Standards for the development and methodology of the 2019 International Working Group on the Diabetic Foot guidelines

Diabetic foot disease is a source of major patient suffering and societal costs. Investing in evidence-based international guidelines on diabetic foot disease is likely among the most cost-effective forms of health care expenditure, provided the guidelines are outcome focused, evidence based, and properly implemented. The International Working Group on the Diabetic Foot (IWGDF) has published and updated international guidelines since 1999. The 2019 updates are based on formulating relevant clinical questions and outcomes, rigorous systematic reviews of the literature, and recommendations that are specific, and unambiguous along with their transparent rationale, all using the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework. We herein describe the development of the 2019 IWGDF guidelines on the prevention and management of diabetic foot disease, which consists of six chapters, each prepared by a separate working group of international experts. These documents provide guidelines related to diabetic foot disease on prevention; offloading; peripheral artery disease; infection; wound healing interventions; and classification of diabetic foot ulcers. Based on these six chapters, the IWGDF Editorial Board also produced a set of practical guidelines. Each guideline underwent extensive review by the members of the IWGDF Editorial Board as well as independent international experts in each field. We believe that adoption and implementation of the 2019 IWGDF guidelines by health care providers, public health agencies, and policymakers will result in improved prevention and management of diabetic foot disease and a subsequent worldwide reduction in the patient and societal burden this disease causes

Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study

Aims/hypothesis Outcome data on individuals with diabetic foot ulcers are scarce, especially in those with peripheral arterial disease (PAD). We therefore examined the clinical characteristics that best predict poor outcome in a large population of diabetic foot ulcer patients and examined whether such predictors differ between patients with and without PAD. Methods Analyses were conducted within the EURODIALE Study, a prospective cohort study of 1,088 diabetic foot ulcer patients across 14 centres in Europe. Multiple logistic regression modelling was used to identify independent predictors of outcome (i.e. non-healing of the foot ulcer). Results After 1 year of follow-up, 23% of the patients had not healed. Independent baseline predictors of non-healing in the whole study population were older age, male sex, heart failure, the inability to stand or walk without help, end-stage renal disease, larger ulcer size, peripheral neuropathy and PAD. When analyses were performed according to PAD status, infection emerged as a specific predictor of non-healing in PAD patients only. Conclusions/Interpretation Predictors of healing differ between patients with and without PAD, suggesting that diabetic foot ulcers with or without concomitant PAD should be defined as two separate disease states. The observed negative impact of infection on healing that was confined to patients with PAD needs further investigation

Bleeding and first-year mortality following hip fracture surgery and preoperative use of low-dose acetylsalicylic acid: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>Hip fracture is associated with high mortality. Cardiovascular disease and other comorbidities requiring long-term anticoagulant medication are common in these mostly elderly patients. The objective of our observational cohort study of patients undergoing surgery for hip fracture was to study the association between preoperative use of low-dose acetylsalicylic acid (LdAA) and intraoperative blood loss, blood transfusion and first-year all-cause mortality.</p> <p>Methods</p> <p>An observational cohort study was conducted on patients with hip fracture (cervical requiring hemiarthroplasty or pertrochanteric or subtrochanteric requiring internal fixation) participating in a randomized trial that found lack of efficacy of a compression bandage in reducing postoperative bleeding. The participants were 255 patients (≥50 years) of whom 118 (46%) were using LdAA (defined as ≤320 mg daily) preoperatively. Bleeding variables in patients with and without LdAA treatment at time of fracture were measured and blood transfusions given were compared using logistic regression. The association between first-year mortality and preoperative use of LdAA was analyzed with Cox regression adjusting for age, sex, type of fracture, baseline renal dysfunction and baseline cardiovascular and/or cerebrovascular disease.</p> <p>Results</p> <p>Blood transfusions were given postoperatively to 74 (62.7%) LdAA-treated and 76 (54%) non-treated patients; the adjusted odds ratio was 1.8 (95% CI 1.04 to 3.3). First-year mortality was significantly higher in LdAA-treated patients; the adjusted hazard ratio (HR) was 2.35 (95% CI 1.23 to 4.49). The mortality was also higher with baseline cardiovascular and/or cerebrovascular disease, adjusted HR 2.78 (95% CI 1.31 to 5.88). Patients treated with LdAA preoperatively were significantly more likely to suffer thromboembolic events (5.7% vs. 0.7%, P = 0.03).</p> <p>Conclusions</p> <p>In patients with hip fracture (cervical treated with hemiarthroplasty or pertrochanteric or subtrochanteric treated with internal fixation) preoperative use of low-dose acetylsalicylic acid was associated with significantly increased need for postoperative blood transfusions and significantly higher all-cause mortality during one year after surgery.</p

Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into β-Cells

The identification of secreted factors that can selectively stimulate the generation of insulin producing β-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based β-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of β-cells during normal pancreatic development such putative factors may be identified. In the mouse, β-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of β-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when β-cells are generated. We also provide evidence that RA induces the generation of Ngn3+ endocrine progenitor cells and stimulates their further differentiation into β-cells by activating a program of cell differentiation that recapitulates the normal temporal program of β-cell differentiation

Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy

Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survival of different tumors, including chronic lymphocytic leukemia (CLL). In this study, we investigated the role of Notch signaling in the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromal cells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis both spontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisone and Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or γ-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL

Identification of Achaete-scute complex-like 1 (ASCL1) target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours

<p>Abstract</p> <p>Background</p> <p><it>ASCL1 </it>role in pancreatic endocrine tumourigenesis has not been established. Recently it was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist <it>DKK1</it>. Notch signalling regulates expression of TPH1, the rate limiting enzyme in the biosyntesis of serotonin. Understanding the development and proliferation of pancreatic endocrine tumours (PETs) is essential for the development of new therapies.</p> <p>Methods</p> <p><it>ASCL1 </it>target genes in the pancreatic endocrine tumour cell line BON1 were identified by RNA interference and microarray expression analysis. Protein expressions of selected target genes in PETs were evaluated by immunohistochemistry.</p> <p>Results</p> <p>158 annotated <it>ASCL1 </it>target genes were identified in BON1 cells, among them DKK1 and TPH1 that were negatively regulated by ASCL1. An inverse relation of ASCL1 to DKK1 protein expression was observed for 15 out of 22 tumours (68%). Nine tumours displayed low ASCL1/high DKK1 and six tumours high ASCL1/low DKK1 expression. Remaining PETs showed high ASCL1/high DKK1 (n = 4) or low ASCL1/low DKK1 (n = 3) expression. Nine of twelve analysed PETs (75%) showed TPH1 expression with no relation to ASCL1.</p> <p>Conclusion</p> <p>A number of genes with potential importance for PET tumourigenesis have been identified. <it>ASCL1 </it>negatively regulated the Wnt signalling antagonist <it>DKK1</it>, and <it>TPH1 </it>expression in BON1 cells. In concordance with these findings DKK1 showed an inverse relation to ASCL1 expression in a subset of PETs, which may affect growth control by the Wnt signalling pathway.</p

A questionnaire for determining prevalence of diabetes related foot disease (Q-DFD): construction and validation

<p>Abstract</p> <p>Background</p> <p>Community based prevalence for diabetes related foot disease (DRFD) has been poorly quantified in Australian populations. The aim of this study was to develop and validate a survey tool to facilitate collection of community based prevalence data for individuals with DRFD via telephone interview.</p> <p>Methods</p> <p>Agreed components of DRFD were identified through an electronic literature search. Expert feedback and feedback from a population based construction sample were sought on the initial draft. Survey reliability was tested using a cohort recruited through a general practice, a hospital outpatient clinic and an outpatient podiatry clinic. Level of agreement between survey findings and either medical record or clinical assessment was evaluated.</p> <p>Results</p> <p>The Questionnaire for Diabetes Related Foot Disease (Q-DFD) comprised 12 questions aimed at determining presence of peripheral sensory neuropathy (PN) and peripheral vascular disease (PVD), based on self report of symptoms and/or clinical history, and self report of foot ulceration, amputation and foot deformity. Survey results for 38 from 46 participants demonstrated agreement with either clinical assessment or medical record (kappa 0.65, sensitivity 89.0%, and specificity 77.8%). Correlation for individual survey components was moderate to excellent. Inter and intrarater reliability and test re-test reliability was moderate to high for all survey domains.</p> <p>Conclusion</p> <p>The development of the Q-DFD provides an opportunity for ongoing collection of prevalence estimates for DRFD across Australia.</p

Руководство и документы Международной рабочей группы по диабетической стопе 2015 г. по профилактике и лечению заболеваний стопы при диабете: достижение доказательного консенсуса (сокращенная русскоязычная версия)

Recommendations for endocrinologists, surgeons, traumatologists, orthopedists, podiatrists, developed by the International Working Group on the Diabetic Foot (IWGDF) and set out in “Manual and documents of IWGDF 2015 for prevention and treatment of diabetic foot diseases: the achievement of argumentative consensus”.Представлены рекомендации для врачей-эндокринологов, хирургов, травматологов, ортопедов, подиатров, разработанные Международной рабочей группой по диабетической стопе (МРГДС) и изложенные в «Руководстве и документах МРГДС 2015 г. по профилактике и лечению заболеваний стопы при диабете: достижение доказательного консенсуса»