Consensus statement on the interhospital transfer of patients with acute aortic syndrome: TRAVERSING Delphi study.

BACKGROUND: Standardisation of referral pathways and the transfer of patients with acute aortic syndromes (AAS) to regional centres are recommended by NHS England in the Acute Aortic Dissection Toolkit. The aim of the Transfer of Thoracic Aortic Vascular Emergencies to Regional Specialist INstitutes Group study was to establish an interdisciplinary consensus on the interhospital transfer of patients with AAS to specialist high-volume aortic centres. METHODS: Consensus on the key aspects of interhospital transfer of patients with AAS was established using the Delphi method, in line with Conducting and Reporting of Delphi Studies guidelines. A national patient charity for aortic dissection was involved in the design of the Delphi study. Vascular and cardiothoracic surgeons, emergency physicians, interventional radiologists, cardiologists, intensivists and anaesthetists in the United Kingdom were invited to participate via their respective professional societies. RESULTS: Three consecutive rounds of an electronic Delphi survey were completed by 212, 101 and 58 respondents, respectively. Using predefined consensus criteria, 60 out of 117 (51%) statements from the survey were included in the consensus statement. The study concluded that patients can be taken directly to a specialist aortic centre if they have typical symptoms of AAS on the background of known aortic disease or previous aortic intervention. Accepted patients should be transferred in a category 2 ambulance (response time <18 min), ideally accompanied by transfer-trained personnel or Adult Critical Care Transfer Services. A clear plan should be agreed in case of a cardiac arrest occurring during the transfer. Patients should reach the aortic centre within 4 hours of the initial referral from their local hospital. CONCLUSIONS: This consensus statement is the first set of national interdisciplinary recommendations on the interhospital transfer of patients with AAS. Its implementation is likely to contribute to safer and more standardised emergency referral pathways to regional high-volume specialist aortic units.

A systematic review of outcome reporting for interventions to treat people with diabetic foot ulceration.

BACKGROUND: Diabetic foot ulceration (DFU) is a challenging clinical problem that affects up to a quarter of patients with diabetes in their lifetime. An agreed set of outcomes for assessing treatments or interventions for DFU has not previously been considered. The aim of this study was to identify outcomes that are reported in clinical studies assessing a treatment or intervention for DFU, to inform the development of a core outcome set (COS). METHODS: Systematic literature searches were performed between January 2016 and March 2019. The search strategy was pre-registered with PROSPERO (CRD42019128250). Two authors independently screened abstracts for full text review. Outcomes were extracted from selected papers verbatim and categorized into domains according to established taxonomy. Consistency of outcome reporting was assessed. Overlapping outcomes were merged independently to condense the extracted list of outcomes for use in forthcoming consensus processes. RESULTS: Of 4645 abstracts identified, 114 studies met the inclusion criteria. There were 69 randomized studies, 40 prospective studies and 5 protocols. Some 948 outcomes were extracted verbatim. Outcome reporting was consistent for 474 (53%) outcomes. De-duplication left 714 unique verbatim outcomes across 33 domains. Merging of overlapping unique verbatim outcomes established 95 merged outcomes. CONCLUSION: This study describes contemporary outcomes reported in studies assessing interventions for DFU. Outcome reporting is considered to be poor as it was consistent in just over half of outcomes extracted. Merging of outcomes has identified 95 outcomes that can be taken forward in the development of a COS.

Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds.

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150-500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

Increased levels of symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease.

OBJECTIVE: Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD). METHODS: In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry. RESULTS: The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] µmol/L vs 0.46 [IQR, 0.39-0.55] µmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] µmol/L vs 0.45 [IQR, 0.39-0.50] µmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively). CONCLUSIONS: The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

Effectiveness of screening for foot complications in people with diabetes - A systematic review.

BACKGROUND: A quarter of people with diabetes develop foot ulcer in their lifetime and are six times more likely to require a major lower limb amputation compared to the general population. Risk stratification tools can reliably identify those at the highest risk of ulceration, but it remains unclear if screening for foot complications can prevent limb loss in people with diabetes. AIMS: The aim of this systematic review was to determine whether population-based foot screening in people with diabetes reduces lower limb complications as assessed by development of foot ulceration, minor and major lower limb amputations, hospitalisation, or death. METHODS: MEDLINE, Embase, Emcare and CINAHL databases were searched to identify randomised and non-randomised controlled trials and observational studies (cohort, case-control and cross-sectional surveys). The screening process, study quality assessment and data extraction were performed by two independent reviewers. RESULTS: Following abstract screening and assessment for eligibility, five out of 10,771 identified studies were included in the analysis. Of these studies, one demonstrated 24 % reduction in development of new ulceration following introduction of screening. Major amputations decreased by between 17 and 96 % in three studies. Hospitalisation rates were contradictory, with one study showing doubling in hospital admissions and another one reduction by 33 %. One study demonstrated no impact of screening on minor or major amputation rates. None of the studies addressed the effect of foot screening on all-cause mortality. CONCLUSIONS: The number and quality of studies to support population-based foot screening to prevent lower limb complications in people with diabetes is low. Current evidence suggests variable impact of screening on important clinical outcomes.

Development of a Core Outcome Set for Studies Assessing Interventions for Diabetes-Related Foot Ulceration.

OBJECTIVE: Diabetes affects 537 million people globally, with 34% expected to develop foot ulceration in their lifetime. Diabetes-related foot ulceration causes strain on health care systems worldwide, necessitating provision of high-quality evidence to guide their management. Given heterogeneity of reported outcomes, a core outcome set (COS) was developed to standardize outcome measures in studies assessing treatments for diabetes-related foot ulceration. RESEARCH DESIGN AND METHODS: The COS was developed using Core Outcome Measures in Effectiveness Trials (COMET) methodology. A systematic review and patient interviews generated a long list of outcomes that were rated by patients and experts using a nine-point Likert scale (from 1 [not important] to 9 [critical]) in the first round of the Delphi survey. Based on predefined criteria, outcomes without consensus were reprioritized in a second Delphi round. Critical outcomes and those without consensus after two Delphi rounds were discussed in the consensus meeting where the COS was ratified. RESULTS: The systematic review and patient interviews generated 103 candidate outcomes. The two consecutive Delphi rounds were completed by 336 and 176 respondents, resulting in an overall second round response rate of 52%. Of 37 outcomes discussed in the consensus meeting (22 critical and 15 without consensus after the second round), 8 formed the COS: wound healing, time to healing, new/recurrent ulceration, infection, major amputation, minor amputation, health-related quality of life, and mortality. CONCLUSIONS: The proposed COS for studies assessing treatments for diabetes-related foot ulceration was developed using COMET methodology. Its adoption by the research community will facilitate assessment of comparative effectiveness of current and evolving interventions.

The good, bad and the ugly of the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis trial from the viewpoint of clinicians.

OBJECTIVE: Acute deep venous thrombosis (DVT) can be complicated by post-thrombotic syndrome, which is associated with significant morbidity and healthcare costs. The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) was the largest and most controversial randomized controlled trial evaluating the use of pharmacomechanical catheter-directed thrombolysis (CDT) for the prevention of post-thrombotic syndrome after acute DVT. This study aimed to evaluate clinicians' opinion on the ATTRACT trial and its impact on clinical practice. METHODS: An online survey consisting of 10 core multiple choice items and a maximum of five follow-up open-ended questions was delivered to vascular surgeons, interventional radiologists, hematologists, and interventional cardiologists affiliated with 10 international societies between April 23 and July 1, 2019. Clinicians' views on the main limitations of the ATTRACT trial, its impact on patient selection for thrombolysis and the need for a new trial were evaluated. RESULTS: Out of 15,650 contacted clinicians, 451 (3%) completed the survey, with 74% vascular surgeons, 24% interventional radiologists, 2% hematologists, and 0.2% interventional cardiologists. The majority of respondents (79%) were aware of the results of the ATTRACT trial before completing the survey and routinely performed pharmacomechanical CDT (PCDT) in their centers (70%). Only 20% of clinicians considered ATTRACT to be a well-designed and well-performed trial. The inclusion of femoropopliteal DVT was reported as the main limitation of the trial by 55% of respondents. Despite half of the participating clinicians reporting no change in their clinical practice, equal number of clinicians (14%) were encouraged and discouraged from treating iliofemoral DVT. More than one-half of the respondents thought that the use of PCDT would be defensible in a court of law despite the increased risk of bleeding reported in the study. Nearly two-thirds of participating clinicians recommended performing a trial limited to iliofemoral DVT, with a follow-up period of 5 years, quality of life as the primary outcome measure, and standardization of thrombolysis protocol across the trial sites. CONCLUSIONS: ATTRACT failed to provide the long-awaited indisputable evidence on the use of PCDT. Surveyed clinicians were aware of the limitations of this trial and the need for further evidence on the subject.

Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10-Dependent, T-Cell-Independent Attenuation of Colonic Mucosal Innate Immune Responses.

BACKGROUND: If treatment with intravenous steroids fail, inflammatory bowel disease patients with acute severe colitis face systemic anti-tumor necrosis factor biologic rescue therapy or colectomy. Interleukin (IL)-27 is a cytokine with an immunosuppressive role in adaptive immune responses. However, the IL-27 receptor complex is also expressed on innate immune cells, and there is evidence that IL-27 can impact the function of innate cell subsets, although this particular functionality in vivo is not understood. Our aim was to define the efficacy of IL-27 in acute severe colitis and characterize novel IL-27-driven mechanisms of immunosuppression in the colonic mucosa. METHODS: We assessed oral delivery of Lactococcus lactis expressing an IL-27 hyperkine on the innate immune response in vivo in a genetically intact, noninfective, acute murine colitis model induced by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid in SJL/J mice. RESULTS: IL-27 attenuates acute severe colitis through the reduction of colonic mucosal neutrophil infiltrate associated with a decreased CXC chemokine gradient. This suppression was T cell independent and IL-10 dependent, initially featuring enhanced mucosal IL-10. IL-27 was associated with a reduction in colonic proinflammatory cytokines and induced a multifocal, strong, positive nuclear expression of phosphorylated STAT-1 in mucosal epithelial cells. CONCLUSION: We have defined novel mechanisms of IL-27 immunosuppression toward colonic innate immune responses in vivo. Mucosal delivery of IL-27 has translational potential as a novel therapeutic for inflammatory bowel disease, and it is a future mucosal directed rescue therapy in acute severe inflammatory bowel disease.