Development and validation of a gene expression test to identify hard-to-heal chronic venous leg ulcers

Background: Chronic venous leg ulcers pose a significant burden to healthcare systems, and predicting wound healing is challenging. The aim of this study was to develop a genetic test to evaluate the propensity of a chronic ulcer to heal. Methods: Sequential refinement and testing of a gene expression signature was conducted using three distinct cohorts of human wound tissue. The expression of candidate genes was screened using a cohort of acute and chronic wound tissue and normal skin with quantitative transcript analysis. Genes showing significant expression differences were combined and examined, using receiver operating characteristic (ROC) curve analysis, in a controlled prospective study of patients with venous leg ulcers. A refined gene signature was evaluated using a prospective, blinded study of consecutive patients with venous ulcers. Results: The initial gene signature, comprising 25 genes, could identify the outcome (healing versus non‐healing) of chronic venous leg ulcers (area under the curve (AUC) 0·84, 95 per cent c.i. 0·73 to 0·94). Subsequent refinement resulted in a final 14‐gene signature (WD14), which performed equally well (AUC 0·88, 0·80 to 0·97). When examined in a prospective blinded study, the WD14 signature could also identify wounds likely to demonstrate signs of healing (AUC 0·73, 0·62 to 0·84). Conclusion: A gene signature can identify people with chronic venous leg ulcers that are unlikely to heal

Development of core outcome sets for people undergoing major lower limb amputation for complications of peripheral vascular disease

Objective Every year, thousands of patients with peripheral vascular disease undergo major lower limb amputation. Despite this, evidence for optimal management is weak. Core outcome sets capture consensus on the most important outcomes for a patient group to improve the consistency and quality of research. The aim was to define short and medium term core outcome sets for studies involving patients undergoing major lower limb amputation. Methods A systematic review of the literature and focus groups involving patients, carers, and healthcare professionals were used to derive a list of potential outcomes. Findings informed a three round online Delphi consensus process, where outcomes were rated for both short and medium term studies. The results of the Delphi process were discussed at a face to face consensus meeting, and recommendations were made for each core outcome set. Results A systematic review revealed 45 themes to cazrry forward to the consensus survey. These were supplemented by a further five from focus groups. The consensus survey received responses from 123 participants in round one, and 91 individuals completed all three rounds. In the final round, nine outcomes were rated as “core” for short term studies and a further nine for medium term studies. Wound infection and healing were rated as “core” for both short and medium term studies. Outcomes related to mortality, quality of life, communication, and additional healthcare needs were also rated as “core” for short term studies. In medium term studies, outcomes related to quality of life, mobility, and social integration/independence were rated as “core”. The face to face stakeholder meeting ratified inclusion of all outcomes from the Delphi and suggested that deterioration of the other leg and psychological morbidity should also be reported for both short and medium term studies. Conclusion Consensus was established on 11 core outcomes for short and medium term studies. It is recommended that all future studies involving patients undergoing major lower limb amputation should report these outcomes

Determination of caspase-3 activation fails to predict chemosensitivity in primary acute myeloid leukemia blasts

BACKGROUND: Ex-vivo chemosensitivity tests that measure cell death induction may predict treatment outcome and, therefore, represent a powerful instrument for clinical decision making in cancer therapy. Such tests are, however, work intensive and, in the case of the DiSC-assay, require at least four days. Induction of apoptosis is the mode of action of anticancer drugs and should, therefore, result in the induction of caspase activation in cells targeted by anticancer therapy. METHODS: To determine, whether caspase activation can predict the chemosensitivity, we investigated enzyme activation of caspase-3, a key executioner caspase and correlated these data with chemosensitivity profiles of acute myeloid leukemia (AML) blasts. RESULTS: There was, however, no correlation between the ex-vivo chemosensitivity assessed by measuring the overall rates of cell death by use of the DiSC-assay and caspase-3 activation. CONCLUSION: Thus, despite a significant reduction of duration of the assay from four to one day, induction of apoptosis evaluated by capase-3 activity does not seem to be a valid surrogate marker for chemosensitivity

Single versus dual antiplatelet therapy following peripheral arterial endovascular intervention for chronic limb threatening ischaemia:retrospective cohort study

ObjectivesAntiplatelet therapy following peripheral arterial endovascular intervention lacks high quality evidence to guide practice. The aim of this study was to assess the effect of three months of dual antiplatelet therapy on amputation-free survival following peripheral arterial endovascular intervention in patients with chronic limb threatening ischemia.MethodsA retrospective review of symptomatic patients undergoing primary peripheral arterial endovascular intervention over a seven-year period was performed. The primary outcome measure was amputation-free survival. A sample size calculation based on previous cohort studies suggested that 629 limbs would be required to show a difference between single and dual therapy. Kaplan-Meier estimates and multivariate logistic regression analysis of recorded baseline characteristics was performed to determine predictors of amputation-free survival. Dual antiplatelet therapy was routinely given for 3 months.Results754 limbs were treated with primary angioplasty and/or stenting over a 7-year period, 508 of these for chronic limb threatening ischemia. There was no difference in unadjusted amputation-free survival between patients with chronic limb threatening ischaemia taking single vs. dual antiplatelet therapy (69% vs. 74% respectively Log rank Chi2 = 0.1, p = .72). After adjusting for confounders, at 1 year there was also no significant difference in amputation-free survival between patients taking single vs. dual antiplatelet therapy [OR 0.8, 95% CI 0.5-1.2, p = .3]. There was no difference in rates of major bleeding between single and dual antiplatelet therapy.ConclusionsThere was no clear evidence of reduced amputation-free survival in patients with chronic limb threatening ischemia undergoing peripheral arterial endovascular intervention being treated with dual antiplatelet therapy for 3 months. This is at odds with other retrospective case series and highlights the limitations in basing clinical practice on such data. There is a need for an adequately powered, independent randomised trial to definitively answer the question

Exploring patients’ experiences of analgesia after major lower limb amputation: A qualitative study

OBJECTIVES: To explore patient experiences, understanding and perceptions of analgesia following major lower limb amputation. DESIGN: Qualitative interview study, conducted as part of a randomised controlled feasibility trial. SETTING: Participants were recruited from two general hospitals in South Wales. PARTICIPANTS: Interview participants were patients enrolled in PLACEMENT (Perineural Local Anaesthetic Catheter aftEr Major lowEr limb amputatioN Trial): a randomised controlled feasibility trial comparing the use of perineural catheter (PNC) versus standard care for postoperative pain relief following major lower limb amputation. PLACEMENT participants who completed 5-day postoperative follow-up, were able and willing to participate in a face-to-face interview, and had consented to be contacted, were eligible to take part in the qualitative study. A total of 20 interviews were conducted with 14 participants: 10 male and 4 female. METHODS: Semi-structured, face-to-face interviews were conducted with participants over two time points: (1) up to 1 month and (2) at least 6 months following amputation. Interviews were audio-recorded, transcribed verbatim and analysed using a framework approach. RESULTS: Interviews revealed unanticipated benefits of PNC usage for postoperative pain relief. Participants valued the localised and continuous nature of this mode of analgesia in comparison to opioids. Concerns about opioid dependence and side effects of pain relief medication were raised by participants in both treatment groups, with some reporting trying to limit their intake of analgesics. CONCLUSIONS: Findings suggest routine placement of a PNC following major lower limb amputation could reduce postoperative pain, particularly for patient groups at risk of postoperative delirium. This method of analgesic delivery also has the potential to reduce preoperative anxiety, alleviate the burden of pain management and minimise opioid use. Future research could further examine the comparison between patient-controlled analgesia and continuous analgesia in relation to patient anxiety and satisfaction with pain management. TRIAL REGISTRATION NUMBER: ISRCTN: 85710690; EudraCT: 2016-003544-37

Angiosome specific revascularisation: does the evidence support it?

Objective To explain the angiosome concept and explore the practical application of the angiosome literature to a clinical scenario, in this case a tibial angioplasty for critical ischaemia. Methods Clinical vignette with explanation of the decisions made and subsequent clinical results based on the theory of the angiosome concept and the literature on angiosomal revascularisation; in this case the results of our group’s recent update to a systematic review and meta-analysis. Results Endovascular combined or direct angiosomal revascularisation if superior to indirect revascularisation. This was borne out in the clinical scenario, where an indirect peroneal reperfusion of the AT angiosome resulted in major amputation. Open surgery is less dependent on the angiosome concept. The presence of adequate collateralisation into a foot arch seems to be the most important factor predicting success of indirect revascularisation. The evidence for both suffers from selection bias and many of the findings in the literature are wholly due to selection bias. Conclusion The angiosome concept is useful during both open and endovascular tibial revascularisation. However, the runoff in the foot is critical to success and may not follow the ‘classic’ angiosome model in diabetes

CASPER plus (CollAborative care in Screen-Positive EldeRs with major depressive disorder): study protocol for a randomised controlled trial

Background: Depression accounts for the greatest disease burden of all mental health disorders, contributes heavily to healthcare costs, and by 2020 is set to become the second largest cause of global disability. Although 10% to 16% of people aged 65 years and over are likely to experience depressive symptoms, the condition is under-diagnosed and often inadequately treated in primary care. Later-life depression is associated with chronic illness and disability, cognitive impairment and social isolation. With a progressively ageing population it becomes increasingly important to refine strategies to identity and manage depression in older people. Currently, management may be limited to the prescription of antidepressants where there may be poor concordance; older people may lack awareness of psychosocial interventions and general practitioners may neglect to offer this treatment option. Methods/design: CASPER Plus is a multi-centre, randomised controlled trial of a collaborative care intervention for individuals aged 65 years and over experiencing moderate to severe depression. Selected practices in the North of England identify potentially eligible patients and invite them to participate in the study. A diagnostic interview is carried out and participants with major depressive disorder are randomised to either collaborative care or usual care. The recruitment target is 450 participants. The intervention, behavioural activation and medication management in a collaborative care framework, has been adapted to meet the complex needs of older people. It is delivered over eight to 10 weekly sessions by a case manager liaising with general practitioners. The trial aims to evaluate the clinical and cost effectiveness of collaborative care in addition to usual GP care versus usual GP care alone. The primary clinical outcome, depression severity, will be measured with the Patient Health Questionnaire-9 (PHQ-9) at baseline, 4, 12 and 18 months. Cost effectiveness analysis will assess health-related quality of life using the SF-12 and EQ-5D and will examine cost-consequences of collaborative care. A qualitative process evaluation will be undertaken to explore acceptability, gauge the extent to which the intervention is implemented and to explore sustainability beyond the clinical trial. Discussion: Results will add to existing evidence and a positive outcome may lead to the commissioning of this model of service in primary care. Trial registration: ISRCTN45842879 (24 July 2012)

The CLEAR (Considering Leading Experts’ Antithrombotic Regimes around peripheral angioplasty) survey:an international perspective on antiplatelet and anticoagulant practice for peripheral arterial endovascular intervention

BACKGROUND: Antiplatelet and anticoagulant therapy are commonly used before, during and after peripheral arterial endovascular intervention. This survey aimed to establish antiplatelet and anticoagulant choice for peripheral arterial endovascular intervention in contemporary clinical practice. METHODS: Pilot-tested questionnaire distributed via collaborative research networks. RESULTS: One hundred and sixty-two complete responses were collected from responders in 22 countries, predominantly the UK (48%) and the rest of the European Union (44%). Antiplatelet monotherapy was the most common choice pre-procedurally (62%). In the UK, there was no difference between dual and single antiplatelet therapy use post procedure (50% vs. 37% p = 0.107). However, a significant majority of EU respondents used dual therapy (68% vs. 20% p < 0.001). There was variation in choice of antiplatelet therapy by the device used and the anatomical location of the intervention artery. The majority (82%) of respondents believed there was insufficient evidence to guide antithrombotic therapy after peripheral endovascular intervention and most (92%) would support a randomised trial. CONCLUSIONS: There is widespread variation in the use of antiplatelet therapy, especially post peripheral arterial endovascular intervention. Clinicians would support the development of a randomised trial comparing dual antiplatelet therapy with monotherapy