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RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.
The Arthroplasty Candidacy Help Engine tool to select candidates for hip and knee replacement surgery: development and economic modelling
Background There is no good evidence to support the use of patient-reported outcome measures (PROMs) in setting preoperative thresholds for referral for hip and knee replacement surgery. Despite this, the practice is widespread in the NHS. Objectives/research questions Can clinical outcome tools be used to set thresholds for hip or knee replacement? What is the relationship between the choice of threshold and the cost-effectiveness of surgery? Methods A systematic review identified PROMs used to assess patients undergoing hip/knee replacement. Their measurement properties were compared and supplemented by analysis of existing data sets. For each candidate score, we calculated the absolute threshold (a preoperative level above which there is no potential for improvement) and relative thresholds (preoperative levels above which individuals are less likely to improve than others). Owing to their measurement properties and the availability of data from their current widespread use in the NHS, the Oxford Knee Score (OKS) and Oxford Hip Score (OHS) were selected as the most appropriate scores to use in developing the Arthroplasty Candidacy Help Engine (ACHE) tool. The change in score and the probability of an improvement were then calculated and modelled using preoperative and postoperative OKS/OHSs and PROM scores, thereby creating the ACHE tool. Markov models were used to assess the cost-effectiveness of total hip/knee arthroplasty in the NHS for different preoperative values of OKS/OHSs over a 10-year period. The threshold values were used to model how the ACHE tool may change the number of referrals in a single UK musculoskeletal hub. A user group was established that included patients, members of the public and health-care representatives, to provide stakeholder feedback throughout the research process. Results From a shortlist of four scores, the OHS and OKS were selected for the ACHE tool based on their measurement properties, calculated preoperative thresholds and cost-effectiveness data. The absolute threshold was 40 for the OHS and 41 for the OKS using the preferred improvement criterion. A range of relative thresholds were calculated based on the relationship between a patient’s preoperative score and their probability of improving after surgery. For example, a preoperative OHS of 35 or an OKS of 30 translates to a 75% probability of achieving a good outcome from surgical intervention. The economic evaluation demonstrated that hip and knee arthroplasty cost of < £20,000 per quality-adjusted life-year for patients with any preoperative score below the absolute thresholds (40 for the OHS and 41 for the OKS). Arthroplasty was most cost-effective for patients with lower preoperative scores. Limitations The ACHE tool supports but does not replace the shared decision-making process required before an individual decides whether or not to undergo surgery. Conclusion The OHS and OKS can be used in the ACHE tool to assess an individual patient’s suitability for hip/knee replacement surgery. The system enables evidence-based and informed threshold setting in accordance with local resources and policies. At a population level, both hip and knee arthroplasty are highly cost-effective right up to the absolute threshold for intervention. Our stakeholder user group felt that the ACHE tool was a useful evidence-based clinical tool to aid referrals and that it should be trialled in NHS clinical practice to establish its feasibility. Future work Future work could include (1) a real-world study of the ACHE tool to determine its acceptability to patients and general practitioners and (2) a study of the role of the ACHE tool in supporting referral decisions.
Who gets referred for knee or hip replacement? A theoretical model of the potential impact of evidence-based referral thresholds using data from a retrospective review of clinic records from an English musculoskeletal referral hub.
OBJECTIVES: To estimate the relationship between patient characteristics and referral decisions made by musculoskeletal hubs, and to assess the possible impact of an evidence-based referral tool. DESIGN: Retrospective analysis of medical records and decision tree model evaluating policy changes using local and national data. SETTING: One musculoskeletal interface clinic (hub) in England. PARTICIPANTS: 922 adults aged ≥50 years referred by general practitioners with symptoms of knee or hip osteoarthritis. INTERVENTIONS: We assessed the current frequency and determinants of referrals from one hub and the change in referrals that would occur at this centre and nationally if evidence-based thresholds for referral (Oxford Knee and Hip Scores, OKS/OHS) were introduced. MAIN OUTCOME MEASURE: OKS/OHS, referrals for surgical assessment, referrals for arthroplasty, costs and quality-adjusted life years. RESULTS: Of 110 patients with knee symptoms attending face-to-face hub consultations, 49 (45%) were referred for surgical assessment; the mean OKS for these 49 patients was 18 (range: 1-41). Of 101 hip patients, 36 (36%) were referred for surgical assessment (mean OHS: 21, range: 5-44). No patients referred for surgical assessment were above previously reported economic thresholds for OKS (43) or OHS (45). Setting thresholds of OKS ≤31 and OHS ≤35 might have resulted in an additional 22 knee referrals and 26 hip referrals in our cohort. Extrapolating hub results across England suggests a possible increase in referrals nationally, of around 13 000 additional knee replacements and 4500 additional hip replacements each year. CONCLUSIONS: Musculoskeletal hubs currently consider OKS/OHS and other factors when making decisions about referral to secondary care for joint replacement. Those referred typically have low OHS/OKS, and introducing evidence-based OKS/OHS thresholds would prevent few inappropriate (high-functioning, low-pain) referrals. However, our findings suggest that some patients not currently referred could benefit from arthroplasty based on OKS/OHS. More research is required to explore other important patient characteristics currently influencing hub decisions.
Lower limb arthroplasty: can we produce a tool to predict outcome and failure, and is it cost-effective? An epidemiological study
Background Although hip and knee arthroplasties are considered to be common elective cost-effective operations, up to one-quarter of patients are not satisfied with the operation. A number of risk factors for implant failure are known, but little is known about the predictors of patient-reported outcomes.
Findings from the Patch Augmented Rotator Cuff Surgery (PARCS) Feasibility Study
<jats:title>Abstract</jats:title> <jats:p>BackgroundA rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The Patch Augmented Rotator Cuff Surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible.MethodsA mixed methods feasibility study of a RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder (BESS) society’s surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires; and a two-day Consensus Meeting. ResultsThe BESS surgeons’ survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting). ConclusionsRandomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders.</jats:p>
In vitro evaluation of the response of human tendon-derived stromal cells to a novel electrospun suture for tendon repair.
Recurrent tears after surgical tendon repair remain common. Repair failures can be partly attributed to the use of sutures not designed for the tendon cellular niche nor for the promotion of repair processes. Synthetic electrospun materials can mechanically support the tendon whilst providing topographical cues that regulate cell behaviour. Here, a novel electrospun suture made from twisted polydioxanone (PDO) polymer filaments is compared to PDS II, a clinically-used PDO suture currently utilised in tendon repair. We evaluated the ability of these sutures to support the attachment and proliferation of human tendon-derived stromal cells using PrestoBlue and Scanning Electron Microscopy. Suture surface chemistry was analysed using X-ray Photoelectron Spectroscopy. Bulk RNA-Seq interrogated the transcriptional response of primary tendon-derived stromal cells to sutures after 14 days. Electrospun suture showed increased initial cell attachment and a stronger transcriptional response compared to PDS II, with relative enrichment of pathways including mTorc1 signalling and depletion of epithelial mesenchymal transition. Neither suture induced transcriptional upregulation of inflammatory pathways compared to baseline. Twisted electrospun sutures therefore show promise in improving outcomes in surgical tendon repair by allowing increased cell attachment whilst maintaining an appropriate tissue response.
Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study.
INTRODUCTION: Increased mortality has been demonstrated in older adults with coronavirus disease 2019 (COVID-19), but the effect of frailty has been unclear. METHODS: This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS) and delirium on risk of increased care requirements on discharge, adjusting for the same variables. RESULTS: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, interquartile range [IQR] 54-83; 55.2% male). The risk of death increased independently with increasing age (>80 versus 18-49: hazard ratio [HR] 3.57, confidence interval [CI] 2.54-5.02), frailty (CFS 8 versus 1-3: HR 3.03, CI 2.29-4.00) inflammation, renal disease, cardiovascular disease and cancer, but not delirium. Age, frailty (CFS 7 versus 1-3: odds ratio 7.00, CI 5.27-9.32), delirium, dementia and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. CONCLUSION: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.
The case for an academic discipline of medical device science.
Medical devices are a very important but largely under-recognized and fragmented component of healthcare.The limited regulation of the past and the lack of systematic rigorous evaluation of devices leading to numerous high-profile failures will now be replaced by stricter legal requirements and more transparent evaluation processes.This constitutes an unprecedented opportunity, but it also uncovers urgent needs in landscaping, methodology development, and independent comprehensive assessment of device risks and benefits for individual patients and society, especially in the context of increasingly complex devices.We argue that an academic discipline of 'medical device science' is well placed to lead and coordinate the efforts necessary to achieve much needed improvement in the medical device sector.Orthopaedics and traumatology could contribute and benefit considerably as one of the medical specialties with the highest use of medical devices. Cite this article: EFORT Open Rev 2021;6:160-163. DOI: 10.1302/2058-5241.6.200094.
Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.
Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.
Will virtual multidisciplinary team meetings become the norm for musculoskeletal oncology care following the COVID-19 pandemic? - experience from a tertiary sarcoma centre.
BACKGROUND: Like with all cancers, multidisciplinary team (MDT) meetings are the norm in bone and soft tissue tumour (BST) management too. Problem in attendance of specialists due to geographical location is the one of the key barriers to effective functioning of MDTs. To overcome this problem, virtual MDTs involving videoconferencing or telemedicine have been proposed, but however this has been seldom used and tested. The COVID-19 pandemic forced the implementation of virtual MDTs in the Oxford sarcoma service in order to maintain normal service provision. We conducted a survey among the participants to evaluate its efficacy. METHODS: An online questionnaire comprising of 24 questions organised into 4 sections was circulated among all participants of the MDT after completion of 8 virtual MDTs. Opinions were sought comparing virtual MDTs to the conventional face-to-face MDTs on various aspects. A total of 36 responses were received and were evaluated. RESULTS: 72.8% were satisfied with the depth of discussion in virtual MDTs and 83.3% felt that the decision-making in diagnosis had not changed following the switch from face-to-face MDTs. About 86% reported to have all essential patient data was available to make decisions and 88.9% were satisfied with the time for discussion of patient issues over virtual platform. Three-fourths of the participants were satisfied (36.1% - highly satisfied; 38.9% - moderately satisfied) with virtual MDTs and 55.6% of them were happy to attend MDTs only by the virtual platform in the future. Regarding future, 77.8% of the participants opined that virtual MDTs would be the future of cancer care and an overwhelming majority (91.7%) felt that the present exercise would serve as a precursor to global MDTs involving specialists from abroad in the future. CONCLUSION: Our study shows that the forced switch to virtual MDTs in sarcoma care following the unprecedented COVID-19 pandemic to be a viable and effective alternative to conventional face-to-face MDTs. With effective and efficient software in place, virtual MDTs would also facilitate in forming extended MDTs in seeking opinions on complex cases from specialists abroad and can expand cancer care globally.
Risk Factors Associated With Infection in Open Fractures of the Upper and Lower Extremities.
INTRODUCTION: Open fractures are associated with a high risk of infection. The prevention of infection is the single most important goal, influencing perioperative care of patients with open fractures. Using data from 2,500 participants with open fracture wounds enrolled in the Fluid Lavage of Open Wounds trial, we conducted a multivariable analysis to determine the factors that are associated with infections 12 months postfracture. METHODS: Eighteen predictor variables were identified for infection a priori from baseline data, fracture characteristics, and surgical data from the Fluid Lavage of Open Wounds trial. Twelve predictor variables were identified for deep infection, which included both surgically and nonoperatively managed infections. We used multivariable Cox proportional hazards regression analyses to identify the factors associated with infection. Irrigation solution and pressure were included as variables in the analysis. The results were reported as adjusted hazard ratios (HRs), 95% confidence intervals (CIs), and associated P values. All tests were two tailed with alpha = 0.05. RESULTS: Factors associated with any infection were fracture location (tibia: HR 5.13 versus upper extremity, 95% CI 3.28 to 8.02; other lower extremity: HR 3.63 versus upper extremity, 95% CI 2.38 to 5.55; overall P < 0.001), low energy injury (HR 1.64, 95% CI 1.08 to 2.46; P = 0.019), degree of wound contamination (severe: HR 2.12 versus mild, 95% CI 1.35 to 3.32; moderate: HR 1.08 versus mild, 95% CI 0.78 to 1.49; overall P = 0.004), and need for flap coverage (HR 1.82, 95% CI 1.11 to 2.99; P = 0.017). DISCUSSION: The results of this study provide a better understanding of which factors are associated with a greater risk of infection in open fractures. In addition, it can allow for surgeons to better counsel patients regarding prognosis, helping patients to understand their individual risk of infection.
Proliferation of mesenchymal stem cell trials for COVID-19: risks and recommendations
<p>At least 20 clinical trials of mesenchymal stem/stromal cells (MSCs) for the treatment of covid-19 have been registered. We assess the emerging trial registrations and argue that the information gain is likely to be low, while the likelihood of false-positives and over-interpretation is high. The rush to test treatments may come at the expense of research quality.</p>
Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials.
BACKGROUND: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. METHODS: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. FINDINGS: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. INTERPRETATION: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. FUNDING: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. VIDEO ABSTRACT.
A novel variant in GLIS3 is associated with osteoarthritis.
OBJECTIVES: Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date. METHODS: We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR. RESULTS: We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10-8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes. CONCLUSIONS: We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.
Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.
OBJECTIVE: Genetic polymorphisms within the HLA region explain only a modest proportion of anti-cyclic citrullinated peptide (anti-CCP)-negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP-negative RA with non-HLA genetic polymorphisms demonstrated in a previous study. METHODS: The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-related regions in 3,339 anti-CCP-negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case-control replication study of the anti-CCP-negative markers with the strongest associations in that discovery study, in an independent cohort of anti-CCP-negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel. RESULTS: After genotyping and imputation quality control procedures, data were available for 15 non-HLA single-nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta-analysis odds ratio [OR] 0.80; P = 2.8 × 10(-13) ) and BLK (OR 1.13; P = 7.0 × 10(-6) ) and identified new and specific markers of anti-CCP-negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10(-6) ] and NFIA [OR 0.85; P = 2.5 × 10(-6) ]). Neither of these loci is associated with other common, complex autoimmune diseases. CONCLUSION: Anti-CCP-negative RA and anti-CCP-positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti-CCP-negative RA.
When should placebo surgery as a control in clinical trials be carried out?
Placebo surgery – often maligned as ‘sham surgery’ – is a tough sell to patients and to many clinicians. But could surgical research benefit from increased use of placebo control groups?