Anti-TNF (adalimumab) injection for the treatment of pain-predominant early-stage frozen shoulder: the Anti-Freaze-Feasibility randomised controlled trial.

OBJECTIVE: The Anti-Freaze-F (AFF) trial assessed the feasibility of conducting a definitive trial to determine whether intra-articular injection of adalimumab can reduce pain and improve function in people with pain-predominant early-stage frozen shoulder. DESIGN: Multicentre, randomised feasibility trial, with embedded qualitative study. SETTING: Four UK National Health Service (NHS) musculoskeletal and related physiotherapy services. PARTICIPANTS: Adults ≥18 years with new episode of shoulder pain attributable to early-stage frozen shoulder. INTERVENTIONS: Participants were randomised (centralised computer generated 1:1 allocation) to either ultrasound-guided intra-articular injection of: (1) adalimumab (160 mg) or (2) placebo (saline (0.9% sodium chloride)). Participants and outcome assessors were blinded to treatment allocation. Second injection of allocated treatment (adalimumab 80 mg) or equivalent placebo was administered 2-3 weeks later. PRIMARY FEASIBILITY OBJECTIVES: (1) Ability to screen and identify participants; (2) willingness of eligible participants to consent and be randomised; (3) practicalities of delivering the intervention; (4) SD of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months. RESULTS: Between 31 May 2022 and 7 February 2023, 156 patients were screened of whom 39 (25%) were eligible. The main reasons for ineligibility were other shoulder disorder (38.5%; n=45/117) or no longer in pain-predominant frozen shoulder (33.3%; n=39/117). Of the 39 eligible patients, nine (23.1%) consented to be randomised (adalimumab n=4; placebo n=5). The main reason patients declined was because they preferred receiving steroid injection (n=13). All participants received treatment as allocated. The mean time from randomisation to first injection was 12.3 (adalimumab) and 7.2 days (placebo). Completion rates for patient-reported and clinician-assessed outcomes were 100%. CONCLUSION: This study demonstrated that current NHS musculoskeletal physiotherapy settings yielded only small numbers of participants, too few to make a trial viable. This was because many patients had passed the early stage of frozen shoulder or had already formulated a preference for treatment. TRIAL REGISTRATION NUMBER: ISRCTN 27075727, EudraCT 2021-03509-23, ClinicalTrials.gov NCT05299242 (REC 21/NE/0214).

Pharmacological interventions for early-stage frozen shoulder: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate the efficacy of pharmacological interventions for treating early-stage, pain predominant, adhesive capsulitis, also known as frozen shoulder. METHODS: We performed a systematic review in accordance with PRSIMA guidelines. Searches were conducted on PUBMED, EMBASE and Cochrane Central Register of Controlled Trials on the 24th of February 2022. Outcomes were shoulder pain, shoulder function and range of movement. Synthesis involved both qualitative analysis for all studies and pairwise meta-analyses followed by a network meta-analysis for randomised controlled trials (RCTs). RESULTS: A total of 3,252 articles were found, of which 31 met inclusion criteria, and 22 of these were RCTs. Intraarticular (IA) injection of corticosteroids (8 RCTS, 340 participants) and IA injection of platelet-rich plasma (PRP) (3 RCTs, 177 participants) showed benefit at 12 weeks compared with physical therapy in terms of shoulder pain and function, while oral non-steroidal anti-inflammatories (NSAIDs) (2 RCTs, 44 participants) and IA injection of hyaluronate (2 RCTs, 42 participants) did not show a benefit. Only IA PRP showed benefit over physical therapy for shoulder range of movement. CONCLUSION: These results shows that IA corticosteroids IA PRP injections are beneficial for early-stage frozen shoulder. These findings should be appraised with care considering the risk of bias, heterogeneity, and inconsistency of the included studies. We believe that research focused on early interventions for frozen shoulder could improve patient outcomes and lead to cost-savings derived from avoiding long-term disability. Further well-designed studies comparing with standardised physical therapy or placebo are required to improve evidence to guide management.

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.

Treatments for early-stage Dupuytren's disease: an evidence-based approach.

Current treatments for Dupuytren's disease are limited to late-stage disease when patients have developed flexion contractures and have impaired hand function. They all have limitations, including the risk of recurrence and complications. The use of treatments for early-stage disease, such as intralesional steroid injections or radiotherapy which lack a clear biological basis or evidence of effectiveness based robust randomized, double blind, placebo-controlled trials, highlights the desire of patients to access treatments before they develop significant flexion contractures. A detailed understanding of the cellular landscape and molecular signalling in nodules of early-stage disease would permit the identification of potential therapeutic targets. This approach led to the identification of tumour necrosis factor (TNF) as a target. A phase 2a clinical trial identified 40 mg in 0.4 mL adalimumab as the most efficacious dose and a subsequent randomized, double blind, placebo-controlled phase 2b trial showed that four intranodular injections at 3-month intervals resulted in decrease in nodule hardness and size on ultrasound scan at 12 months, and both parameters continued to decrease further at 18 months, 9 months after the final injection. This type of approach provides clinicians with a robust evidence base for advising their patients.

Standardising the management of open extremity fractures: a scoping review of national guidelines.

INTRODUCTION: Open extremity fractures can be life-changing events. Clinical guidelines on the management of these injuries aim to standardise the care of patients by presenting evidence-based recommendations. We performed a scoping systematic review to identify all national clinical practice guidelines published to date. MATERIALS AND METHODS: A PRISMA-compliant scoping systematic review was designed to identify all national or federal guidelines for the management of open fractures, with no limitations for language or publication date. EMBASE and MEDLINE database were searched. Article screening and full-text review was performed in a blinded fashion in parallel by two authors. RESULTS: Following elimination of duplicates, 376 individual publications were identified and reviewed. In total, 12 clinical guidelines were identified, authored by groups in the UK, USA, the Netherlands, Finland, and Malawi. Two of these focused exclusively on antibiotic prophylaxis and one on combat-related injuries, with the remaining nine presented wide-scope recommendations with significant content overlap. DISCUSSION: Clinical practice guidelines serve clinicians in providing evidence-based and cost-effective care. We only identified one open fractures guideline developed in a low- or middle-income country, from Malawi. Even though the development of these guidelines can be time and resource intensive, the benefits may outweigh the costs by standardising the care offered to patients in different healthcare settings. International collaboration may be an alternative for adapting guidelines to match local resources and healthcare systems for use across national borders.

Dupuytren's disease: a localised and accessible human fibrotic disorder.

We review the biology of Dupuytren's disease (DD), a common localised fibrotic disorder of the hand. The disease develops through a complex interplay of genetic and environmental factors, and epigenetic signalling. The early-stage disease nodules comprise a complex milieu of stromal and immune cells which interact to promote disease development. Recently, inhibition of tumour necrosis factor (TNF) locally resulted in softening and a decrease in nodule size, potentially controlling disease progression. Unlike fibrotic disorders of the visceral organs, the easy access to tissue in DD patients enables dissection of the cellular landscape and molecular signalling pathways. In addition, the study of DD may have wider benefits in enhancing our understanding of less-accessible fibrotic tissues.

Cost-effectiveness of adalimumab for early-stage Dupuytren's disease : an economic evaluation based on a randomized controlled trial and individual-patient simulation model.

AIMS: To estimate the potential cost-effectiveness of adalimumab compared with standard care alone for the treatment of early-stage Dupuytren's disease (DD) and the value of further research from an NHS perspective. METHODS: We used data from the Repurposing anti-TNF for Dupuytren's disease (RIDD) randomized controlled trial of intranodular adalimumab injections in patients with early-stage progressive DD. RIDD found that intranodular adalimumab injections reduced nodule hardness and size in patients with early-stage DD, indicating the potential to control disease progression. A within-trial cost-utility analysis compared four adalimumab injections with no further treatment against standard care alone, taking a 12-month time horizon and using prospective data on EuroQol five-dimension five-level questionnaire (EQ-5D-5L) and resource use from the RIDD trial. We also developed a patient-level simulation model similar to a Markov model to extrapolate trial outcomes over a lifetime using data from the RIDD trial and a literature review. This also evaluated repeated courses of adalimumab each time the nodule reactivated (every three years) in patients who initially responded. RESULTS: The within-trial economic evaluation found that adalimumab plus standard care cost £503,410 per quality-adjusted life year (QALY) gained versus standard care alone over a 12-month time horizon. The model-based extrapolation suggested that, over a lifetime, repeated courses of adalimumab could cost £14,593 (95% confidence interval £7,534 to £42,698) per QALY gained versus standard care alone. If the NHS was willing to pay £20,000/QALY gained, there is a 77% probability that adalimumab with retreatment is the best value for money. CONCLUSION: Repeated courses of adalimumab are likely to be a cost-effective treatment for progressive early-stage DD. The value of perfect parameter information that would eliminate all uncertainty around the parameters estimated in RIDD and the duration of quiescence was estimated to be £105 per patient or £272 million for all 2,584,411 prevalent cases in the UK. Cite this article: Bone Jt Open 2022;3(11):898-906.

Anti-tumour necrosis factor therapy for early-stage Dupuytren's disease (RIDD): a phase 2b, randomised, double-blind, placebo-controlled trial.

Background: Dupuytren's disease is a common fibrotic condition that causes the fingers to flex irreversibly into the palm. Treatments for late-stage disease all have limitations, and there is no approved treatment for early-stage disease. We identified tumour necrosis factor as a therapeutic target in Dupuytren's disease, and in a dose ranging trial found 40 mg adalimumab in 0·4 mL to be most efficacious. Here we aimed to assess the effects of intranodular injection of adalimumab in early-stage disease. Methods: In this phase 2b, randomised, double-blind, placebo-controlled trial adults with early-stage Dupuytren's disease and an established clinically distinct nodule with a clear history of progression in the preceding 6 months were recruited from two clinical centres in the UK and were randomly assigned 1:1 to receive four injections of adalimumab or saline every 3 months. Participants and assessors were masked. The primary outcome was nodule hardness measured with a durometer at 12 months. Data were analysed by linear mixed effects regression models in the intention-to-treat population with multiple imputation for missing primary outcome data. The trial is registered at the ISRCTN registry, ISRCTN 27786905 and is complete. Findings: Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were enrolled. 47 (34%) participants were female and 93 (66%) were male. Mean age of participants was 59·7 years (SD 10·0). Primary outcome data were available from 113 participants. Nodule hardness was lower (-4·6 AU [95% CI -7·1 to -2·2], p=0·0002) in the adalimumab compared with the saline group at 12 months. There were no related serious adverse events; the most common adverse events were minor injection site reactions. Interpretation: Intranodular injections of adalimumab in participants with early-stage Dupuytren's disease resulted in softening and reduction in size of the nodules. Longer follow-up would be required to assess the effect of tumour necrosis factor inhibition on disease progression, extension deficit and hand function.

Timing of antibiotic administration, wound debridement, and the stages of reconstructive surgery for open long bone fractures of the upper and lower limbs.

BACKGROUND: Open fractures of the major long bones are complex limb-threatening injuries that are predisposed to deep infection. Treatment includes antibiotics and surgery to debride the wound, stabilise the fracture and reconstruct any soft tissue defect to enable infection-free bone repair. There is a need to assess the effect of timing and duration of antibiotic administration and timing and staging of surgical interventions to optimise outcomes. OBJECTIVES: To assess the effects (risks and benefits) of the timing of antibiotic administration, wound debridement and the stages of surgical interventions in managing people with open long bone fractures of the upper and lower limbs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trial registers in February 2021. We also searched conference proceedings and reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs that recruited adults with open fractures of the major long bones, comparing: 1) timings of prophylactic antibiotic treatment, 2) duration of prophylactic antibiotic treatment, 3) timing of wound debridement following injury or 4) timing of the stages of reconstructive surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We aimed to collect data for the following outcomes: limb function, health-related quality of life (HRQoL), deep surgical site infection, delayed or non-union, adverse events (in the short- and long-term course of recovery), and resource-related outcomes. MAIN RESULTS: We included three RCTs of 613 randomised participants with 617 open fractures. Studies were conducted in medical and trauma centres in the USA and Kenya. Where reported, there was a higher proportion of men and a mean age of participants between 30 and 34 years old. Fractures were in the upper and lower limbs in one study, and were tibia fractures in two studies; where reported, these were the result of high-energy trauma such as road traffic accidents. No studies compared the timing of antibiotic treatment or wound debridement. Duration of prophylactic antibiotic treatment (1 study, 77 participants available for analysis) One study compared antibiotic treatment for 24 hours with antibiotic treatment for five days. We are very uncertain about the effects of different durations of antibiotic treatment on superficial infections (risk ratio (RR) 1.19, 95% CI 0.49 to 2.87, favours 5 day treatment; 1 study, 77 participants); this was very low-certainty evidence derived from one small study with unclear and high risks of bias, and with an imprecise effect estimate. This study reported no other review outcomes. Reconstructive surgery: timing of the stages of surgery (2 studies, 458 participants available for analysis) Two studies compared the timing of wound closure, which was completed immediately or delayed. In one study, the mean time of delay was 5.9 days; in the other study, the time of delay was not reported. We are very uncertain about the effects of different timings of wound closure on deep infections (RR 0.82, 95% CI 0.37 to 1.80, favours immediate closure; 2 studies, 458 participants), delayed union or non-union (RR 1.13, 95% CI 0.83 to 1.55, favours delayed closure; 1 study, 387 participants), or superficial infections (RR 6.45, 95% CI 0.35 to 120.43, favours delayed closure; 1 study, 71 participants); this was very low-certainty evidence. We downgraded the certainty of the evidence for very serious risks of bias because both studies had unclear and high risks of bias. We also downgraded for serious imprecision because effect estimates were imprecise, including the possibility of benefits as well as harms, and very serious imprecision when the data were derived from single small study. These studies reported no other review outcomes. AUTHORS' CONCLUSIONS: We could not determine the risks and benefits of different treatment protocols for open long bone fractures because the evidence was very uncertain for the two comparisons and we did not find any studies addressing the other possible comparisons. Well-designed randomised trials with adequate power are needed to guide surgical and antibiotic treatment of open fractures, particularly with regard to timing and duration of antibiotic administration and timing and staging of surgery.

A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

Anti-TNF (adalimumab) injection for the treatment of adults with frozen shoulder during the pain predominant stage protocol for a multi-centre, randomised, double blind, parallel group, feasibility trial.

Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months (i.e. 12 weeks) post-randomisation in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. Research Ethics Committee approval (REC 21/NE/0214). Trial registration number: ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.

Frozen shoulder is a common condition affecting approximately 9% of people aged 25­64 years. During the early phase the pain is usually unbearable and the later restriction in movement is severely limiting. It occurs when the flexible tissue (capsule) that surrounds the shoulder joint becomes inflamed, thickened and tight. It's not fully understood why this happens but it is more common in people with diabetes or Dupuytren's disease, which causes the fingers to curl into the palm. It can also occur following shoulder injury or surgery. The pain can be very severe and lasts 3­9 months, followed by a 4­12 month period of increasing stiffness, after which the condition usually improves. Frozen shoulder often affects a person's ability to sleep, carry out everyday activities, and work. Current treatments include rest, painkillers, anti-inflammatories, physiotherapy and steroid injections. If stiffness persists, surgery is sometimes recommended. However, there is no evidence that any of these treatments lead to significant benefit in the long term, with many being ineffective. Steroid injections only help in the short term. Adalimumab has been used very successfully to treat other inflammatory diseases such as rheumatoid arthritis. More recently, adalimumab has also been used to treat Dupuytren's disease, where we found it helps to stop the cells causing the disease and softening and shrinking the diseased diseased tissue. The biological processes underlying frozen shoulder are similar to those in Dupuytren's disease. The aim of this study is to find out if it is possible to run a larger trial to test whether an injection of adalimumab can reduce pain and prevent the disease from getting worse, if given during the early painful phase of frozen shoulder. We need to conduct this smaller study first to be sure it's possible to identify and treat people with early-stage frozen shoulder within the current NHS system, before we conduct a much larger trial to find out if this treatment works. In this study we will include 84 adults with painful early stage frozen shoulder who have not yet received treatment. People will be randomised to receive either an injection of the drug adalimumab or a dummy injection of saline (placebo) directly into the shoulder joint, both guided by ultrasound. All participants will also receive standardized advice on how to manage their shoulder pain. We will assess participants before treatment and three months later.

Collagen VI as a driver and disease biomarker in human fibrosis.

Fibrosis of visceral organs such as the lungs, heart, kidneys and liver remains a major cause of morbidity and mortality and is also associated with many other disorders, including cancer and metabolic disease. In this review, we focus upon the microfibrillar collagen VI, which is present in the extracellular matrix (ECM) of most tissues. However, expression is elevated in numerous fibrotic conditions, such as idiopathic pulmonary disease (IPF), and chronic liver and kidney diseases. Collagen VI is composed of three subunits α1, α2 and α3, which can be replaced with alternate chains of α4, α5 or α6. The C-terminal globular domain (C5) of collagen VI α3 can be proteolytically cleaved to form a biologically active fragment termed endotrophin, which has been shown to actively drive fibrosis, inflammation and insulin resistance. Tissue biopsies have long been considered the gold standard for diagnosis and monitoring of progression of fibrotic disease. The identification of neoantigens from enzymatically processed collagen chains have revolutionised the biomarker field, allowing rapid diagnosis and evaluation of prognosis of numerous fibrotic conditions, as well as providing valuable clinical trial endpoint determinants. Collagen VI chain fragments such as endotrophin (PRO-C6), C6M and C6Mα3 are emerging as important biomarkers for fibrotic conditions.

Alternative physical treatments for deep venous thrombosis prophylaxis in surgical patients: a systematic review.

INTRODUCTION: Venous thromboembolism (VTE) represents a major cause of morbidity and mortality. A variety of novel physical therapies have been proposed for patients in whom standard prophylaxis, including early mobilisation, is contraindicated. This article presents a systematic literature review of alternative physical treatments for VTE prophylaxis, focusing on surgical and trauma patients. METHODS: Following protocol registration in PROSPERO, a systematic review was conducted in accordance with PRISMA. MEDLINE and EMBASE databases were searched for all studies indexed before 27th of July 2019. Two authors independently screened these articles. Data gathering for eligible articles was also undertaken in parallel by two authors. A formal risk of bias assessment was conducted for each study along with an assessment on the quality of the evidence using the GRADE framework. RESULTS: A total of 272 abstracts were identified. After exclusion of duplicates and non-eligible articles, 10 publications were reviewed in detail. Two studies involving electrostimulation, another using a portable intermittent compression device and one study using postoperative calf massage reported a statistically significant reduction in the incidence of deep venous thrombosis when used in conjunction with LMWH. The remaining six articles did not show any significant benefits. DISCUSSION: All studies reporting significant benefits have methodological flaws, with a high risk of bias. The evidence base informing alternative physical treatments as prophylactic measures in VTE is limited. Our data suggest that the use of these physical modalities can be beneficial in patients who also received LMWH, whilst these alone are of no benefit. LEVEL OF EVIDENCE: II - Systematic Review Systematic Review Registration Number PROSPERO CRD42019133684.

Accuracy of infrared thermography for perforator mapping: A systematic review and meta-analysis of diagnostic studies.

INTRODUCTION: Infrared thermography allows the detection of infrared radiation which can be reliably associated with skin temperature. Modern portable thermography devices have been used to identify the location of skin perforators by detecting subtle differences in skin temperature. The aim of this study is to conduct a diagnostic accuracy systematic review to determine the specificity and sensitivity of infrared thermography. MATERIALS AND METHODS: A PRISMA-compliant systematic review and meta-analysis was conducted, scrutinising PUBMED and EMBASE databases for diagnostic studies measuring the accuracy of infrared thermography for perforator identification. Article screening, review and data gathering was conducted in parallel by two independent authors. Eligible studies were subject to a formal risk of bias was assessment using the QUADAS2 instrument. RESULTS: A total of 254 entries were obtained, of which 7 satisfied our pre-established inclusion criteria. These studies reported a total of 435 perforators in 133 individuals. The most commonly investigated locations were the antero-lateral thigh and abdominal wall. Reported sensitivity values ranged from 73.7% to 100%. A meta-analysis demonstrated a cumulative sensitivity of 95%. Specificity was not routinely reported. All studies presented a moderate to high risk of bias according to QUADAS2. DISCUSSION: Affordable infrared thermography devices are an interesting alternative to traditional preoperative investigations for perforator mapping. They are sensitive enough to reliably identify a large proportion of perforators as "hot-spots". However, there is limited evidence to estimate the specificity of this technology, as studies have failed to report true negative values associated with "cold-spots".

Negative-pressure wound therapy compared with standard dressings following surgical treatment of major trauma to the lower limb: the WHiST RCT.

BACKGROUND: Major trauma is the leading cause of death in people aged < 45 years. Patients with major trauma usually have lower-limb fractures. Surgery to fix the fractures is complicated and the risk of infection may be as high as 27%. The type of dressing applied after surgery could potentially reduce the risk of infection. OBJECTIVES: To assess the deep surgical site infection rate, disability, quality of life, patient assessment of the surgical scar and resource use in patients with surgical incisions associated with fractures following major trauma to the lower limbs treated with incisional negative-pressure wound therapy versus standard dressings. DESIGN: A pragmatic, multicentre, randomised controlled trial. SETTING: Twenty-four specialist trauma hospitals representing the UK Major Trauma Network. PARTICIPANTS: A total of 1548 adult patients were randomised from September 2016 to April 2018. Exclusion criteria included presentation > 72 hours after injury and inability to complete questionnaires. INTERVENTIONS: Incisional negative-pressure wound therapy (n = 785), in which a non-adherent absorbent dressing covered with a semipermeable membrane is connected to a pump to create a partial vacuum over the wound, versus standard dressings not involving negative pressure (n = 763). Trial participants and the treating surgeon could not be blinded to treatment allocation. MAIN OUTCOME MEASURES: Deep surgical site infection at 30 days was the primary outcome measure. Secondary outcomes were deep infection at 90 days, the results of the Disability Rating Index, health-related quality of life, the results of the Patient and Observer Scar Assessment Scale and resource use collected at 3 and 6 months post surgery. RESULTS: A total of 98% of participants provided primary outcome data. There was no evidence of a difference in the rate of deep surgical site infection at 30 days. The infection rate was 6.7% (50/749) in the standard dressing group and 5.8% (45/770) in the incisional negative-pressure wound therapy group (intention-to-treat odds ratio 0.87; 95% confidence interval 0.57 to 1.33; p = 0.52). There was no difference in the deep surgical site infection rate at 90 days: 13.2% in the standard dressing group and 11.4% in the incisional negative-pressure wound therapy group (odds ratio 0.84, 95% confidence interval 0.59 to 1.19; p = 0.32). There was no difference between the two groups in disability, quality of life or scar appearance at 3 or 6 months. Incisional negative-pressure wound therapy did not reduce the cost of treatment and was associated with a low probability of cost-effectiveness. LIMITATIONS: Owing to the emergency nature of the surgery, we anticipated that some patients who were randomised would subsequently be unable or unwilling to participate. However, the majority of the patients (85%) agreed to participate. Therefore, participants were representative of the population with lower-limb fractures associated with major trauma. CONCLUSIONS: The findings of this study do not support the use of negative-pressure wound therapy in patients having surgery for major trauma to the lower limbs. FUTURE WORK: Our work suggests that the use of incisional negative-pressure wound therapy dressings in other at-risk surgical wounds requires further investigation. Future research may also investigate different approaches to reduce postoperative infections, for example the use of topical antibiotic preparations in surgical wounds and the role of orthopaedic implants with antimicrobial coatings when fixing the associated fracture. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12702354 and UK Clinical Research Network Portfolio ID20416. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 38. See the NIHR Journals Library for further project information.

WHAT DID THE TRIAL FIND?: We found no evidence of a difference in the rate of surgical site infection between those patients randomised to negative-pressure wound therapy and those patients randomised to standard wound dressings. There was no difference in the rate of other wound healing complications or in the patients' self-report of disability, health-related quality of life or scar healing. Negative-pressure wound therapy is very unlikely to be cost-effective for the NHS. In conclusion, and contrary to previous reports, the findings of this study do not support the use of negative-pressure wound therapy in patients having surgery for major trauma to their legs.

Major trauma is the leading cause of death worldwide in people aged < 45 years and a significant cause of short- and long-term health problems. In 85% of major trauma patients, the injury involves broken bones. Surgery to fix broken bones in the lower limbs is complicated and has risks, one of the main ones being wound infection. In these patients, rates of wound infection have been reported to be as high as 27%. One factor that may affect the risk of infection is the type of dressing applied after surgery. In this trial, we compared standard wound dressings with a new treatment called incisional negative-pressure wound therapy. Negative-pressure wound therapy is a special type of dressing whereby gentle suction is applied to the surface of the wound. A total of 1548 patients from 24 specialist trauma hospitals in the UK agreed to take part and were assigned at random to receive either a standard wound dressing or negative-pressure wound therapy after their surgery. We reviewed the recovery of the patients for 6 months. We recorded how many had an infection in the surgical wound and asked the patients to rate the extent of their disability, their quality of life and the scar healing. We also collected information about the cost of treatment.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300.

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.