Autologous bone marrow derived mesenchymal stem cells are safe for the treatment of Achilles tendinopathy.

Achilles tendinopathy is a disabling condition that affects more than 50% of runners. Pre-clinical studies in a large animal model of naturally-occurring tendinopathy similar to human Achilles tendinopathy has shown benefits of autologous bone marrow-derived mesenchymal stem cell (MSC) implantation. However, MSCs are advanced therapies medicinal products (ATMPs), with strict regulatory requirements. Guided by the regulator we carried out a first in man study to assess the safety and efficacy of autologous MSC injection in human patients with non-insertional Achilles tendinopathy. Ten patients, mean age 47 with mid-portion Achilles tendon pain and swelling for more than 6 months, underwent autologous cultured cell injections (median 12.2 × 106, range 5-19 × 106 cells) into their Achilles tendon. At 24 weeks follow-up, no serious adverse reactions or important medical events were observed. MOXFQ, EQ-5D-5L, and VISA-A scores improved clinically at 12 and 24 weeks. VAS pain improved increasingly at 6, 12 and 24 weeks. MOXFQ Pain and VISA-A Scores improved > 12 points from baseline to 24 weeks in 8 patients. Maximum anteroposterior tendon thickness as measured by greyscale US decreased by mean 0.8 mm at 24 weeks. This phase IIa study demonstrated the safety of autologous MSC injection for non-insertional Achilles tendinopathy and provides proof-of-concept of the technique in patients, all of whom had previously failed conservative treatments for chronic disease and leads the way for a larger randomised controlled trial.

Cost-Utility Analysis of Total Ankle Replacement Compared with Ankle Arthrodesis for Patients Aged 50-85 Years with End-Stage Ankle Osteoarthritis: The TARVA Study.

BACKGROUND: Patients with end-stage ankle osteoarthritis suffer from reduced mobility and quality of life and the main surgical treatments are total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVES: Our aim was to calculate the mean incremental cost per quality-adjusted life-year (QALY) of TAR compared with AF in patients with end-stage ankle osteoarthritis, over 52 weeks and over the patients' lifetime. METHOD: We conducted a cost-utility analysis of 282 participants from 17 UK centres recruited to a randomised controlled trial (TARVA). QALYs were calculated using index values from EQ-5D-5L. Resource use information was collected from case report forms and self-completed questionnaires. Primary analysis was within-trial analysis from the National Health Service (NHS) and Personal Social Services (PSS) perspective, while secondary analyses were within-trial analysis from wider perspective and long-term economic modelling. Adjustments were made for baseline resource use and index values. RESULTS: Total cost at 52 weeks was higher in the TAR group compared with the AF group, from the NHS and PSS perspective (mean adjusted difference £2539, 95% confidence interval [CI] £1142, £3897). The difference became very small from the wider perspective (£155, 95% CI -  £1947, £2331). There was no significant difference between TAR and AF in terms of QALYs (mean adjusted difference 0.02, 95% CI -  0.015, 0.05) at 52 weeks post-operation. The incremental cost-effectiveness ratio (ICER) was £131,999 per QALY gained 52 weeks post-operation. Long-term economic modelling resulted in an ICER of £4200 per QALY gained, and there is a 69% probability of TAR being cost effective at a cost-effectiveness threshold of £20,000 per QALY gained. CONCLUSION: TAR does not appear to be cost effective over AF 52 weeks post-operation. A decision model suggests that TAR can be cost effective over the patients' lifetime but there is a need for longer-term prospectively collected data. Clinical trial registration ISRCTN60672307 and ClinicalTrials.gov NCT02128555.

Two to Five-Year Outcomes of Total Ankle Arthroplasty with the Infinity Fixed-Bearing Implant: A Concise Follow-up of a Previous Report.

LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Survival of revision ankle arthroplasty.

Aims: The number of revision total ankle arthroplasties (TAAs) which are undertaken is increasing. Few studies have reported the survival after this procedure. The primary aim of this study was to analyze the survival of revision ankle arthroplasties using large datasets. Secondary aims were to summarize the demographics of the patients, the indications for revision TAA, further operations, and predictors of survival. Methods: The study combined data from the National Joint Registry and NHS Digital to report the survival of revision TAA. We have previously reported the failure rates and risk factors for failure after TAA, and the outcome of fusion after a failed TAA, using the same methodology. Survival was assessed using life tables and Kaplan Meier graphs. Cox proportional hazards regression models were fitted to compare failure rates. Results: A total of 228 patients underwent revision TAA. The mean follow-up was 2.6 years (SD 2.0). The mean time between the initial procedure and revision was 2.3 years (SD 1.8). The most commonly used implant was the Inbone which was used in 81 patients. A total of 29 (12.7%) failed; nine (3.9%) patients underwent a further revision, 19 (8.3%) underwent a fusion, and one (0.4%) had an amputation. The rate of survival was 95.4% (95% confidence interval (CI) 91.6 to 97.5) at one year, 87.7% (95% CI 81.9 to 91.7; n = 124) at three years and 77.5% (95% CI 66.9 to 85.0; n = 57) at five years. Revision-specific implants had a better survival than when primary implants were used at revision. A total of 50 patients (21.9%) had further surgery; 19 (8.3%) underwent reoperation in the first 12 months. Cox regression models were prepared. In crude analysis the only significant risk factors for failure were the use of cement (hazard ratio (HR) 3.02 (95% CI 1.13 to 8.09)) and the time since the primary procedure (HR 0.67 (95% CI 0.47 to 0.97)). No risk factors for failure were identified in multivariable Cox regression modelling. Conclusion: Revision TAAs have good medium term survival and low rates of further surgery. New modular revision implants appear to have improved the survival compared with the use of traditional primary implants at revision.

Fusion after a failed primary total ankle arthroplasty.

Aims: When a total ankle arthroplasty (TAA) fails, it can be converted to a fusion or a revision arthroplasty. Despite the increasing numbers of TAAs being undertaken, there is little information in the literature about the management of patients undergoing fusion following a failed TAA. The primary aim of this study was to analyze the survival of fusions following a failed TAA using a large dataset from the National Joint Registry (NJR). Methods: A data linkage study combined NJR and NHS Digital data. Failure of a TAA was defined as a fusion, revision to a further TAA, or amputation. Life tables and Kaplan-Meier graphs were used to record survival. Cox proportional hazards regression models were fitted to compare the rates of failure. Results: A total of 131 patients underwent fusion as a salvage procedure following TAA. Their mean age was 65.7 years (SD 10.6) and 73 (55.7%) were male. The mean follow-up was 47.5 months (SD 27.2). The mean time between TAA and fusion was 5.3 years (SD 2.7). Overall, 32 (24.4%) underwent reoperations other than revision and 29 (22.1%) failed. Of these 24 (18.3%) underwent revision of the fusion and five (3.8%) had a below-knee amputation. No patients underwent conversion to a further TAA. Failure usually occurred in the first three postoperative years with one-year survival of fusion being 96.0% (95% confidence interval (CI) 90.7 to 98.3) and three-year survival in 69 patients being 77.5% (95% CI 68.3 to 84.4). Conclusion: Salvage fusion after a failed TAA shows moderate rates of failure and reoperations. Nearly 25% of patients required revision within three years. This study is an extension of studies using the same methodology reporting the failure rates and risk factors for failure, which have recently been published, and also one reporting the outcome of revision TAA for a failed primary TAA, using the same methodology, which will shortly be published.

Outcomes in Ankle Replacement Study (OARS).

Aims: The aim of this study was to capture 12-month outcomes from a representative multicentre cohort of patients undergoing total ankle arthroplasty (TAA), describe the pattern of patient-reported outcome measures (PROMs) at 12 months, and identify predictors of these outcome measures. Methods: Patients listed for a primary TAA at 19 NHS hospitals between February 2016 and October 2017 were eligible. PROMs data were collected preoperatively and at six and 12 months including: Manchester-Oxford Foot and Ankle Questionnaire (MOXFQ (foot and ankle)) and the EuroQol five-dimension five-level questionnaire (EQ-5D-5L). Radiological pre- and postoperative data included Kellgren-Lawrence score and implant position measurement. This was supplemented by data from the National Joint Registry through record linkage to determine: American Society of Anesthesiologists (ASA) grade at index procedure; indication for surgery, index ankle previous fracture; tibial hind foot alignment; additional surgery at the time of TAA; and implant type. Multivariate regression models assessed outcomes, and the relationship between MOXFQ and EQ-5D-5L outcomes, with patient characteristics. Results: Data from 238 patients were analyzed. There were significant improvements in MOXFQ and EQ-5D-5L among people who underwent TAA at six- and 12-month assessments compared with preoperative scores (p < 0.001). Most improvement occurred between preoperative and six months, with little further improvement at 12 months. A greater improvement in MOXFQ outcome postoperatively was associated with older age and more advanced radiological signs of ankle osteoarthritis at baseline. Conclusion: TAA significantly benefits patients with end-stage ankle disease. The lack of substantial further overall change between six and 12 months suggests that capturing PROMs at six months is sufficient to assess the success of the procedure. Older patients and those with advanced radiological disease had the greater gains. These outcome predictors can be used to counsel younger patients and those with earlier ankle disease on the expectations of TAA.

Pembrolizumab-associated chronic rhinosinusitis: A new endotype and management considerations.

KEY POINTS: Patients treated with pembrolizumab experience an increase in paranasal sinus inflammation Use of topical triamcinolone in carboxymethylcellulose is a treatment option for such patients.

Total ankle replacement versus ankle arthrodesis for patients aged 50-85 years with end-stage ankle osteoarthritis: the TARVA RCT.

Background: We aimed to compare the clinical effectiveness, cost-effectiveness and complication rates of total ankle replacement with those of arthrodesis (i.e. ankle fusion) in the treatment of end-stage ankle osteoarthritis. Methods: This was a pragmatic, multicentre, parallel-group, non-blinded randomised controlled trial. Patients with end-stage ankle osteoarthritis who were aged 50-85 years and were suitable for both procedures were recruited from 17 UK hospitals and randomised using minimisation. The primary outcome was the change in the Manchester-Oxford Foot Questionnaire walking/standing domain scores between the preoperative baseline and 52 weeks post surgery. Results: Between March 2015 and January 2019, 303 participants were randomised using a minimisation algorithm: 152 to total ankle replacement and 151 to ankle fusion. At 52 weeks, the mean (standard deviation) Manchester-Oxford Foot Questionnaire walking/standing domain score was 31.4 (30.4) in the total ankle replacement arm (n = 136) and 36.8 (30.6) in the ankle fusion arm (n = 140); the adjusted difference in the change was -5.6 (95% confidence interval -12.5 to 1.4; p = 0.12) in the intention-to-treat analysis. By week 52, one patient in the total ankle replacement arm required revision. Rates of wound-healing issues (13.4% vs. 5.7%) and nerve injuries (4.2% vs. < 1%) were higher and the rate of thromboembolic events was lower (2.9% vs. 4.9%) in the total ankle replacement arm than in the ankle fusion arm. The bone non-union rate (based on plain radiographs) in the ankle fusion arm was 12.1%, but only 7.1% of patients had symptoms. A post hoc analysis of fixed-bearing total ankle replacement showed a statistically significant improvement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score (-11.1, 95% confidence interval -19.3 to -2.9; p = 0.008). We estimate a 69% likelihood that total ankle replacement is cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over the patient's lifetime. Limitations: This initial report contains only 52-week data, which must therefore be interpreted with caution. In addition, the pragmatic nature of the study means that there was heterogeneity between surgical implants and techniques. The trial was run across 17 NHS centres to ensure that decision-making streams reflected the standard of care in the NHS as closely as possible. Conclusions: Both total ankle replacement and ankle fusion improved patients' quality of life at 1 year, and both appear to be safe. When total ankle replacement was compared with ankle fusion overall, we were unable to show a statistically significant difference between the two arms in terms of our primary outcome measure. The total ankle replacement versus ankle arthrodesis (TARVA) trial is inconclusive in terms of superiority of total ankle replacement, as the 95% confidence interval for the adjusted treatment effect includes both a difference of zero and the minimal important difference of 12, but it can rule out the superiority of ankle fusion. A post hoc analysis comparing fixed-bearing total ankle replacement with ankle fusion showed a statistically significant improvement of total ankle replacement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score. Total ankle replacement appears to be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime based on long-term economic modelling. Future work: We recommend long-term follow-up of this important cohort, in particular radiological and clinical progress. We also recommend studies to explore the sensitivity of clinical scores to detect clinically important differences between arms when both have already achieved a significant improvement from baseline. Trial registration: This trial is registered as ISRCTN60672307 and ClinicalTrials.gov NCT02128555. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 5. See the NIHR Journals Library website for further project information.

Each year, over 29,000 patients with ankle osteoarthritis seek a specialist opinion, of whom 4000 undergo NHS surgical treatment. The main surgical treatments for severe ankle osteoarthritis are total ankle replacement or arthrodesis (i.e. ankle fusion). Both are known to be good treatments to relieve pain, and each has its advantages. Total ankle replacement is a more popular patient choice than ankle fusion. When deciding whether to undergo ankle replacement or fusion, patients consult various sources, but the majority of them rely on the advice of their surgeon to make a final decision. To the best of our knowledge, there has never been a high-quality randomised clinical trial comparing these two treatments and there are no published guidelines on the most suitable management. In this study, 303 patients were randomised to a type of ankle surgery: 138 in the total ankle replacement arm and 144 in the ankle fusion arm received surgery. We found that both total ankle replacement and ankle fusion improved patients' walking ability, but we did not find a statistically significant difference between the treatment arms based on our primary outcome measure at 1 year. When we considered the type of total ankle replacement implant, we found that the implant most commonly used in the NHS (a fixed-bearing two-component implant) had better outcomes at 1 year than ankle fusion. Both total ankle replacement and ankle fusion appear to be safe. However, there were more wound-healing issues and nerve injuries in the total ankle replacement arm than in the ankle fusion arm. Twelve per cent of patients experienced bone non-union in the ankle fusion arm, but only 7.1% experienced symptoms. We estimate that there is a 69% chance that total ankle replacement would be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime. This study provides the NHS with important information that could help to obtain the best possible outcome for patients with severe ankle arthritis.

Distance mapping and volumetric assessment of the ankle and syndesmotic joints in progressive collapsing foot deformity.

The early effects of progressive collapsing foot deformity (PCFD) on the ankle and syndesmotic joints have not been three-dimensionally quantified. This case-control study focused on using weight bearing CT (WBCT) distance (DM) and coverage maps (CM) and volumetric measurements as 3D radiological markers to objectively characterize early effects of PCFD on the ankle and syndesmotic joints. Seventeen consecutive patients with symptomatic stage I flexible PCFD and 20 matched controls that underwent foot/ankle WBCT were included. Three-dimensional DM and CM of the ankle and syndesmotic joints, as well volumetric assessment of the distal tibiofibular syndesmosis was performed as possible WBCT markers of early PCFD. Measurements were compared between PCFD and controls. Significant overall reductions in syndesmotic incisura distances were observed in PCFD patients when compared to controls, with no difference in the overall syndesmotic incisura volume at 1, 3, 5 and 10 cm proximally to the ankle joint. CMs showed significantly decreased articular coverage of the anterior regions of the tibiotalar joint as well as medial/lateral ankle joint gutters in PCFD patients. This study showed syndesmotic narrowing and decreased articular coverage of the anterior aspect of the ankle gutters and talar dome in stage I PCFD patients when compared to controls. These findings are consistent with early plantarflexion of the talus within the ankle Mortise, and absence of true syndesmotic overload in early PCFD, and support DM and CM as early 3D PCFD radiological markers.

Total Talus Replacements.

Background: Total talus replacements are a surgical treatment for talar avascular necrosis (AVN) replacing the entire talus. The potential for total talus replacements has increased with the advent of patient-specific implants using 3D printing based on computed tomographic scanning of the ipsilateral or contralateral talus. The primary aim of this review is to summarize the literature on total talus replacements, providing a historical survey, indications, controversies, complications, survival, and functional outcomes. Methods: A systematic review was performed. Articles with survival of total talus replacements were included. Basic percentages and a critical review of the literature was performed. Results: Nine articles with 115 patients were included. The mean age ranged from 27.6 to 72 years, but with 5 studies having a mean age of <50 years. Mean follow-up ranged from 12.8 to 152 months. The most common indication was avascular necrosis in 67 patients (58%). Five studies used customized implants and 4 studies used 3D printing. Four studies used ceramic prostheses, 3 cobalt chromium, 1 stainless steel, and 1 titanium with ceramic surface. Three studies involved a talus replacement in conjunction with an ankle replacement. Postoperative complications ranged from 0% to 33%. Of 24 functional outcomes scores, 66.7% demonstrated significant improvement. Conclusion: Total talus replacements are a promising alternative to tibiotalocalcaneal fusion for patients with avascular necrosis of the talus; however, further studies are required to ensure reliable outcomes prior to widespread adoption of this technology. Level of Evidence: Level IV, review of case series.

How long do ankle arthroplasties last?

Despite the increasing numbers of ankle arthroplasties, there are limited studies on their survival and comparisons between different implants. The primary aim of this study was to determine the failure rates of primary ankle arthroplasties commonly used in the UK. A data linkage study combined National Joint Registry (NJR) data and NHS Digital data. The primary outcome of failure was defined as the removal or exchange of any components of the implanted device. Life tables and Kaplan-Meier survival charts were used to illustrate survivorship. Cox proportional hazards regression models were fitted to compare failure rates between 1 April 2010 and 31 December 2018. Overall, 5,562 primary ankle arthroplasties were recorded in the NJR. Linked data show a one-year survivorship of 98.8% (95% confidence interval (CI) 98.4% to 99.0%), five-year survival in 2,725 patients of 90.2% (95% CI 89.2% to 91.1%), and ten-year survival in 199 patients of 86.2% (95% CI 84.6% to 87.6%). The five-year survival for fixed-bearing implants was 94.3% (95% CI 91.3% to 96.3%) compared to 89.4% (95% CI 88.3% to 90.4%) for mobile-bearing implants. A Cox regression model for all implants with over 100 implantations using the implant with the best survivorship (Infinity) as the reference, only the STAR (hazard ratio (HR) 1.60 (95% CI 0.87 to 2.96)) and INBONE (HR 0.38 (95% CI 0.05 to 2.84)) did not demonstrate worse survival at three and five years. Ankle arthroplasties in the UK have a five-year survival rate of 90.2%, which is lower than recorded on the NJR, because we have shown that approximately one-third of ankle arthroplasty failures are not reported to the NJR. There are statistically significant differences in survival between different implants. Fixed-bearing implants appear to demonstrate higher survivorship than mobile-bearing implants.

IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis.

BACKGROUND: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described. OBJECTIVE: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS. METHODS: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls. RESULTS: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures. CONCLUSIONS: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

RNA Sequencing and Gene Ontology Analysis in Acute Invasive Fungal Sinusitis.

BACKGROUND: Acute invasive fungal sinusitis (AIFS) is an aggressive and dangerous disease of the paranasal sinuses with high morbidity and mortality. The immune response at the level of the nasal mucosa, the site of entry, has not been previously evaluated. OBJECTIVE: To evaluate differential gene expression in the sinonasal mucosa of AIFS patients as compared to control patients using RNA sequencing. METHODS: Sinonasal tissue samples were prospectively obtained from consenting patients undergoing surgery between November, 2020 and November, 2021. RNA extraction and sequencing were performed and differential expression was analyzed to detect transcriptional differences between patient groups. RESULTS: Tissue samples were collected from 4 patients with active AIFS diagnoses, 2 patients with recovered AIFS, 1 patient with a diagnosis of non-invasive fungal ball, and 4 healthy controls. 255 genes were differentially expressed in AIFS patients as compared to control patients. Specific Gene Ontology (GO) biological processes that were identified as differentially expressed in AIFS patients as compared to controls included the following: 1. GO:0007155 (cell adhesion), 2. GO:0030199 (collagen fibril organization) and 3. GO:0001525 (angiogenesis). CONCLUSION: Transcriptional differences were noted between AIFS and control patients in sinonasal tissue samples. Future work is necessary to determine causes of the differential gene expressions between AIFS and control patients, specifically those who are immunosuppressed, or with preexisting non-invasive forms of fungal sinusitis, to guide treatment and prevention strategies.

International Consensus Statement on Obstructive Sleep Apnea.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

Total Ankle Replacement Versus Arthrodesis for End-Stage Ankle Osteoarthritis: A Randomized Controlled Trial.

BACKGROUND: End-stage ankle osteoarthritis causes severe pain and disability. There are no randomized trials comparing the 2 main surgical treatments: total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVE: To determine which treatment is superior in terms of clinical scores and adverse events. DESIGN: A multicenter, parallel-group, open-label randomized trial. (ISRCTN registry number: 60672307). SETTING: 17 National Health Service trusts across the United Kingdom. PATIENTS: Patients with end-stage ankle osteoarthritis, aged 50 to 85 years, and suitable for either procedure. INTERVENTION: Patients were randomly assigned to TAR or AF surgical treatment. MEASUREMENTS: The primary outcome was change in Manchester-Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores between baseline and 52 weeks after surgery. No blinding was possible. RESULTS: Between 6 March 2015 and 10 January 2019, a total of 303 patients were randomly assigned; mean age was 68 years, and 71% were men. Twenty-one patients withdrew before surgery, and 281 clinical scores were analyzed. At 52 weeks, the mean MOXFQ-W/S scores improved for both groups. The adjusted difference in the change in MOXFQ-W/S scores from baseline was -5.6 (95% CI, -12.5 to 1.4), showing that TAR improved more than AF, but the difference was not considered clinically or statistically significant. The number of adverse events was similar between groups (109 vs. 104), but there were more wound healing issues in the TAR group and more thromboembolic events and nonunion in the AF group. The symptomatic nonunion rate for AF was 7%. A post hoc analysis suggested superiority of fixed-bearing TAR over AF (-11.1 [CI, -19.3 to -2.9]). LIMITATION: Only 52-week data; pragmatic design creates heterogeneity of implants and surgical techniques. CONCLUSION: Both TAR and AF improve MOXFQ-W/S and had similar clinical scores and number of harms. Total ankle replacement had greater wound healing complications and nerve injuries, whereas AF had greater thromboembolism and nonunion, with a symptomatic nonunion rate of 7%. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Heath Technology Assessment Programme.

Ca2+ and Mg2+ Influence the Thermodynamics of Peptide-Membrane Interactions.

Accurate quantitative estimates of protein-membrane interactions are critical to studies of membrane proteins. Here, we demonstrate that thermodynamic analyses based on current hydropathy scales do not account for the significant and experimentally determined effects that Ca2+ or Mg2+ have on protein-membrane interactions. We examined distinct modes of interaction (interfacial partitioning and folding and transmembrane insertion) by studying three highly divergent peptides: Bid-BH3 (derived from apoptotic regulator Bid), peripherin-2-derived prph2-CTER, and the cancer-targeting pH-Low-Insertion-Peptide (pHLIP). Fluorescence experiments demonstrate that adding 1-2 mM of divalent cations led to a substantially more favorable bilayer partitioning and insertion, with free energy differences of 5-15 kcal/mol.

The outcomes of revision surgery for a failed ankle arthroplasty : a systematic review and meta-analysis.

AIMS: Revision rates for ankle arthroplasties are higher than hip or knee arthroplasties. When a total ankle arthroplasty (TAA) fails, it can either undergo revision to another ankle replacement, revision of the TAA to ankle arthrodesis (fusion), or amputation. Currently there is a paucity of literature on the outcomes of these revisions. The aim of this meta-analysis is to assess the outcomes of revision TAA with respect to surgery type, functional outcomes, and reoperations. METHODS: A systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Medline, Embase, Cinahl, and Cochrane reviews were searched for relevant papers. Papers analyzing surgical treatment for failed ankle arthroplasties were included. All papers were reviewed by two authors. Overall, 34 papers met the inclusion criteria. A meta-analysis of proportions was performed. RESULTS: Six papers analyzed all-cause reoperations of revision ankle arthroplasties, and 14 papers analyzed failures of conversion of a TAA to fusion. It was found that 26.9% (95% confidence interval (CI) 15.4% to 40.1%) of revision ankle arthroplasties required further surgical intervention and 13.0% (95% CI 4.9% to 23.4%) of conversion to fusions; 14.4% (95% CI 8.4% to 21.4%) of revision ankle arthroplasties failed and 8% (95% CI 4% to 13%) of conversion to fusions failed. CONCLUSION: Revision of primary TAA can be an effective procedure with improved functional outcomes, but has considerable risks of failure and reoperation, especially in those with periprosthetic joint infection. In those who undergo conversion of TAA to fusion, there are high rates of nonunion. Further comparative studies are required to compare both operative techniques.Cite this article: Bone Jt Open 2022;3(7):596-606.

IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function.

Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor-dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.

Patient reported outcome measures in ankle replacement versus ankle arthrodesis - A systematic review.

OBJECTIVES: Compare the functional outcomes of comparative studies of ankle arthrodesis (AA) and total ankle replacements (TAR). DESIGN: Systematic review using PRISMA guidelines. DATA SOURCES: Medline, Cochrane and EMBASE databases in July 2020. ELIGIBILITY CRITERIA: Studies that directly compared TAR and AA which reported patient reported outcomes measures (PROMs) of pain, function and quality of life. DATA EXTRACTION AND SYNTHESIS: Two authors independently reviewed all papers. PROMs were allocated into pain, function or quality of life domains. Two summary statistics were created to allow for analysis of the PROMs. These statistics were the mean difference in post-operative score and the mean difference in the change of score. RESULTS: 1323 papers were assessed of which 20 papers were included. 898 ankle arthrodesis and 1638 ankle replacements were evaluated. The mean follow up was 3.3 years (range 0.5-13.0 years). AA patients had a mean age of 55.7 (range 20-82) and TAR 62.5 (range 21-89). There was major heterogeneity in outcomes used. We were unable to find a significant difference between the reported change in PROMs following TAR and AA. 29.3% of PROMs and their subscores showed TAR had better outcomes, 68.7% showed no significant difference and only 2.0% showed AA to have better outcomes. CONCLUSIONS: The majority of published studies found equality in patient reported outcomes following TAR and AA although the quality of the studies was of low-level evidence. There is an urgent need for randomised controlled studies to definitively answer this important clinical question.