Search results
Found 9879 matches for
Unicompartmental compared with total knee replacement for patients with multimorbidities: a cohort study using propensity score stratification and inverse probability weighting
Background: Although routine NHS data potentially include all patients, confounding limits their use for causal inference. Methods to minimise confounding in observational studies of implantable devices are required to enable the evaluation of patients with severe systemic morbidity who are excluded from many randomised controlled trials. Objectives: Stage 1 – replicate the Total or Partial Knee Arthroplasty Trial (TOPKAT), a surgical randomised controlled trial comparing unicompartmental knee replacement with total knee replacement using propensity score and instrumental variable methods. Stage 2 – compare the risk benefits and cost-effectiveness of unicompartmental knee replacement with total knee replacement surgery in patients with severe systemic morbidity who would have been ineligible for TOPKAT using the validated methods from stage 1. Design: This was a cohort study. Setting: Data were obtained from the National Joint Registry database and linked to hospital inpatient (Hospital Episode Statistics) and patient-reported outcome data. Participants: Stage 1 – people undergoing unicompartmental knee replacement surgery or total knee replacement surgery who met the TOPKAT eligibility criteria. Stage 2 – participants with an American Society of Anesthesiologists grade of ≥ 3. Intervention: The patients were exposed to either unicompartmental knee replacement surgery or total knee replacement surgery. Main Outcome Measures: The primary outcome measure was the postoperative Oxford Knee Score. The secondary outcome measures were 90-day postoperative complications (venous thromboembolism, myocardial infarction and prosthetic joint infection) and 5-year revision risk and mortality. The main outcome measures for the health economic analysis were health-related quality of life (EuroQol-5 Dimensions) and NHS hospital costs. Results: In stage 1, propensity score stratification and inverse probability weighting replicated the results of TOPKAT. Propensity score adjustment, propensity score matching and instrumental variables did not. Stage 2 included 2256 unicompartmental knee replacement patients and 57,682 total knee replacement patients who had severe comorbidities, of whom 145 and 23,344 had linked Oxford Knee Scores, respectively. A statistically significant but clinically irrelevant difference favouring unicompartmental knee replacement was observed, with a mean postoperative Oxford Knee Score difference of Limitations: Although some propensity score methods successfully replicated TOPKAT, unresolved confounding may have affected stage 2. Missing Oxford Knee Scores may have led to information bias. Conclusions: Propensity score stratification and inverse probability weighting successfully replicated TOPKAT, implying that some (but not all) propensity score methods can be used to evaluate surgical innovations and implantable medical devices using routine NHS data. Unicompartmental knee replacement was safer and more cost-effective than total knee replacement for patients with severe comorbidity and should be considered the first option for suitable patients. Future work: Further research is required to understand the performance of propensity score methods for evaluating surgical innovations and implantable devices. Trial registration: This trial is registered as EUPAS17435. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 66. See the NIHR Journals Library website for further project information.
The role of intraoperative cell salvage for musculoskeletal sarcoma surgery.
BACKGROUND: The efficacy and safety of cell salvage for musculoskeletal sarcoma surgery have not been reported, and concerns over re-infusion of tumour cells remain. This study aims to i) describe the intra-operative blood loss and cell salvage reinfusion volumes for lower limb sarcoma and pelvic sarcoma procedures ii) and explore whether there is evidence of tumour cells in reinfused blood. METHODS: Retrospective analysis of 109 consecutive surgical procedures for biopsy-proven sarcoma or bone metastasis performed between 1 July 2015 and 30 October 2019. Salvaged blood was processed and reinfused when intraoperative blood loss exceeded 500 ml. Primary bone tumour (n = 86(79%)) and metastasis (n = 23(21%) constituted the study group and surgeries were classified under hemipelvectomy (n = 43(39%)), lower limb endoprosthesis replacement (LLE) (n = 50(46%)) and wide excision surgery (WE) (n = 16(15%)). Microscopic examination of imprint cytology of leuco-depletion(LD) filters, and peripheral smear examination was performed for reinfused blood. RESULTS: Median (IQR) intra-operative blood loss was 1750 (600-3000) ml for hemipelvectomy, 850 (600-1200) ml for LLE, and 1000 (550-2000) ml for WE. Salvaged blood was re-infused in 102 of 109 (94%) patients. The mean (SD) volume of re-infusion was 445(4 2 5) ml for hemipelvectomy, 206(1 3 1) ml for LLE, and 184(1 0 6) ml for WE. In total, 64 of 109 (59%) patients received an allogeneic red blood transfusion within 72 h of surgery. Cytology analysis of imprints taken from the filtered blood available in 95(87%) patients and peripheral smear examination of reinfused blood available in 32(29%) patients did not reveal evidence of tumour cells on microscopic examination of any samples. CONCLUSION: Our study demonstrates that musculoskeletal sarcoma surgery is associated with significant blood loss, and cell salvage permits reinfusion of autologous blood in most patients. The cytological analysis did not reveal evidence of tumour cells in reinfused blood, consistent with other studies where cell salvage is used for cancer surgery.
Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
Base of thumb osteoarthritis in UK interface services-a cohort and survey-based study to assess current practice.
OBJECTIVE: Base of thumb OA (BTOA) is a common age-related disease that has a significant negative impact on quality of life, while little is known about the structure and pathways of interface services. Our aim was to assess disease burden, referral pathways, service structure and management pathways in UK interface services. METHODS: A structured questionnaire was carried out with a participating clinician at each centre to detail the local guidelines and management of BTOA. Five patients referred with BTOA were prospectively identified in each of 32 UK interface centres. RESULTS: Most centres (72%) had a local guideline and a standardized treatment regime consisting of education (100%), joint protection (100%), range of motion exercises (84%), strengthening exercises (88%), splintage (100%) and use of assistive devices (78%). No centre routinely offered a steroid injection at the first appointment and no centre had a specific threshold for offering an injection. Injection delivery was variable. Most patients had not been referred previously (82%). Most patients used analgesia (72%), but a minority of patients had been treated with a splint (46%), therapy (43%) and steroid injection (27%) prior to their latest attendance. CONCLUSION: Most BTOA patients newly referred to interface services have been treated with analgesics and have not received comprehensive multimodal intervention. The management of BTOA at interface services is standardized in terms of education, splintage and therapy. However, there is a lack of standardization in terms of both the threshold for, timing of and mode of delivery of injection therapy.
Findings from the patch augmented rotator cuff surgery (PARCS) feasibility study.
BACKGROUND: A 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. METHODS: A mixed methods feasibility study of conducing a subsequent RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder Society's (BESS) surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting. RESULTS: The 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. CONCLUSIONS: Randomised 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.
Pain in women: bridging the gender pain gap.
Bridging the gender pain gap requires collaborative efforts that address female-specific biological and psychosocial dimensions of pain through evidence-based, compassionate and empathy-driven approaches.
Bone turnover in pregnancy, measured by urinary CTX, is influenced by vitamin D supplementation and is associated with maternal bone health: findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial.
BACKGROUND: The pattern of change in maternal bone turnover throughout pregnancy is poorly characterized. OBJECTIVES: We investigated changes across pregnancy in a marker of maternal bone resorption, urinary C-terminal telopeptide of type I collagen (CTX), the influence of gestational vitamin D supplementation, and associations between CTX and maternal postnatal bone indices. METHODS: MAVIDOS (the Maternal Vitamin D Osteoporosis Study) is a randomized, double-blind, placebo-controlled trial of 1000 IU cholecalciferol/d compared with placebo from 14 weeks of gestation to birth. Maternal second-void urinary α- and β-CTX were measured (ELISA) at 14 and 34 weeks of gestation; DXA was performed within 2 wk postpartum. The Mann-Whitney Rank Sum test, Spearman's rank correlation, and linear regression were used to compare median CTX values within and between groups from early to late pregnancy, and associations with maternal bone outcomes. RESULTS: In total, 372 women had CTX and 25-hydroxyvitamin D [25(OH)D] measured in early and late pregnancy. CTX at 14 and 34 weeks of gestation were correlated in both placebo (r = 0.31) and cholecalciferol (r = 0.45) groups (P
Humanoid robots to mechanically stress human cells grown in soft bioreactors.
For more than 20 years, robotic bioreactor systems have facilitated the growth of tissue-engineered constructs using mechanical stimulation. However, we are still unable to produce functional grafts that can translate into clinical use. Humanoid robots offer the prospect of providing physiologically-relevant mechanical stimulation to grafts and implants which may expedite their clinical deployment. To investigate the feasibility of a humanoid bioreactor, we have designed a flexible bioreactor chamber that can be attached to a modified musculoskeletal (MSK) humanoid robot shoulder joint. We demonstrate that fibroblast cells can be grown in this chamber while undergoing physiological adduction-abduction on the robotic arm. A preliminary evaluation of the transcriptome of the cells after 14 days indicated a clear influence of the loading regime on the gene expression profile. These early results will facilitate the exploration of MSK humanoid robots as a biomechanically more realistic platform for tissue engineering and biomaterial testing applications.
Interleukin-17 Cytokines and Receptors: Potential Amplifiers of Tendon Inflammation.
Interleukin (IL)-17A, a pro-inflammatory cytokine that is linked to the pathology of several inflammatory diseases, has been shown to be upregulated in early human tendinopathy and to mediate inflammatory and tissue remodelling events. However, it remains unclear which cells in tendons can respond to IL-17A, and how IL-17A, and its family members IL-17F and IL-17AF, can affect intracellular signalling activation and mRNA expression in healthy and diseased tendon-derived fibroblasts. Using well-phenotyped human tendon samples, we show that IL-17A and its receptors IL-17RA and IL-17RC are present in healthy hamstring, and tendinopathic and torn supraspinatus tendon tissue. Next, we investigated the effects of IL-17A, IL-17F, or IL-17AF on cultured patient-derived healthy and diseased tendon-derived fibroblasts. In these experiments, IL-17A treatment significantly upregulated IL6, MMP3, and PDPN mRNA expression in diseased tendon-derived fibroblasts. IL-17AF treatment induced moderate increases in these target genes, while little change was observed with IL-17F. These trends were reflected in the activation of intracellular signalling proteins p38 and NF- κ B p65, which were significantly increased by IL-17A, modestly increased by IL-17AF, and not increased by IL-17F. In combination with TNF-α, all three IL-17 cytokines induced IL6 and MMP3 mRNA expression to similar levels. Therefore, this study confirms that healthy and diseased tendon-derived fibroblasts are responsive to IL-17 cytokines and that IL-17A induces the most profound intracellular signalling activation and mRNA expression of inflammatory genes, followed by IL-17AF, and finally IL-17F. The ability of IL-17 cytokines to induce a direct response and activate diverse pro-inflammatory signalling pathways through synergy with other inflammatory mediators suggests a role for IL-17 family members as amplifiers of tendon inflammation and as potential therapeutic targets in tendinopathy.
Cellular characterisation of advanced osteoarthritis knee synovium.
OBJECTIVES: Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores. METHODS: Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected. RESULTS: The proportion of immune cells in OA synovium varied between patients (8-38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45-PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer. CONCLUSIONS: There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes.
ACL Surgery Necessity in Non-Acute Patients (ACL SNNAP): a statistical analysis plan for a randomised controlled trial.
BACKGROUND: Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries. METHODS/DESIGN: ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously. DISCUSSION: The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results. TRIAL REGISTRATION: ISRCTN ISRCTN10110685 . Registered on 16 November 2016.
Comparison of Cellular Responses to TGF-β1 and BMP-2 Between Healthy and Torn Tendons.
BACKGROUND: Tendons heal by fibrotic repair, increasing the likelihood of reinjury. Animal tendon injury and overuse models have identified transforming growth factor beta (TGF-β) and bone morphogenetic proteins (BMPs) as growth factors actively involved in the development of fibrosis, by mediating extracellular matrix synthesis and cell differentiation. PURPOSE: To understand how TGF-β and BMPs contribute to fibrotic processes using tendon-derived cells isolated from healthy and diseased human tendons. STUDY DESIGN: Controlled laboratory study. METHODS: Tendon-derived cells were isolated from patients with a chronic rotator cuff tendon tear (large to massive, diseased) and healthy hamstring tendons of patients undergoing anterior cruciate ligament repair. Isolated cells were incubated with TGF-β1 (10 ng/mL) or BMP-2 (100 ng/mL) for 3 days. Gene expression was measured by real-time quantitative polymerase chain reaction. Cell signaling pathway activation was determined by Western blotting. RESULTS: TGF-β1 treatment induced ACAN mRNA expression in both cell types but less in the diseased compared with healthy cells (P < .05). BMP-2 treatment induced BGN mRNA expression in healthy but not diseased cells (P < .01). In the diseased cells, TGF-β1 treatment induced increased ACTA2 mRNA expression (P < .01) and increased small mothers against decapentaplegic (SMAD) signaling (P < .05) compared with those of healthy cells. Moreover, BMP-2 treatment induced ACTA2 mRNA expression in the diseased cells only (P < .05). CONCLUSION: Diseased tendon-derived cells show reduced expression of the proteoglycans aggrecan and biglycan in response to TGF-β1 and BMP-2 treatments. These same treatments induced enhanced fibrotic differentiation and canonical SMAD cell signaling in diseased compared with healthy cells. CLINICAL RELEVANCE: Findings from this study suggest that diseased tendon-derived cells respond differently than healthy cells in the presence of TGF-β1 and BMP-2. The altered responses of diseased cells may influence fibrotic repair processes during tendon healing.
Single cell multi-omics characterise discrete human tendon cells populations that persist in vitro and on fibrous scaffolds.
Chronic tendinopathy represents a growing healthcare burden in the ageing global population. Curative therapies remain elusive as the mechanisms that underlie chronic inflammation in tendon disease remain unclear. Identifying and isolating key pathogenic and reparative cells is essential in developing precision therapies and implantable materials for improved tendon healing. Multiple discrete human tendon cell populations have been previously described ex vivo. To determine if these populations persist in vitro, healthy human hamstring tenocytes were cultured for 8 d on either tissue culture plastic or aligned electrospun fibres of absorbable polydioxanone. Novel single-cell surface proteomics combined with unbiased single-cell transcriptomics (CITE-Seq) was used to identify discrete tenocyte populations. 6 cell populations were found, 4 of which shared key gene expression determinants with ex vivo human cell clusters: PTX3_PAPPA, POSTN_SCX, DCN_LUM and ITGA7_NES. Surface proteomics found that PTX3_PAPPA cells were CD10+CD26+CD54+. ITGA7_NES cells were CD146+ and POSTN_SCX cells were CD90+CD95+CD10+. Culture on the aligned electrospun fibres favoured 3 cell subtypes (DCN_LUM, POSTN_SCX and PTX3_ PAPPA), promoting high expression of tendon-matrix-associated genes and upregulating gene sets enriched for TNF-a and IL-6/STAT3 signalling. Discrete human tendon cell subpopulations persisted in in vitro culture and could be recognised by specific gene and surface-protein signatures. Aligned polydioxanone fibres promoted the survival of 3 clusters, including pro-inflammatory PTX3-expressing CD10+CD26+CD54+ cells found in chronic tendon disease. These results improved the understanding of preferred culture conditions for different tenocyte subpopulations and informed the development of in vitro models of tendon disease.
Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial.
BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. METHODS: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. FINDINGS: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. INTERPRETATION: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. FUNDING: The UK National Institute for Health Research Health Technology Assessment Programme.
Serious adverse event rates and reoperation after arthroscopic shoulder surgery: population based cohort study.
OBJECTIVE: To provide clinicians and patients with accurate risk estimates of serious adverse events after common elective shoulder arthroscopic procedures, including reoperation within one year. DESIGN: Population based cohort study. SETTING: Hospital Episode Statistics for NHS England, including civil registration mortality data from the Office for National Statistics. PARTICIPANTS: 288 250 arthroscopic shoulder procedures performed in 261 248 patients aged ≥16 years between 1 April 2009 and 31 March 2017. Elective procedures were grouped into subacromial decompression, rotator cuff repair, acromioclavicular joint excision, glenohumeral stabilisation, and frozen shoulder release. MAIN OUTCOME MEASURES: The primary outcomes were rates of serious adverse events (mortality, pulmonary embolism, pneumonia, myocardial infarction, acute kidney injury, stroke, and urinary tract infection) requiring inpatient care within 90 days post-surgery. Secondary outcomes were specific adverse event rates at 90 days, and reoperations (including for deep infection) within one year. RESULTS: The overall rate of complications within 90 days after arthroscopic shoulder surgery (including reoperation) was low at 1.2% (95% confidence interval 1.2% to 1.3%), with one in 81 patients at risk, and varied according to type of procedure, from 0.6% (0.5% to 0.8%) for glenohumeral stabilisation to 1.7% (1.5% to 1.8%) for frozen shoulder release. After adjustment for age, comorbidities, and sex, no effect of procedure type was observed. Pneumonia was the most common adverse event (0.3%, 0.3% to 0.4%), with one in 303 patients at risk. Pulmonary embolic events were rare, at 0.1% (0.1% to 0.1%), with one in 1428 patients at risk. At one year, the overall rate for reoperation was 3.8% (3.8% to 3.9%), with one in 26 patients at risk, ranging from 2.7% (2.5% to 3.0%) for glenohumeral stabilisation to 5.7% (5.4% to 6.1%) for frozen shoulder release. The overall rate of further surgery for deep infection was low, at 0.1% (0.1% to 0.1%), with one in 1111 patients at risk, but was higher after rotator cuff repair (0.2%, 0.2% to 0.2%), with one in 526 patients at risk. Over the study period the number of arthroscopic shoulder procedures increased, except for subacromial decompression, which decreased. CONCLUSIONS: The findings of this study suggest that risks of serious adverse events associated with common shoulder arthroscopy procedures are low. Nevertheless, serious complications do occur, and include the risk of reoperation in one in 26 patients within one year. STUDY REGISTRATION: Clinical. TRIALS: gov NCT03573765.
Early development of a polycaprolactone electrospun augment for anterior cruciate ligament reconstruction.
Despite the clinical success of Anterior Cruciate Ligament reconstruction (ACLR) in some patients, unsatisfactory clinical outcomes secondary to graft failure are seen, indicating the need to develop new regeneration strategies. The use of degradable and bioactive textiles has the potential to improve the biological repair of soft tissue. Electrospun (ES) filaments are particularly promising as they have the ability to mimic the structure of natural tissues and influence endogenous cell behaviour. In this study, we produced continuous polycaprolactone (PCL) ES filaments using a previously described electrospinning collection method. These filaments were stretched, twisted, and assembled into woven structures. The morphological, tensile, and biological properties of the woven fabric were then assessed. Scanning electron microscopy (SEM) images highlighted the aligned and ACL-like microfibre structure found in the stretched filaments. The tensile properties indicated that the ES fabric reached suitable strengths for a use as an ACLR augmentation device. Human ACL-derived cell cultured on the fabric showed approximately a 3-fold increase in cell number over 2 weeks and this was equivalent to a collagen coated synthetic suture commonly used in ACLR. Cells generally adopted a more elongated cell morphology on the ES fabric compared to the control suture, aligning themselves in the direction of the microfibres. A NRU assay confirmed that the ES fabric was non-cytotoxic according to regulatory standards. Overall, this study supports the development of ES textiles as augmentation devices for ACLR.
Immunotherapy for atherosclerosis.
Cardiovascular disease is the global #1 cause of mortality and morbidity. The majority of cardiovascular diseases is caused by atherosclerosis, a lipid-driven, inflammatory disease of the middle- and large-sized arteries. The disease is characterized by the formation of atherosclerotic plaques throughout the arterial tree. Over the years, insights into the pathogenesis of atherosclerosis have shifted from a 'lipid-driven' model to a 'response-to-injury' perspective, and more recently to a 'lipid-driven inflammatory disease' viewpoint. We are now aware that a network of multiple immune cell-types and -subsets of the innate and adaptive immune system inhabit our arteries. Intricate interactions between these immune cellsubsets, non-immune cells, and local environmental substances such as lipids, cell debris and calcium cause a fluidic balance of pro-inflammatory and regulatory responses. A dysregulation of this balance towards a pro-inflammatory milieu drives atherosclerotic disease progression. Although we have acknowledged that atherosclerosis is an inflammatory disease, state-of-theart treatments are still based on lipid lowering, anti-hypertensive and lifestyle-changing strategies. In the past decade, clinical phase I, II and III trials targeting the immune system revealed that patients tolerate immunotherapy, show decreased inflammation and/or had a reduction in cardiovascular endpoints. However, the search for novel immunotherapeutic targets and treatment regimens as well as stratification of patients who would benefit from such treatments to combat atherosclerotic cardiovascular disease is only just beginning. In this review article, we will highlight the newest insights on the different cell subsets and components of the immune system in atherosclerosis and elaborate on current and future immunotherapeutics to treat atherosclerotic cardiovascular disease.
Flap reconstruction of pressure ulcers in patients with spinal cord injury: a retrospective cohort study.
STUDY DESIGN: Retrospective case series. OBJECTIVES: To describe our five-year experience of surgical excision and flap reconstruction of pressure ulcers in individuals with spinal cord injury (SCI). SETTING: Tertiary spinal centre in Stoke Mandeville, United Kingdom. METHODS: All spinal injury patients that underwent surgical reconstruction of pressure ulcers at the Stoke Mandeville Hospital National Spinal Injury Centre between 2018 and 2022 inclusive were included. Ulcers underwent 'pseudotumour' excision followed by either immediate or staged flap reconstruction. The primary outcome was complete healing at one year. Secondary outcomes included flap loss, complications, and return to theatre. RESULTS: 52 cases were included across 44 patients. 43 cases (82.7%) underwent immediate debridement and reconstruction. The mean number of procedures was 1.9 (range 1-6). Local flaps were used in 22 (41.5%) cases. There was one (1.9%) free flap (anterolateral thigh), eight (15.4%) pedicled flaps, and 21 (39.6%) flaps based on single perforators. 49 cases completed follow-up; 41 (83.7%) were healed at one year after their initial surgery. Immediate reconstructions were 36.7% more likely to achieve healing at this time point than staged cases (P = .028, Fisher's exact). There was partial or total flap loss in 15 (28.8%) cases. Thirty-nine complications were seen in 24 (46.2%) cases. Twenty-three cases (44.2%) required returns to theatre. CONCLUSIONS: Surgical debridement with flap reconstruction is a safe and reliable treatment approach for pressure ulcers in those with SCI, with a complication rate comparable to existing literature. Immediate flap reconstruction and local flap designs may be associated with a lower risk of complications and higher healing rates.
Outcomes of Flap Reconstruction for Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis of Clinical Studies.
BACKGROUND: People with diabetic foot ulcers (DFUs) are at risk of major amputation, which is associated with a high mortality rate (exceeding 50% at 5 years) and reduced quality of life. The authors hypothesized that flap reconstruction of DFUs improves patient outcomes in comparison with standard treatment modalities, including major amputation. METHODS: MEDLINE, Embase, the Cochrane Library, and gray literature were searched on February 9, 2022. Comparative and single-arm studies reporting outcomes of DFUs treated with local, regional, or free flaps that included function, limb loss, mortality rates, and flap failure rates were included. Risk of bias was assessed, and meta-analysis of proportions was performed. RESULTS: A total of 3878 records were retrieved, of which 45 met the inclusion criteria, including the records of 1681 patients who underwent flap reconstruction of DFUs. Free flaps were most commonly performed ( n = 1257 [72%]). Only one study used a verified functional outcome measure. At 12 months, the mortality rate was 6.35% (95% CI, 3.89% to 10.20%), the limb loss rate was 11.39% (95% CI, 7.02% to 17.96%), and the free flap failure rate was 9.95% (95% CI, 8.19% to 12.05%). All studies were at high risk of bias. A comparative meta-analysis of interventions was not performed because of study method and outcome heterogeneity. CONCLUSIONS: There is short-term evidence that flap reconstruction (including microsurgical transfer) has low mortality, limb loss, and flap failure rates. However, there are limited high-quality comparative studies, and uncertainty remains regarding the outcome of DFU flap reconstruction in comparison to other treatments.
Functional and Immunologic Mapping of Domains of the Reticulocyte-Binding Protein Plasmodium vivax PvRBP2a.
We previously described a novel Plasmodium vivax invasion mechanism into human reticulocytes via the PvRBP2a-CD98 receptor-ligand pair. Using linear epitope mapping, we assessed the PvRBP2a epitopes involved in CD98 binding and recognized by antibodies from patients who were infected. We identified 2 epitope clusters mediating PvRBP2a-CD98 interaction. Cluster B (PvRBP2a431-448, TAALKEKGKLLANLYNKL) was the target of antibody responses in humans infected by P vivax. Peptides from each cluster were able to prevent live parasite invasion of human reticulocytes. These results provide new insights for development of a malaria blood-stage vaccine against P vivax.