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Mucosal signatures of pathogenic T cells in HLA-B*27+ anterior uveitis and axial spondyloarthritis.
HLA-B*27 was one of the first HLA alleles associated with an autoimmune disease, i.e., axial spondyloarthritis (axSpA) and acute anterior uveitis (B27AAU), which cause joint and eye inflammation, respectively. Gastrointestinal inflammation has been suggested as a trigger of axSpA. We recently identified a bacterial peptide (YeiH) that can be presented by HLA-B*27 to expanded public T cell receptors in the joint in axSpA and the eye in B27AAU. While YeiH is present in enteric microbiota and pathogens, additional evidence that pathogenic T cells in HLA-B*27-associated autoimmunity may have had a prior antigenic encounter within the gastrointestinal tract remains lacking. Here, we analyzed ocular, synovial, and blood T cells in B27AAU and axSpA, showing that YeiH-specific CD8+ T cells express a mucosal gene set and surface proteins consistent with intestinal differentiation, including CD161, integrin α4β7, and CCR6. In addition, we found an expansion of YeiH-specific CD8+ T cells in axSpA and B27AAU blood compared with that from individuals acting as healthy controls, whereas influenza-specific CD8+ T cells were equivalent across groups. Finally, we demonstrated the dispensability of TRBV9 for antigen recognition. Collectively, our data suggest that, in HLA-B27-associated autoimmunity, early antigen exposure and differentiation of pathogenic CD8+ T cells may occur in enteric organs.
High prevalence of MASLD in psoriasis and psoriatic arthritis assessed with multiparametric magnetic resonance imaging.
OBJECTIVES: Psoriatic disease (PsD) is a chronic inflammatory condition associated with obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). We aimed to determine the prevalence of MASLD/MASH in a real-world psoriatic cohort using advanced imaging. METHODS: COLIPSO is a multicentre, prospective study of adults with PsD receiving standard systemic therapy in secondary care. Fifty participants underwent clinical assessments and non-invasive tests of liver health, including MRI-biomarkers of liver fibro-inflammation and fat content. These were compared with 360 individuals with PsD, with 150 controls without PsD (matched for age, sex, BMI and comorbidities) and 150 healthy controls from the UK Biobank and COVERSCAN studies. Associations were investigated with Spearman's rank correlations and multivariate linear regression models. RESULTS: The prevalence of steatotic liver disease was 44% in the PsD group (aged 48 years, 58% male, BMI 29 kg/m2) and higher than in matched controls (25%, p= 0.02). MASH was prevalent in 22% of PsD patients (vs 3% in matched controls, p< 0.001). Thirteen of the 24 (54%) individuals with PsD and liver disease had normal liver function blood tests. No significant difference in levels of liver disease was observed between those with or without prior exposure to methotrexate. CONCLUSIONS: Individuals with PsD exhibit higher prevalence of MASLD and MASH that was missed by blood tests and was present even in individuals with no methotrexate exposure. These findings underscore the importance of routine MASLD screening in this population with more sensitive tools, such as multi parametric MRI.
Developing generic clinical trial animated explainer videos in the UK: results of a survey and case study.
BACKGROUND: Animated short videos used to explain a concept or project are often called animated explainer videos (AEVs). AEVs can supplement or provide an alternative to participant information sheets as a means of giving information about clinical research to potential participants. Current use of AEVs tends to focus on the specifics of a particular trial, yet there are many common aspects of clinical research regardless of the interventions being investigated that can be poorly covered in current trial materials. The EXPLAIN initiative aimed to determine the top generic clinical trial topics considered most important by different UK trial stakeholders. The top three topics were then turned into AEVs and have been made freely available for use. METHOD: A list of generic clinical trial topics which often need explaining to potential trial participants when they are approached to take part in research was developed. Using a two-round Delphi survey of stakeholder groups (trial participants, patients, members of the public, site staff and clinical trials unit staff), the list of topics was expanded and prioritised to identify the topics most in need of clear explanation. The top three topics formed the basis of three AEVs, co-developed with patient and public partners. RESULTS: Two hundred twenty-eight responses were received to the first round of the Delphi survey, and 167 of these respondents also completed the second round of the survey. The three topics prioritised for creation of animated explainer videos were as follows: (1) What is consent? (2) Who decides what treatment I get/What is randomisation? (3) Is it safe to take part in a trial/How do you know a trial is safe? Following virtual meetings with patient and public partners recruited from the Delphi respondents, a script for each AEV was co-produced before being developed into an AEV by a company specialising in animated video production. CONCLUSION: There are a wide range of generic concepts in which the use of animated explainer videos could be useful to improve participant understanding of clinical research. Via consensus survey across multiple stakeholders, we have determined a hierarchy of the importance of explaining these concepts. We envisage that the three AEVs created from this project will form the basis of a readily accessible library of animations to be utilised by trialists.
A viro-immunological model to characterize the antiviral effect of molnupiravir in SARS-CoV-2-infected outpatients: implication for treatment duration.
BACKGROUND: The antiviral efficacy of molnupiravir against SARS-CoV-2 is controversial. Here, we develop a model integrating viral and immune dynamics to characterize the mechanism of action of molnupiravir in vivo and its impact on viral dynamics, during and after treatment. METHODS: We analysed data from the PANORAMIC trial, where 577 outpatients were randomised shortly after symptom onset to receive usual care or molnupiravir for 5 days, and where viral and immunological data were collected for two weeks. We developed a mathematical model that characterized virus/host interaction and accounted for the impact of molnupiravir on viral replication and mutagenesis. The model was used to explore the impact of longer treatment duration. RESULTS: Molnupiravir reduced RNA replication with an efficacy that reached 93% at the end of a five-day treatment. This effect was mediated through two different pathways, one that increased transition mutation frequency, and other that directly inhibited viral production. Accordingly five-day treatment shortened the median time to clearance of both RNA and infectious virus by approximately 2 days. Treatment duration of 10 days could reduce the time to RNA clearance by 5 days and reduce the occurrence of viral rebounds. Longer treatment durations might be needed in case of post-exposure prophylaxis. CONCLUSIONS: Our model suggests that molnupiravir acts primarily on viral replication, and does not act specifically on viral infectivity. Longer administration of molnupiravir may reduce rebound rate and shorten time to viral clearance.
Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype.
This corrects the article DOI: 10.1038/npp.2016.60.
Quantitative liver function imaging and whole genome sequencing - Effective modalities for a new era in personalised decision-making for operable colorectal liver metastases?
BACKGROUND: The optimal strategy for patients with colorectal liver metastases (CRLM) is unclear. The Precision1 prospective, observational trial assessed whether pre-operative functional imaging and whole genome sequencing (WGS), could enhance individualized decision-making. METHODS: Patients with CRLM considered for hepatectomy were recruited. In addition to standard staging, patients underwent a quantitative multiparametric MRI (mpMRI) scan, to assess liver function. Use of mpMRI to aid surgical decision-making, was prospectively recorded, as were short-term clinical outcomes in patients who underwent hepatectomy. In the first 45 patients, WGS was performed on blood and liver tumour samples collected per-operatively. RESULTS: 95 mpMRI scans were performed in 84 patients, who underwent 87 resections. The mpMRI scan affected surgical decision-making in 41 % (39/95) of scans, with 11 undergoing dual-vein embolization, 16 undergoing more conservative parenchymal-sparing surgery, 11 having more extensive surgery, and one patient following a low calorie diet pre-operatively. There were significant (Clavien-Dindo grades 3/4) complications in 5 % of patients, no Grade C post-hepatectomy liver failure, and zero 90-day mortality. WGS suggested additional therapeutic options and prognostic factors for 22 of 35 (63 %) evaluable patients. CONCLUSION: Precision1 shows mpMRI can aid surgical decision-making, and optimise clinical outcomes. WGS provides additional information, to further enhance personalised decision-making.
Myeloma Genome Project Panel is a Comprehensive Targeted Genomics Panel for Molecular Profiling of Patients with Multiple Myeloma.
PURPOSE: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS: Canonical immunoglobulin heavy chain translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for 1 patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2 = 0.969. Variant allele frequency (VAF) for 74 mutations were compared between sequencing and ddPCR with concordance of R2 = 0.9849. CONCLUSIONS: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost-effective, comprehensive, clinically actionable, and can be routinely deployed to assist risk stratification at diagnosis or posttreatment to guide sequencing of therapies.
Association of MSY haplotype background with nonobstructive azoospermia is AZF-dependent: A case-control study.
Identifying causal genes of spermatogenic failure on the male-specific region of Y chromosome (MSY) has been a challenging process. Due to the nonrecombining nature of MSY, haplotype-based approaches have recently been shown to be promising in identifying associated MSY haplogroups. We conducted an MSY analysis of nonobstructive azoospermia (NOA) patients in a case-control setting (N = 278 and 105 respectively) to identify modal haplogroups strongly associated with NOA. Patients with AZF deletions (AZF+) and no AZF deletions (AZF-) were compared with the control group. Given the larger sample set of AZF- NOA patients, we further investigated the association based on histopathological severity, namely Sertoli cell-only syndrome and maturation arrest subtypes. We observed no significant enrichment of MSY haplogroups in AZF- azoospermic patients (or its subtypes). However, we observed a strongly significant association between haplogroup J2a* and AZF+ patients (FDR-corrected p = .0056; OR = 7.02, 95%CI 1.89 to 39.20), a haplogroup which also showed significant enrichment for AZFa/b deletions (p = 4x10-4 ). We conclude that unlike AZF+ patients, AZF- NOA are less likely to have an MSY causative factor with large effect size, thus indicating that the aetiology of AZF- NOA, and to some extent AZFc NOA, is more likely to be based on non-MSY factors.
Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.
The acquisition of a multidrug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the cereblon (CRBN) protein include widely used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here, we investigate alternative genomic associations of IMiD resistance, using large whole-genome sequencing patient datasets (n = 522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriches between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 ubiquitin ligase. This region may represent a novel marker of IMiD resistance with clinical utility.
Systematic review and meta-analysis of mobilisation following open reduction and internal fixation of hand fractures.
Delayed mobilisation following open reduction and internal fixation (ORIF) of hand fractures may contribute to stiffness and poor functional recovery. The aim of this systematic review and meta-analysis was to evaluate whether timing of mobilisation post-ORIF impacts patient-reported and clinical post-operative outcomes. The review was conducted according to the Cochrane Handbook and was reported in concordance with PRISMA guidelines. All studies reporting mobilisation regimens following ORIF performed within two weeks of metacarpal or phalangeal fractures were included. Of 794 abstracts screened, 53 studies were included, evaluating 1822 hand fractures treated with ORIF. We found differences between mobilisation timing in patient-reported outcome measures (PROMs), adverse events and time to radiological fracture union. Immediate mobilisation (≤1 day of ORIF) had the shortest mean bone healing time of 38.7 days (95% CI 34.3, 42.3) compared to early mobilisation (≤7 days) (49.6 days [95% CI 42.8, 56.5]). Delayed mobilisation (>7 days) had the lowest rate of adverse events at 9.3% [95% CI 5.6, 15.2] compared to early mobilisation at 25.0% [95% CI 17.1, 35.0]. However, variable outcome reporting and inconsistent diagnostic criteria limited definitive conclusions. The current literature on post-ORIF mobilisation is heterogeneous. Our meta-analysis demonstrated wide variability in outcomes across different regimens, with overlapping confidence intervals across most summary estimates. A definitive, multi-centre RCT comparing time to mobilisation post-ORIF, including comprehensive outcome reporting and cost-effectiveness analysis, is warranted to inform clinical practice.
Computerized adaptive testing with the I-HaND scale for monitoring patients with upper limb nerve pathology.
The Impact of Hand Nerve Disorders scale is a patient-reported outcome measure for upper limb nerve pathology. We aimed to assess its structural validity using item response theory and to develop computerized adaptive testing algorithms. We conducted a series of psychometric studies to assess constructs measured, applied an item response theory model to the data, then developed computerized adaptive testing algorithms. The results showed two distinct factors: 'Motor Function' and 'Pain'. We developed two separate computerized adaptive tests which reduced the number of questions from six ('Pain') and 16 ('Motor Function') to a median of three questions each at a high level of precision (standard error of measurement <0.3). For optimal measurement precision, the Impact of the Hand Nerve Disorders scale should be divided into two subscales and administered through computerized adaptive testing. In some circumstances (such as screening for specific issues) it may be preferable to administer all 32 items.
Early detection to improve outcome in people with undiagnosed psoriatic arthritis: the PROMPT research programme including RCT
Background Longitudinal observational studies suggest that patients who present early to secondary care with psoriatic arthritis have a better outcome. Outcome needs to be measured including domains important to patients. Objectives To identify disease activity and impact outcomes important to patients with psoriatic arthritis in comparison to existing ones (Patient-Reported Outcome Measurement Study). To assess the validity of new measures of disease activity in psoriatic arthritis derived from patient engagement (ASSESSment of modified composite disease measures study). To explore patients’ experiences of diagnosis in psoriatic arthritis? (Experiences of screening and diaGnosis from the perspective of pAtients with PSoriasis and psoriatic arthritis study). To identify modifiable risk factors for the development of psoriatic arthritis using the Clinical Practice Research Datalink (EPIdemiology of psoriatiC arthritis study). To compare the performance of screening tools for detecting undiagnosed psoriatic arthritis (COMparison of Psoriatic Arthritis scREening tools study). To investigate the clinical effectiveness (Total bUrDen Of psoRiasis trial) and cost-effectiveness (COSt of screening for Psoriatic Arthritis study) of detecting undiagnosed psoriatic arthritis. Design and methods Mixed methods using data from patient focus groups, a multicentre cohort study, primary care health records (Clinical Practice Research Datalink) and a prospective randomised clinical trial (Total bUrDen Of psoRiasis trial, COMparison of Psoriatic Arthritis scREening tools study, COSt of screening for Psoriatic Arthritis study). Setting and participants Focus groups and cohort studies of 221 patients with psoriatic arthritis including newly diagnosed cases (Patient-Reported Outcome Measurement Study, ASSESSment of modified composite disease measures study, experiences of screening and diaGnosis from the perspective of pAtients with PSoriasis and psoriatic arthritis study) and 2225 patients with psoriasis from primary care not known to have psoriatic arthritis from 135 randomised general practices (COMparison of Psoriatic Arthritis scREening tools study, Total bUrDen Of psoRiasis trial randomised clinical trial, COSt of screening for Psoriatic Arthritis study). Intervention Randomised controlled trial comparing the early identification of psoriatic arthritis by annual rheumatological assessment (enhanced surveillance) in people with psoriasis identified in primary care (n = 1123) with standard care (n = 1102). Participants with suspected inflammatory arthritis were referred to the local rheumatology clinic for an assessment of psoriatic arthritis (enhanced surveillance arm: at baseline, 12 and 24 months; standard care arm: at 24 months). Data sources Cohort studies of incident psoriasis (n = 90,189) or psoriatic arthritis (n = 6783) patients from the Clinical Practice Research Datalink (EPIdemiology of psoriatiC arthritis study). Cost-effective analysis using data collected in Total bUrDen Of psoRiasis trial. Modelling exercise to extrapolate screening performance from Total bUrDen Of psoRiasis trial to long-term costs and quality-adjusted life-years (COSt of screening for Psoriatic Arthritis study). Main outcome measure In Total bUrDen Of psoRiasis trial the primary outcome was the Health Assessment Questionnaire Disability Index at 24 months post registration in participants diagnosed with psoriatic arthritis. Results Patient-Reported Outcome Measurement Study: Patients rated pain and fatigue as the most important outcomes when receiving treatment for psoriatic arthritis. ASSESSment of modified composite disease measures study: Shortened versions of visual analogue scales performed well in detecting treatment change and responsiveness over 6 months. Experiences of screening and diaGnosis from the perspective of pAtients with PSoriasis and psoriatic arthritis study: Missed opportunities for psoriatic arthritis diagnosis has implications for well-being including mental health, and there is a need for provision of psychological support and self-management guidance. Screening for psoriatic arthritis was generally regarded as a positive experience. EPIdemiology of psoriatiC arthritis study: Bayesian networks identified clusters of symptoms that can accurately predict the development of psoriatic arthritis (area under the curve 0.73, 95% CI 0.70 to 0.75). Obesity is a modifiable lifestyle factor that increases the risk of developing psoriatic arthritis and diminishes linearly over a 10-year period with a reduction in body mass index. Diabetes, cardiovascular disease, uveitis and Crohn’s disease are associated with psoriatic arthritis and may appear early in the disease course. COMparison of Psoriatic Arthritis scREening tools study: The Psoriasis Epidemiology Screening Tool questionnaire remains the preferred screening tool, given its simplicity with no significant differences in performance (sensitivity: 0.625, specificity: 0.757, area under the curve 0.787) compared to COmparisoN of ThreE Screening Tools to detect psoriatic arthritis in patients with psoriasis. Total bUrDen Of psoRiasis trial: The primary analysis population consisted of 87 participants with a positive diagnosis of psoriatic arthritis: 64 in enhanced surveillance, 23 in standard care (overall mean Health Assessment Questionnaire Disability Index score at 24 months was 0.45). The adjusted odds ratio for achieving a Health Assessment Questionnaire Disability Index score of 0 at 24 months post registration in enhanced surveillance compared to standard care was 0.64 (95% CI 0.17 to 2.38), and the adjusted odds ratio of achieving a higher (non-zero) Health Assessment Questionnaire Disability Index score at 24 months post registration in enhanced surveillance relative to standard care arm was 1.12 (95% CI 0.67 to 1.86), indicating no evidence of a difference between the two treatment groups (p = 0.6612). COSt of screening for Psoriatic Arthritis study: The within-trial cost-effectiveness analysis suggests that enhanced surveillance may be associated with higher mean quality-adjusted life-years, although the difference was very small (+0.002, 95% CI –0.03 to 0.03), and lower mean costs (−£120.54, 95% CI –£540.57 to £288.99). Using the cost-effectiveness model based on the sensitivity, specificity and the psoriatic arthritis incidence from the Total bUrDen Of psoRiasis trial, Psoriasis Epidemiology Screening Tool is the most expensive and has the highest lifetime quality-adjusted life-years with an incremental cost-effectiveness ratio of £14,964 per additional quality-adjusted life-year compared to CONTEST, CONTESTjt and no screening using a lifetime time horizon. Limitations The Total bUrDen Of psoRiasis trial was underpowered due to a lower proportion of patients developing psoriatic arthritis than expected (87 compared to 148) and disruption to follow-up due to the coronavirus pandemic. COSt of screening for Psoriatic Arthritis study analyses were limited by the extent of missing data. Conclusion The benefit of early detection of psoriatic arthritis in a primary care psoriasis population remains unproven. Surveillance for undiagnosed psoriatic arthritis generally detects mild cases as measured by physical function. Patients rate pain and fatigue as the most important outcomes. Future work Five-year follow-up of Total bUrDen Of psoRiasis trial participants to investigate longer-term benefits of earlier diagnosis comparing treatment arms and to assess risk factors for psoriatic arthritis development is underway. Trial registration This trial is registered as Current Controlled Trials ISRCTN38877516. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1212-20007) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 6. See the NIHR Funding and Awards website for further award information.