent of the CRBN pathway. In this review, we provide a comprehensive overview of the existing work on IMiD resistance in MM, focusing specifically on the emerging evidence of CRBN pathway-independent mechanisms. Finally, we discuss the plausible actionable strategies and outlook for IMiD-based therapies moving forward.
The Role of Social Prescribers in Engaging Older Adults in Strength and Balance Training After Being Discharged From Physiotherapy Rehabilitation: A Qualitative Investigation
Background: Older adults are advised to undertake strength and balance training (SBT) to prevent falls. This can be provided by physiotherapy services for a limited time, but long-term engagement is required to maintain the benefits. Finding ways to support long-term engagement is needed. Aim: To understand if it is feasible to develop a referral pathway from physiotherapy services to social prescribers for engaging older adults in long-term SBT within their daily lives. Methods: We purposefully recruited and interviewed social prescribers via Microsoft Teams. We undertook a framework analysis based on the Capability-Opportunity-Motivation behaviour change framework. Results: We interviewed eight social prescribers including one manager and two whose role was related specifically to physical activity and exercise. All participants demonstrated motivation to engage older adults in SBT. However, there was variation in their perceived capability and opportunity to do this. Some felt their roles were well suited to encourage SBT as their role was linked to exercise provision, but others felt less confident and identified barriers. All participants identified that the social prescribers were becoming overwhelmed by their workload. They identified motivation as the most potent barrier to older adults engaging in SBT along with opportunity and capability barriers. Participants felt that improving motivation would be the biggest driver of behaviour change but not all felt equipped to do this. Conclusion: It may be feasible to trial setting up a referral pathway from physiotherapy services to social prescribing to support older adults to engage in SBT. However, services may lack capacity, and there was variability in how services work and social prescribers identified barriers to engaging older adults in SBT. A better option may be to explore the development of a pathway from outpatient physiotherapy services directly to community physical activity services.
Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses, and outcomes in the 2022 prospective audit of 5000 patients
Aims: With the evolving landscape of acute upper GI bleeding (AUGIB) management, a comprehensive understanding of changing clinical outcomes becomes imperative. This report presents findings from the 2022 UK-wide multi-centre AUGIB audit, drawing comparisons to the previous 2007 study. Methods: A prospective multi-centre audit, conducted between May 3 and July 2, 2022, included adults (≥16 years) presenting with AUGIB in UK hospitals. Results: Data on 5101 patients (median age 69yr) from 152 participating hospitals are reported. New admissions with AUGIB (n=3905) were younger than inpatients developing AUGIB (median age 67.5 vs 74 yrs, respectively) with fewer comorbidities (63% vs 80%, respectively). At presentation, 17% (877/5101) had chronic liver disease (CLD), 30% (n=1528) a history of regular alcohol use, 7% (n=371) were taking non-steroidal anti-inflammatory drugs and 46%(n=2339) antiplatelets and/or anticoagulants (18% direct oral anticoagulants, 10% heparin and 3% warfarin). 83%(n=4228) patients had an inpatient endoscopy; 30%(1277/4228) had peptic ulcer disease (PUD), 9%(417/4228) had varices, and 27%(1135/4228) received endoscopic therapy. Reasons for no endoscopy (n=873) were: 56%(n=491) not clinically indicated/27%(n=234) outpatient procedure /18%(n=156) not for active treatment /7%(n=64) self-discharged /1%(n=7) transferred to other hospital /6%(n=51) death. 10% (416/4228) had evidence of further in-patient bleeding after index endoscopy. 9%(440) underwent>1 endoscopy during inpatient stay; 0.8%(n=42) underwent surgery, 2.6%(n=134) had interventional radiology (IR) and 49%(n=2511) were transfused≥1 packed red blood cells; 4%(n=212) platelets; and 5%(n=282) fresh frozen plasma for AUGIB. Median length of stay was 5 days (IQR 3-9). In-hospital mortality was 9%(n=461); 5.7% in new admissions and 18.4% in inpatients. Comparisons with the 2007 audit revealed significant differences in patient profiles in 2022, including an increase in comorbid patients (67% vs 50%), higher prevalence of anticoagulant use (31% vs 13%), and a greater proportion with underlying CLD (17% vs 9%). A higher percentage of patients underwent inpatient endoscopy (83% vs 74%) in 2022, with reductions in PUD (30% vs 36%) and varices (9% vs 11%). There was a significant increase in those receiving endotherapies (27% vs 24%) and undergoing IR procedures (2.6% vs 1.2%), along with a lower likelihood of further in-patient bleeding after an index endoscopy (10% vs 13%), surgery (0.8% vs 1.9%), and in-hospital mortality (9% vs 10%). All differences were found to be statistically significant (p<0.05). Conclusions: Despite a more co-morbid population, there was reduced recurrent bleeding, need for surgery and in-hospital mortality for AUGIB since 2007. These improvements may be associated with improved management and better endoscopic therapy.
Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells.
Cell identity genes that exhibit complex regulation are marked by super-enhancer (SE) architecture. Assessment of SEs in natural killer (NK) cells identified Ugcg, encoding the enzyme responsible for glycosphingolipid (GSL) synthesis. Conditional deletion of Ugcg in early hematopoiesis abrogated NK cell generation while sparing other lineages. Pharmacological inhibition of UGCG disrupted cytotoxic granules and cytotoxicity, reduced expansion after viral infection, and promoted apoptosis. B4galt5 transcribes an enzyme downstream of UGCG and possesses SE structure. Addition of its product, lactosylceramide (LacCer), reversed apoptosis due to UGCG inhibition. By contrast, complex GSLs, such as asialo-GM1, were not required for NK cell viability and granule integrity. Ugcg and B4galt5 were upregulated in CD8+ T cells during viral infection, correlating with the acquisition of cytotoxic machinery. Antigen-specific CD8+ T cells lacking Ugcg failed to expand during infection. Our study reveals a selective and essential role of GSL metabolism in NK and CD8+ T cell biology.
Temporary 2-week suspension of methotrexate treatment to enhance COVID-19 vaccine response in people with immune-mediated inflammatory diseases: the VROOM RCT
Objective Methotrexate is first-line treatment for many immune-mediated inflammatory diseases. However, it inhibits vaccine-induced immunity – a major concern for this vulnerable group of patients. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster improved antibody response against spike protein of the receptor binding domain and live virus neutralisation (ancestral Wuhan and Omicron BA.1) in patients with immune-mediated inflammatory diseases. Design Open-label, prospective, individually randomised, parallel-group, controlled superiority trial with 1 : 1 randomisation. Setting Multicentre, secondary-care rheumatology and dermatology outpatient clinics. Participants Adults with immune-mediated inflammatory diseases attending rheumatology and dermatology clinics taking methotrexate (≤ 25 mg/week) for ≥ 3 months. Intervention Suspending methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination. Main outcome(s) and measure(s) The primary outcome was spike protein of the receptor binding domain antibody level 4 weeks after COVID-19 booster vaccination. Secondary outcomes were spike protein of the receptor binding domain antibody levels 12 and 26 weeks after COVID-19 vaccine dose; live virus neutralisation (ancestral Wuhan Hu-1, Omicron BA.1) at weeks 4, 12 and 26; and self-reported inflammatory disease activity, flare-ups, quality of life, global assessment of inflammatory disease and adherence with trial allocation. Results A total of 383 participants (61% female, average age 59.0 years) were randomised to either suspend or continue methotrexate. The geometric mean (95% confidence interval) spike protein of the receptor binding domain antibody titre was 25,413 (22,227 to 29,056) and 12,326 (10,538 to 14,418) U/ml in those who suspended and continued methotrexate, respectively. The geometric mean ratio (95% confidence interval) was 2.08 (1.59 to 2.70), p < 0.0001. The intervention effect was present across prognostic subgroups, for example, age groups, methotrexate dose, methotrexate administration route, diseases and past severe acute respiratory syndrome coronavirus 2 infection. Enhanced antibody responses were sustained at 12 and 26 weeks with geometric mean ratio (95% confidence interval) 1.88 (1.44 to 2.46) and 1.50 (1.12 to 2.01), respectively. Interruption of treatment improved neutralisation of Wuhan and Omicron BA.1 at 4 weeks with geometric mean ratio (95% confidence interval) 2.56 (1.21 to 5.44) and 2.42 (1.45 to 4.05), respectively. Self-reported inflammatory disease activity initially deteriorated in the suspended methotrexate group, but the groups were comparable at week 12. Conclusion Two-week interruption of methotrexate treatment for immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 vaccination that were sustained at 12 and 26 weeks. Limitations Lack of participant masking which could have affected self-reported outcomes. Condition-specific disease activity was not used as we recruited participants with a range of diseases, with many lacking validated outcome measures. We did not have data for memory B-cell and T-cell responses. Some hospitals declined to participate in the 26-week follow-up visit which was added to the study after interim analysis, due to lack of capacity, contributing to increased attrition at week 26. Future work Future research should evaluate whether interrupting other immune-suppressing treatments soon after vaccination against COVID-19 or other infectious diseases can improve immune responses. Further research should also evaluate whether a shorter hold in methotrexate would improve the immune response elicited by vaccination. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR134607.
Implementation framework for AI deployment at scale in healthcare systems
Artificial intelligence (AI) and digital health technologies are increasingly used in the medical field. Despite promises of leading the future of personalized medicine and better clinical outcomes, implementation of AI faces barriers for deployment at scale. We introduce a novel implementation framework that can facilitate digital health designers, developers, patient groups, policymakers, and other stakeholders, to co-create and solve issues throughout the life cycle of designing, developing, deploying, monitoring, and maintaining algorithmic models. This framework targets health systems that integrate multiple machine learning (ML) models with various modalities. This design thinking approach promotes clinical utility beyond model prediction, combining privacy preservation with clinical parameters to establish a reward function for reinforcement learning, ranking competing models. This allows leveraging explainable AI (xAI) methods for clinical interpretability. Governance mechanisms and orchestration platforms can be integrated to monitor and manage models. The proposed framework guides users toward human-centered AI design and developing AI-enhanced health system solutions.