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Fiona Powrie, Director of the Kennedy Institute of Rheumatology is joining Wellcome as a new Governor in Jan 2018. Fiona says she’s thrilled to join Wellcome: "It’s an organisation I’ve admired since I started my research career. Through funding great scientific ideas, Wellcome is committed to promoting health around the world. It will be an honour to help deliver this goal."
Pharmacological interventions for early-stage frozen shoulder: a systematic review and network meta-analysis.
OBJECTIVES: To evaluate the efficacy of pharmacological interventions for treating early-stage, pain predominant, adhesive capsulitis, also known as frozen shoulder. METHODS: We performed a systematic review in accordance with PRSIMA guidelines. Searches were conducted on PUBMED, EMBASE and Cochrane Central Register of Controlled Trials on the 24th of February 2022. Outcomes were shoulder pain, shoulder function and range of movement. Synthesis involved both qualitative analysis for all studies and pairwise meta-analyses followed by a network meta-analysis for randomised controlled trials (RCTs). RESULTS: A total of 3,252 articles were found, of which 31 met inclusion criteria, and 22 of these were RCTs. Intraarticular (IA) injection of corticosteroids (8 RCTS, 340 participants) and IA injection of platelet-rich plasma (PRP) (3 RCTs, 177 participants) showed benefit at 12 weeks compared with physical therapy in terms of shoulder pain and function, while oral non-steroidal anti-inflammatories (NSAIDs) (2 RCTs, 44 participants) and IA injection of hyaluronate (2 RCTs, 42 participants) did not show a benefit. Only IA PRP showed benefit over physical therapy for shoulder range of movement. CONCLUSION: These results shows that IA corticosteroids IA PRP injections are beneficial for early-stage frozen shoulder. These findings should be appraised with care considering the risk of bias, heterogeneity, and inconsistency of the included studies. We believe that research focused on early interventions for frozen shoulder could improve patient outcomes and lead to cost-savings derived from avoiding long-term disability. Further well-designed studies comparing with standardised physical therapy or placebo are required to improve evidence to guide management.
Mobility and strength training with and without protein supplements for pre-frail or frail older adults with low protein intake: the Maximising Mobility and Strength Training (MMoST) feasibility randomised controlled trial protocol
Background Frailty is a common syndrome affecting older people and puts them at risk of hospitalisation, needing care or death. First signs of frailty include reduced muscle strength and mobility decline. A key cause of mobility decline as we age is sarcopenia (age related reduction in muscle strength and mass). Poor nutrition contributes to sarcopenia. A shortfall in protein is associated with reduced muscle mass and strength. This may be due to inadequate intake but also because older people have higher protein needs, especially those with multimorbidity. We need to develop effective treatment to reduce or slow the onset of frailty and mobility decline. Exercise is a recommended treatment. Protein supplements to address the shortfall in protein have the potential to enhance the benefit of regular exercise in frail or pre-frail older adults. This has yet to be definitively demonstrated. Aim To establish the feasibility of conducting an RCT evaluating mobility and strength training with or without protein supplements for people over 60 years old who are frail or pre-frail with a low protein intake. Methods A multicentre, parallel, 2-group, feasibility RCT. Participants (recruitment target = 50) with problems walking, low protein intake and classified as frail or pre-frail will be recruited from four NHS Physiotherapy community services. Participants will be randomised (secure computer-generated: 1:1) to receive 24 weeks of mobility and strength training (delivered in 16 group sessions plus home exercises) or 24 weeks of mobility and strength training with daily protein supplements. Primary feasibility objectives are to estimate 1) ability to screen and recruit eligible participants, 2) intervention fidelity, adherence, and tolerance and 3) retention of participants at follow up. Secondary objectives are to 1) test data collection procedures, 2) assess data completeness and 3) confirm sample size calculation for a definitive RCT. Registration ISRCTN Registry (ISRCTN30405954; 18/10/2022).
Trends of use and characterisation of anti-dementia drugs users: a large multinational-network population-based study.
BACKGROUND: An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia using real-world data. SETTING: Primary care data (country/database) from the UK/CPRD-GOLD (2007-20), Spain/SIDIAP (2010-20) and the Netherlands/IPCI (2008-20), standardised to a common data model. METHODS: Cohort study. Participants: dementia patients ≥40 years old with ≥1 year of previous data. Follow-up: until the end of the study period, transfer out of the catchment area, death or incident prescription of rivastigmine, galantamine, donepezil or memantine. Other variables: age/sex, type of dementia, comorbidities. Statistics: overall and yearly age/sex IR, with 95% confidence interval, per 100,000 person-years (IR per 105 PY (95%CI)). RESULTS: We identified a total of (incident anti-dementia users/dementia patients) 41,024/110,642 in UK/CPRD-GOLD, 51,667/134,927 in Spain/SIDIAP and 2,088/17,559 in the Netherlands/IPCI.In the UK, IR (per 105 PY (95%CI)) of ADD decreased from 2007 (30,829 (28,891-32,862)) to 2010 (17,793 (17,083-18,524)), then increased up to 2019 (31,601 (30,483 to 32,749)) and decrease in 2020 (24,067 (23,021-25,148)). In Spain, IR (per 105 PY (95%CI)) of ADD decreased by 72% from 2010 (51,003 (49,199-52,855)) to 2020 (14,571 (14,109-15,043)). In the Netherlands, IR (per 105 PY (95%CI)) of ADD decreased by 77% from 2009 (21,151 (14,967-29,031)) to 2020 (4763 (4176-5409)). Subjects aged ≥65-79 years and men (in the UK and the Netherlands) initiated more frequently an ADD. CONCLUSIONS: Treatment of dementia remains highly heterogeneous. Further consensus in the pharmacological management of patients living with dementia is urgently needed.
Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia.
Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex is an essential innate immune signaling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labeling, affinity purification, and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-interleukin-1β (IL-1β) levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1β cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1β production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.
Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.
INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.
Device-Measured Physical Activity in 3506 Individuals with Knee or Hip Arthroplasty.
PURPOSE: Hip and knee arthroplasty aims to reduce joint pain and increase functional mobility in patients with osteoarthritis; however, the degree to which arthroplasty is associated with higher physical activity is unclear. The current study sought to assess the association of hip and knee arthroplasty with objectively measured physical activity. METHODS: This cross-sectional study analyzed wrist-worn accelerometer data collected in 2013-2016 from UK Biobank participants (aged 43-78 yr). Multivariable linear regression was performed to assess step count, cadence, overall acceleration, and activity behaviors between nonarthritic controls, end-stage arthritic, and postoperative cohorts, controlling for demographic and behavioral confounders. From a cohort of 94,707 participants with valid accelerometer wear time and complete self-reported data, electronic health records were used to identify 3506 participants having undergone primary or revision hip or knee arthroplasty and 68,389 nonarthritic controls. RESULTS: End-stage hip or knee arthritis was associated with taking 1129 fewer steps per day (95% confidence interval (CI), 811-1447; P < 0.001) and having 5.8 fewer minutes per day (95% CI, 3.0-8.7; P < 0.001) of moderate-to-vigorous activity compared with nonarthritic controls. Unilateral primary hip and knee arthroplasties were associated with 877 (95% CI, 284-1471; P = 0.004) and 893 (95% CI, 232-1554; P = 0.008) more steps than end-stage osteoarthritic participants, respectively. Postoperative unilateral hip arthroplasty participants demonstrated levels of moderate-to-vigorous physical activity and daily step count equivalent to nonarthritic controls. No difference in physical activity was observed between any cohorts in terms of overall acceleration, or time spent in daily light activity, sedentary behavior, or sleep. CONCLUSIONS: Hip and knee arthroplasties are associated with higher levels of physical activity compared with participants with end-stage arthritis. Unilateral hip arthroplasty patients, in particular, demonstrate equivalence to nonarthritic peers at more than 1 yr after surgery.
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.
Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.
BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minutes, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03855332.
Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma.
Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.
Overcoming barriers to single-cell RNA sequencing adoption in low- and middle-income countries.
The advent of single-cell resolution sequencing and spatial transcriptomics has enabled the delivery of cellular and molecular atlases of tissues and organs, providing new insights into tissue health and disease. However, if the full potential of these technologies is to be equitably realised, ancestrally inclusivity is paramount. Such a goal requires greater inclusion of both researchers and donors in low- and middle-income countries (LMICs). In this perspective, we describe the current landscape of ancestral inclusivity in genomic and single-cell transcriptomic studies. We discuss the collaborative efforts needed to scale the barriers to establishing, expanding, and adopting single-cell sequencing research in LMICs and to enable globally impactful outcomes of these technologies.
A Chemical Probe For Tudor Domain Protein Spindlin1 to Investigate Chromatin Functions
Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that contain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional co-activator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis.
A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson's disease: a study protocol for a randomised controlled trial.
BACKGROUND: Parkinson's disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals' needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. METHODS/DESIGN: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. PRIMARY OUTCOME: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson's Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. DISCUSSION: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016.
An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn's disease with defective antimicrobial activity.
Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn's disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn's disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn's disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease.
Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease.
Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.