Search results
Found 30519 matches for
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.
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).
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.
Management of metacarpal shaft fractures.
AIMS: The aims of this study were to describe the epidemiology of metacarpal shaft fractures (MSFs), assess variation in treatment and complications following standard care, document hospital resource use, and explore factors associated with treatment modality. METHODS: A multicentre, cross-sectional retrospective study of MSFs at six centres in the UK. We collected and analyzed healthcare records, operative notes, and radiographs of adults presenting within ten days of a MSF affecting the second to fifth metacarpal between 1 August 2016 and 31 July 2017. Total emergency department (ED) attendances were used to estimate prevalence. RESULTS: A total of 793 patients (75% male, 25% female) with 897 MSFs were included, comprising 0.1% of 837,212 ED attendances. The annual incidence of MSF was 40 per 100,000. The median age was 27 years (IQR 21 to 41); the highest incidence was in men aged 16 to 24 years. Transverse fractures were the most common. Over 80% of all fractures were treated non-surgically, with variation across centres. Overall, 12 types of non-surgical and six types of surgical treatment were used. Fracture pattern, complexity, displacement, and age determined choice of treatment. Patients who were treated surgically required more radiographs and longer radiological and outpatient follow-up, and were more likely to be referred for therapy. Complications occurred in 5% of patients (39/793). Most patients attended planned follow-up, with 20% (160/783) failing to attend at least one or more clinic appointments. CONCLUSION: MSFs are common hand injuries among young, working (economically active) men, but there is considerable heterogeneity in treatment, rehabilitation, and resource use. They are a burden on healthcare resources and society, thus further research is needed to optimize treatment.
Optimising the manufacture of perfluorocarbon nanodroplets through varying sonication parameters.
Perfluorocarbon nanodroplets (PFC-NDs) are promising ultrasound-responsive theranostic agents with applications in both diagnostic imaging and drug delivery. The acoustic vaporisation threshold, extravasation potential, and stability of PFC-NDs are all affected by their size. However, methods to ensure reproducible size and concentration during production by sonication are lacking. To address this need, we examined the effect of temperature, sonication time, sonication intensity, PFC concentration and sonicator tip height on ND characteristics. PFC-NDs with a perfluoro-n-pentane (PFP) core and a phospholipid shell were manufactured by probe-sonication. Pulsed sonication was used to maintain the sample temperature below the boiling point of PFP. Median particle diameter was measured using nanoparticle tracking analysis. PFC-ND diameter increased with increasing PFP concentration, with a stronger relationship as sonicator tip height increased. Above 5% v/v PFP, there was a qualitative increase in the number of particles visible by light microscopy. Increasing the sonication duration did not yield a significant change in ND size. A minimum amplitude of 60% was required for mixing to occur, with amplitudes of 80% and 100% resulting in foam production. Sonicator power output was linear with respect to time but differed depending on sample volume, composition, and vessel geometry. This study indicates that controlling the processing parameters can facilitate reproducible manufacturing of PFC-NDs.