Publications by authors named "Edward B Jude"

68 Publications

Editorial: Understanding Diabetic Foot Disease: Current Status and Emerging Treatment Approaches.

Front Endocrinol (Lausanne) 2021 16;12:753181. Epub 2021 Sep 16.

First Department of Propaedeutic and Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.

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http://dx.doi.org/10.3389/fendo.2021.753181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481651PMC
September 2021

Interplay between endocrinology, metabolism and COVID-19 infection.

Clin Med (Lond) 2021 09;21(5):e499-e504

Tameside and Glossop Integrated Care NHS Foundation Trust, Manchester, UK, honorary professor, University of Manchester, Manchester, UK, and honorary professor, Manchester Metropolitan University, Manchester, UK.

There are more than 170 million confirmed cases of COVID-19 worldwide, yet its effects on the endocrine system remain under-reported due to lack of awareness by the public, primary care givers and specialists. This is a narrative review using up-to-date literature discussing the consequences that infection with SARS-CoV-2 can have on diabetes and the endocrine glands including the adrenals, thyroid and pituitary, as well as hyponatremia and hypogonadism. Endocrinologists, internists and primary care physicians need to be aware of the involvement of the endocrine organs when dealing with people recovering from COVID-19 and actively manage any complications to reduce mortality and improve the quality of life of those affected.
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http://dx.doi.org/10.7861/clinmed.2021-0200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439497PMC
September 2021

COVID-19-related vasculopathy of the brain.

BMJ Case Rep 2021 Jul 27;14(7). Epub 2021 Jul 27.

Diabetes and Endocrinology, Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK.

The COVID-19 pandemic is revealing growing reports of atypical presentation of the disease beyond the respiratory system. SARS-CoV-2 infection has been linked to multisystem vasculopathy including cardiopulmonary, cerebral and renal vasculature, potentially brought on by a dysregulated host immune response in a probable setting of a cytokine storm. Here, we describe a case of a previously healthy and active 74-year-old man presenting with acute cognitive decline with preceding non-specific influenza-like symptoms. He was then diagnosed with cerebral amyloid angiopathy (CAA)-associated intracerebral haemorrhage and was found to be COVID-19 positive. COVID-19-induced immune response may have further compromised the cerebral vessels already weakened by CAA, triggering multiple microhaemorrhages leading to clinical presentation. The limited evidence about the heterogeneity of COVID-19 manifestations suggests that clinicians should be aware and screen for concurrent COVID-19 in patients presenting with neurological features during the peak of this pandemic, as this offers the best chance for better clinical outcome.
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http://dx.doi.org/10.1136/bcr-2021-242028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316986PMC
July 2021

COVID-19 and peripheral arterial complications in people with diabetes and hypertension: A systematic review.

Diabetes Metab Syndr 2021 Sep-Oct;15(5):102204. Epub 2021 Jul 9.

Tameside and Glossop Integrated Care NHS Foundation Trust, Tameside on Lyne, UK.

Aims: Identify the prevalence, risk factors and outcomes of lower extremity ischemic complications.

Methods: A systematic review was conducted by searching PubMed and SCOPUS databases for SARS-CoV-2, COVID-19 and peripheral arterial complications.

Results: Overall 476 articles were retrieved and 31 articles describing 133 patients were included. The mean age was 65.4 years. Pain and gangrene were the most common presentation. Hypertension (51.3%), diabetes (31.9%) and hypercholesterolemia (17.6%) were associated co-morbidities. Overall, 30.1% of patients died and amputation was required in 11.8% patients.

Conclusions: COVID-19 patients with diabetes or hypertension are susceptible for lower limb complications and require therapeutic anti-coagulation.
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http://dx.doi.org/10.1016/j.dsx.2021.102204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266514PMC
October 2021

Vitamin D deficiency is associated with higher hospitalisation risk from COVID-19: a retrospective case-control study.

J Clin Endocrinol Metab 2021 Jun 17. Epub 2021 Jun 17.

The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.

Context: One of the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is postulated to be vitamin D deficiency. To understand better the role of vitamin D deficiency in the disease course of COVID-19, we undertook a retrospective case-control study in the North West of England (NWE).

Objective: To examine whether hospitalisation with COVID-19 is more prevalent in individuals with lower vitamin D levels.

Methods: The study included individuals with results of serum 25-hydroxyvitamin D (25[OH]D) between 1 st April 2020 and 29th January 2021. Patients were recruited from two districts in NWE. The last 25(OH)D level in the previous 12 months was categorised as 'deficient' if less than 25 nmol/L and 'insufficient' if 25-50 nmol/L.

Results: 80,670 participants were entered into the study. Of these, 1,808 were admitted to hospital with COVID-19, of whom 670 died. In a primary cohort, median serum 25(OH)D in participants who were not hospitalised with COVID-19 was 50.0 [interquartile range, IQR 34.0-66.7] nmol/L versus 35.0 [IQR 21.0-57.0] nmol/L in those admitted with COVID-19 (p <0.005). There were similar findings in a validation cohort (median serum 25(OH)D 47.1 [IQR 31.8-64.7] nmol/L in non-hospitalised versus 33.0 [IQR 19.4-54.1] nmol/L in hospitalised patients). Age-, sex- and seasonal variation-adjusted odds ratios for hospital admission were 2.3-2.4 times higher among participants with serum 25(OH)D <50 nmol/L, compared to those with normal serum 25(OH)D levels, without any excess mortality risk.

Conclusions: Vitamin D deficiency is associated with higher risk of COVID-19 hospitalisation. Widespread measurement of serum 25(OH)D and treating any unmasked insufficiency or deficiency through testing may reduce this risk.
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http://dx.doi.org/10.1210/clinem/dgab439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344535PMC
June 2021

CORRIGENDUM: A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

J Cell Physiol 2021 May 26. Epub 2021 May 26.

Department of Cell Biology, University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1002/jcp.30441DOI Listing
May 2021

Virtual triage and outcomes of diabetic foot complications during Covid-19 pandemic: A retro-prospective, observational cohort study.

PLoS One 2021 6;16(5):e0251143. Epub 2021 May 6.

Tameside and Glossop Integrated Care NHS Foundation Trust, Tameside on Lyne, United Kingdom and Manchester Metropolitan University, Manchester, United Kingdom.

Aims: Limb and patient outcomes in people with diabetic foot complications including diabetic foot ulcer (DFU) provided virtual triage and personalized video consultations during COVID-19 pandemic are not known.

Methods: Patients with foot complications attending the diabetic foot clinic prior to lockdown who sought teleconsultations during COVID-19 lockdown underwent virtual triage to include clinical history, visual inspection of feet, domiciliary wound care (community nurse assisted dressings) and offloading instructions. The subsequent ulcer, limb and mortality outcomes during the following 24 weeks of COVID-19 lockdown (April-September 2020, group 1) were assessed and compared with those who attended foot clinic during the same period in 2019 (April-September, group 2).

Results: Group 1 included 561 participants with foot complications provided with teleconsultations, median age 57 (51 to 63) years and diabetes duration of 10 (5 to 16) years. Twelve patients with severe DFU were excluded and 549 patients [357 (65%) neuropathic foot, 104 (18.9%) ischemic foot and 88 (16%) chronic Charcot foot with deformities] were evaluated. There were 227 (41.3%) participants with active DFU at start of lockdown, 32 (5.8%) with new onset ulcer during lockdown (47.1%) and 290 patients without ulcers. Group 2 included 650 participants; active foot ulcer was present in 366 patients. Wound closed or reduced in area in 78.4% of participants of group 1 compared to 76.0% (p = 0.318) in group 2. Fourteen (5.4%) patients required amputations [3 major and 11 minor] in group 1 during the study period compared to 6.8% in group 2 (p = 0.191). Twenty-one (3.8%) and 28 (4.3%) patients died (p = 0.532) during 24 weeks of follow up in group 1 and 2, respectively.

Conclusions: Targeted foot-care service through virtual triage and teleconsultations during COVID-19 pandemic for people with foot complications have similar ulcer and limb outcomes compared to face-to-face foot care delivery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101747PMC
May 2021

Main Factors Predicting Nonresponders to Autologous Cell Therapy for Critical Limb Ischemia in Patients With Diabetic Foot.

Angiology 2021 10 30;72(9):861-866. Epub 2021 Mar 30.

Diabetes Centre, Tameside Hospital NHS Foundation Trust and University of Manchester, Lancashire, United Kingdom.

Autologous cell therapy (ACT) is a new treatment for patients with no-option critical limb ischemia (NO-CLI). We evaluated the factors involved in the nonresponse to ACT in patients with CLI and diabetic foot. Diabetic patients (n = 72) with NO-CLI treated using ACT in our foot clinic over a period of 8 years were divided into responders (n = 57) and nonresponders (n = 15). Nonresponder was defined as an insufficient increase in transcutaneous oxygen pressure by <5 mm Hg, 3 months after ACT. Patient demographics, diabetes duration and treatment, and comorbidities as well as a cellular response to ACT, limb-related factors, and the presence of inherited thrombotic disorders were compared between the 2 groups. The main independent predictors for an impaired response to ACT were heterozygote Leiden mutation (OR 10.5; 95% CI, 1.72-4) and homozygote methylenetetrahydrofolate reductase (MTHFR 677) mutation (OR 3.36; 95% CI, 1.0-14.3) in stepwise logistic regression. Univariate analysis showed that lower mean protein C levels ( = .041) were present in nonresponders compared with responders. In conclusion, the significant predictors of an impaired response to ACT in diabetic patients with NO-CLI were inherited thrombotic disorders.
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http://dx.doi.org/10.1177/00033197211005614DOI Listing
October 2021

Titratable fixed-ratio combination of basal insulin plus a glucagon-like peptide-1 receptor agonist: A novel, simplified alternative to premix insulin for type 2 diabetes.

Diabetes Obes Metab 2021 07 31;23(7):1445-1452. Epub 2021 Mar 31.

Dallas Diabetes Research Center at Medical City, Dallas, Texas, USA.

Despite novel therapeutic options, many people with type 2 diabetes (T2D) do not achieve their HbA1c targets. Given the progressive nature of T2D, many individuals not controlled with oral therapy will require advancement to injectable therapy using either a glucagon-like peptide-1 receptor agonist (GLP-1 RA), recently recommended as a first option, or traditionally a basal insulin. However, premix insulins remain frequently used, either as initial injectable therapy or as intensification from basal insulin. Premix insulin injections can potentially provide significant glycaemic improvements to basal insulin but at the expense of increased hypoglycaemia and weight gain and the need for multiple daily doses, which may affect treatment adherence. Real-world evidence suggests that glycaemic control often remains suboptimal with premix insulins. Fixed-ratio combinations (FRCs) of basal insulin and GLP-1 RAs provide a novel alternative to premix insulin for therapy intensification. While no direct comparisons between premix insulins and FRCs are available, results from meta-analyses suggest that FRCs may offer better HbA1c reductions, a lower risk of hypoglycaemia and less weight gain compared with premix insulin in a simplified treatment regimen. A head-to-head trial of T2D treatment intensification with premix insulin and a FRC of basal insulin plus a GLP-1 RA is currently in progress, which should help to clarify the outcomes for each treatment option. This review discusses the unmet needs of people with T2D treated with premix insulin and provides evidence supporting FRCs of basal insulin and GLP-1 RAs as an alternative treatment option.
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http://dx.doi.org/10.1111/dom.14365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252507PMC
July 2021

The Performance and Interrater Agreement of Vibration Perception for the Diagnosis of Loss of Protective Sensation in People With Diabetes Mellitus.

Int J Low Extrem Wounds 2021 Feb 24:1534734621994058. Epub 2021 Feb 24.

Tameside Hospital, NHS Foundation and Trust, Ashton under Lyne, England, UK.

This study examined the performance of VibraTip for the diagnosis of loss of protective sensation (LOPS) and the interrater agreement of different neurological modalities performed by 3 health care professionals, a consultant diabetologist, a diabetes specialist nurse, and a podiatrist. Diagnosis of LOPS was based on 10-g Semmes Weinstein monofilament testing performed by a consultant diabetologist (reference method), while examination with a 128-Hz tuning form was also performed. The performance of VibraTip for the diagnosis of LOPS was examined using the receiver operating characteristic curves analysis. Interrater agreement was determined by weighted kappa (κ) statistics. Diagnosis of LOPS (%) was 37.5%. Receiver operating characteristic curve analysis showed that VibraTip examination versus 10-g monofilament, both performed by a consultant, could diagnose LOPS ( < .001). Sensitivity, specificity, positive predictive value, and negative predictive value of VibraTip versus 10-g monofilament, both performed by a consultant (value, 95% confidence interval), was 0.705 (0.591-0.803), 0.836 (0.758-0.897), 0.733 (0.642-0.808), and 0.816 (0.757-0.863), respectively. The interrater agreement among the health care professionals for 10-g monofilament, VibraTip, and 128-Hz tuning fork in neurological assessment was good with κ > 0.61. VibraTip can be used as a screening tool for the detection of LOPS. There was good overall agreement in the results of neurological examination using 10-g monofilament, 128-Hz tuning fork, and VibraTip among health care professionals.
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http://dx.doi.org/10.1177/1534734621994058DOI Listing
February 2021

Efficacy of medical treatment for Charcot neuroarthropathy: a systematic review and meta-analysis of randomized controlled trials.

Acta Diabetol 2021 Jun 13;58(6):687-696. Epub 2021 Jan 13.

Diabetes and Endocrinology Department,, Tameside and Glossop Integrated Care NHS FT, Ashton under Lyne, Lancs, OL69RW, UK.

No pharmacotherapeutic agents are yet recommended for active CN though many anti-resorptive agents have been studied. We conducted a systematic review and meta-analysis of the randomized placebo-controlled trials (RCTs) evaluating the time to remission of active CN with anti-resorptive or antiinflammatory drugs. RCTs published in PubMed, EMBASE, SCOPUS and Cochrane Library from January 1994 to December 2019 were accessed. We reviewed studies and extracted information on study design, participants' characteristics, time to remission, bone turnover markers, bone mineral content (BMC) and temperature difference between feet. Five RCTs out of 588 total identified records were included. Standardized mean differences (SMD) between groups with 95% CI are summarized. Pharmacotherapy nonsignificantly increased time to remission [SMD 0.52 weeks (- 0.71, 1.75), p = 0.402; I2 = 88.6%] as compared to TCC alone. The pooled median time to remission with the intervention was 18.5 weeks (11.2, 28.1) compared to 16.8 weeks (8.7, 27.7) with TCC. A nonsignificant increase in BMC [SMD 3.39% (- 0.78, 7.56), p = 0.109; I2 = 96.7%], a decrease in foot temperature [SMD - 0.42 °C (- 0.78, - 0.07), p = 0.020; I2 = 0%] and alkaline phosphatase [SMD = -2.51% (- 3.24, - 1.77), p < 0.001; I2 = 0%] was observed with intervention. Limited evidence from available studies does not support the role of anti-resorptive or anti-inflammatory drugs for earlier remission when added to offloading with total contact cast for active CN of the foot.
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http://dx.doi.org/10.1007/s00592-020-01664-9DOI Listing
June 2021

High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study.

Nutrients 2020 Dec 11;12(12). Epub 2020 Dec 11.

Tameside and Glossop Integrated Care NHS Foundation Trust, Fountain Street, Ashton-under-Lyne OL6 9RW, UK.

The worldwide pandemic of 2019 novel coronavirus disease (COVID-19) has posed the most substantial and severe public health issue for several generations, and therapeutic options have not yet been optimised. Vitamin D (in its "parent" form, cholecalciferol) has been proposed in the pharmacological management of COVID-19 by various sources. We aimed to determine whether COVID-19 mortality was affected by serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D status, or cholecalciferol therapy, and to elucidate any other predictors of COVID-19 mortality. Patients hospitalised with COVID-19 were opportunistically recruited from three UK hospitals, and their data were collected retrospectively. Logistic regression was used to determine any relationships between COVID-19 mortality and potential predictors, including 25(OH)D levels and cholecalciferol booster therapy. A total of 986 participants with COVID-19 were studied, of whom 151 (16.0%) received cholecalciferol booster therapy. In the primary cohort of 444 patients, cholecalciferol booster therapy was associated with a reduced risk of COVID-19 mortality, following adjustment for potential confounders (OR 0.13, 95% CI 0.05-0.35, < 0.001). This finding was replicated in a validation cohort of 541 patients (OR 0.38, 95% CI 0.17-0.84, = 0.018). In this observational study, treatment with cholecalciferol booster therapy, regardless of baseline serum 25(OH)D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with COVID-19. Further work with large population studies needs to be carried out to determine adequate serum 25(OH)D levels, as well as multi-dose clinical trials of cholecalciferol therapy to assess maximum efficacy.
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http://dx.doi.org/10.3390/nu12123799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763301PMC
December 2020

Effectiveness of premixed insulin to achieve glycaemic control in type 2 diabetes: A retrospective UK cohort study.

Diabetes Obes Metab 2021 04 26;23(4):929-937. Epub 2021 Jan 26.

Endocrinology and Nutrition Unit, Segovia General Hospital, Segovia, Spain.

Aim: To investigate the effectiveness of premixed insulin for achieving glycaemic outcomes in clinical practice in the UK.

Materials And Methods: Electronic medical record data from The Health Improvement Network database were captured for adults with type 2 diabetes (T2D) uncontrolled (HbA1c ≥9%) on two or more oral antihyperglycaemic drugs (OADs) initiating premixed insulin. Effectiveness of premixed insulin was assessed by the probability and incidence of achieving glycaemic outcomes (target HbA1c <7.5% [<58 mmol/mol] and a ≥1% or ≥2% HbA1c reduction) over 24 months.

Results: Data from 974 participants (mean age 62 years; 56% male; 52% obese or extremely obese; mean HbA1c 11.3% [100 mmol/mol]; hypertension 64%, dyslipidaemia 23% and nephropathy 21%) were analysed. The probability of achieving HbA1c  <7.5% was highest during months 3-6 (18.2%), while the cumulative probability of achieving this target plateaued between months 15-24 (15.7%-16.0%). Incidence of achieving all glycaemic outcomes plateaued after 12 months and differed by baseline HbA1c, but not OAD use. Factors affecting some glycaemic outcomes included a body mass index >40 kg/m and co-morbidities including nephropathy and stroke.

Conclusions: In people with uncontrolled T2D (HbA1c ≥9%), glycaemic outcome achievement on premixed insulin was low at 6 months with little additional clinical benefit beyond 12 months, suggesting a high unmet need for early, timely treatment changes with more effective, simpler therapies.
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http://dx.doi.org/10.1111/dom.14298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048616PMC
April 2021

Vitamin D Status in a Bulgarian Population With Type 2 Diabetes and Diabetic Foot Ulcers.

Int J Low Extrem Wounds 2020 Oct 23:1534734620965820. Epub 2020 Oct 23.

Medical University of Sofia, Sofia, Bulgaria.

The aim of this study was to assess vitamin D status in patients with type 2 diabetes and diabetic foot ulcers (DFU). A total of 242 participants with type 2 diabetes, mean age 59.1 ± 10 years, mean body mass index 31.4 ± 6.3 kg/m, and estimated glomerular filtration rate ≥45 mL/min/1.73m, were divided into 2 groups: 73 with DFU (35 with and 38 without active infection) and 169 without DFU (106 with diabetic peripheral neuropathy, 63 without complications). Neuropathy was assessed by 10 g monofilament, Rydel-Seiffer 128 Hz tuning fork, and temperature discrimination. Serum 25(OH)D (25-hydroxy vitamin D) was assessed by ECLIA (electro-chemiluminescence immunoassay) method. Median 25(OH)D level was 12.6 ng/mL (IQR [interquartile range] 9.3-17.6 ng/mL) in the studied cohort. The DFU group presented with lower 25(OH)D level as compared with diabetic patients without foot ulcers (non-DFU group): 11.6 ng/mL (IQR 8.5-15.8 ng/mL) versus 13.5 ng/mL (IQR 9.6-18.6 ng/mL), = .001; the diabetic peripheral neuropathy subgroup demonstrated lower 25(OH)D level in comparison with participants without complications: 12.5 ng/mL (IQR 9-17.2 ng/mL) versus 15.9 ng/mL (IQR 10.4-20.8 ng/mL), = .031. This remained significantly different even after correction for age and duration of diabetes. There was no difference in 25(OH)D level between the subgroups according to the presence of active infection. In conclusion, vitamin D deficiency may play a role in the development of diabetes complications.
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http://dx.doi.org/10.1177/1534734620965820DOI Listing
October 2020

Dryness of Foot Skin Assessed by the Visual Indicator Test and Risk of Diabetic Foot Ulceration: A Prospective Observational Study.

Front Endocrinol (Lausanne) 2020 8;11:625. Epub 2020 Sep 8.

First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.

Previous cross-sectional studies have shown an association between sudomotor dysfunction and diabetic foot ulceration (DFU). The aim of this prospective multicenter study was to determine the role of dryness of foot skin and of established neurological modalities in the prediction of risk for foot ulceration in a cohort of individuals with diabetes mellitus (DM). The study was conducted from 2012 to 2017. A total of 308 subjects with DM without history of DFU or critical limb ischemia completed the study. Diabetic neuropathy was assessed using the neuropathy symptom score (NSS) and neuropathy disability score (NDS). In a subset of participants, vibration perception threshold (VPT) was evaluated. Dryness of foot skin was assessed by the visual indicator plaster method (IPM). The diagnostic performance of the above neurological modalities for prediction of DFU was tested by receiver operating characteristic curve (ROC) analysis. During the 6-year follow-up, 55 patients (annual ulceration incidence 2.97%) developed DFU. Multivariate Cox-regression analysis after controlling for the effect of age, gender, and DM duration demonstrated that the risk (hazard ratio, 95% confidence intervals) of DFU increased significantly with either abnormal IPM (3.319, 1.460-7.545, = 0.004) or high (≥6) NDS (2.782, 1.546-5.007, = 0.001) or high (≥25 volts) VPT (2.587, 1.277-5.242, = 0.008). ROC analysis showed that all neurological modalities could discriminate participants who developed DFU ( < 0.001). IPM testing showed high sensitivity (0.86) and low specificity (0.49), while high vs. low NDS and VPT showed low sensitivity (0.40 and 0.39, respectively) and high specificity (0.87 and 0.89, respectively) for identification of patients at risk for DFU. Dryness of foot skin assessed by the IPM predicts the development of DFU. IPM testing has high sensitivity, whereas high NDS and VPT have high specificity in identifying subjects at risk for DFU. The IPM can be included in the screening methods for identification of the foot at risk.
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http://dx.doi.org/10.3389/fendo.2020.00625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506164PMC
May 2021

High-Dose Vitamin D Supplementation Improves Microcirculation and Reduces Inflammation in Diabetic Neuropathy Patients.

Nutrients 2020 Aug 20;12(9). Epub 2020 Aug 20.

Tameside Hospital NHS Foundation Trust, Ashton Under Lyne OL69RW, UK.

We assessed the effect of different doses of vitamin D supplementation on microcirculation, signs and symptoms of peripheral neuropathy and inflammatory markers in patients with type 2 diabetes (T2DM). Sixty-seven patients with T2DM and peripheral neuropathy (34 females) were randomized into two treatment groups: Cholecalciferol 5000 IU and 40,000 IU once/week orally for 24 weeks. Severity of neuropathy (NSS, NDS scores, visual analogue scale), cutaneous microcirculation (MC) parameters and inflammatory markers (ILs, CRP, TNFα) were assessed before and after treatment. Vitamin D deficiency/insufficiency was detected in 78% of the 62 completed subjects. Following treatment with cholecalciferol 40,000 IU/week, a significant decrease in neuropathy severity (NSS, = 0.001; NDS, = 0.001; VAS, = 0.001) and improvement of cutaneous MC were observed ( < 0.05). Also, we found a decrease in IL-6 level (2.5 pg/mL vs. 0.6 pg/mL, < 0.001) and an increase in IL-10 level (2.5 pg/mL vs. 4.5 pg/mL, < 0.001) after 24 weeks of vitamin D supplementation in this group. No changes were detected in the cholecalciferol 5000 IU/week group. High-dose cholecalciferol supplementation of 40,000 IU/week for 24 weeks was associated with improvement in clinical manifestation, cutaneous microcirculation and inflammatory markers in patients with T2DM and peripheral neuropathy.
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http://dx.doi.org/10.3390/nu12092518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551635PMC
August 2020

A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

J Cell Physiol 2020 12 27;235(12):9974-9991. Epub 2020 May 27.

Department of Physiology, College of Medicine (QU Health), Qatar University, Doha, Qatar.

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.
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http://dx.doi.org/10.1002/jcp.29812DOI Listing
December 2020

Long term outcomes after incident diabetic foot ulcer: Multicenter large cohort prospective study (EDI-FOCUS investigators) epidemiology of diabetic foot complications study: Epidemiology of diabetic foot complications study.

Diabetes Res Clin Pract 2020 Apr 9;162:108113. Epub 2020 Mar 9.

Deptt. of Endocrinology, PGIMER, Chandigarh, India.

Aims: This long-term prospective study evaluated limb amputation and mortality after the first neuropathic diabetic foot ulcer (DFU).

Methods: A total of 2880 patients with neuropathic DFU (DFU group) and a similar number of patients of diabetes without DFU (nDFU) matched for age and diabetes duration were prospectively assessed at five referral-centers over 14 years. Pre-defined outcome was death during follow-up. Various diabetic co-morbidities and amputation were assessed as mortality predictors.

Results: Overall, 501 (17.4%) patients in DFU group died compared to 89 (3.1%) (p < 0.01) in nDFU group during a median follow-up of 7(1-14) years. The 5- and 10-year mortality was 22% and 71% in the DFU group with a median survival of 7.72 (7.37-8.08) years compared to 3% (p < 0.01) and 5% (p < 0.01) and survival of 12.6 (10.5-12.7) years (p < 0.001) in nDFU group. 29.3% patients had limb amputations. The mortality risk was independent of glycemic control [OR 1.03 (0.80-1.32; p = 0.83)]. However, diabetes duration > 10 years [OR 1.31(1.02-1.70, p = 0.035)], nephropathy [OR 1.47 (1.04-2.09, p < 0.030)], minor 1.85 (1.40-2.44; p < 0.001) or major amputation 2.96 (2.01-4.34, p < 0.001)] predicted mortality.

Conclusions: Every one-in-three individual with neuropathic DFU has amputation and every sixth individual has an early demise. Prevalent nephropathy and incident amputation following DFU predicts mortality.
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http://dx.doi.org/10.1016/j.diabres.2020.108113DOI Listing
April 2020

Evaluating glycaemic control in patients poorly controlled on oral antidiabetic drugs in real-world setting: Results from assessing the Appropriate Timing of Type 2 diAbetes INtensification (ATTAIN).

Endocrinol Diabetes Metab 2020 Jan 29;3(1):e00094. Epub 2019 Sep 29.

Sanofi Chilly-Mazarin France.

Introduction: Many patients with type 2 diabetes mellitus (DM) fail to achieve glycaemic control despite recommended treatment strategies to reduce glycated haemoglobin (HbA1c). This real-world retrospective cohort study compared HbA1c change and treatment patterns between those intensifying and not intensifying therapy with oral antidiabetic drugs (OADs).

Materials And Methods: Patients suboptimally controlled on OADs (>58 mmol/mol [>7.5%] or >64 mmol/mol [>8.0%] for high risk, index 1) were included from IQVIA Medical Research Data. Intensifiers within 12 months of index 1 were matched (1:1) to nonintensifiers. Primary outcomes were HbA1c change and proportion of participants achieving HbA1c targets 6 and 12 months post-index 2 (date of intensification [intensifiers] or pseudodate [nonintensifiers]). Therapy adherence was also assessed.

Results: A total of 10 832 participants (5539 intensifiers and 5293 nonintensifiers) were included. Mean HbA1c decrease from baseline to 6 months was -1.13% (intensifiers) vs -0.75% (nonintensifiers), with no substantial further change at 12 months. Cox proportional hazards (PH) analysis suggested a nearly 20% greater chance of target achievement at 6 months for intensifiers vs nonintensifiers (hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.73-0.86]), which was similar at 12 months (HR: 0.80 [95% CI: 0.74-0.86]). Intensifiers tended towards greater adherence to baseline therapy (90% [standard deviation (SD): 14.9] vs nonintensifiers 87% [SD: 16.0]), which decreased following intensification.

Conclusions: Significant reductions in HbA1c were evident at 6 months and were greater in intensifiers vs nonintensifiers. Little additional clinical benefit was seen 12 months postintensification. Despite good treatment adherence, many participants failed to achieve target HbA1c; actions beyond improved adherence are needed to improve suboptimal HbA1c.
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http://dx.doi.org/10.1002/edm2.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947702PMC
January 2020

Effect of Methylprednisolone or Zoledronic Acid on Resolution of Active Charcot Neuroarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study.

Diabetes Care 2019 12 9;42(12):e185-e186. Epub 2019 Oct 9.

Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

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http://dx.doi.org/10.2337/dc19-1659DOI Listing
December 2019

Evaluating Glycemic Control in Patients with Type 2 Diabetes Suboptimally Controlled on Basal Insulin: UK ATTAIN Real-World Study.

Diabetes Ther 2019 Oct 18;10(5):1847-1858. Epub 2019 Jul 18.

Sanofi, Chilly-Mazarin, France.

Introduction: This retrospective, observational cohort study evaluated the effect of therapy intensification on change in glycated hemoglobin (HbA1c) at 6 and 12 months post intensification in patients with type 2 diabetes (T2D) suboptimally controlled on basal insulin (BI) (i.e., HbA1c ≥ 7.5% [≥ 58 mmol/mol]).

Methods: Patients with T2D with suboptimal glycemic control using BI were identified from The Health Improvement Network (THIN) database. Patients who underwent therapy intensification (intensifiers) within 12 months of index 1 (the date of the first incidence of suboptimally controlled HbA1c) were matched (1:1) to patients who did not intensify therapy (non-intensifiers). Index 2 was the date of therapy intensification for intensifiers, or a pseudo date for non-intensifiers that resulted in the same duration from index 1 to index 2 as their matched intensifier patient. Primary outcomes were HbA1c change and proportion of patients achieving the HbA1c target at 6 and 12 months post index 2.

Results: A total of 1342 patients (n = 646 intensifiers; n = 696 non-intensifiers) were included in the analysis. At post index 2, mean HbA1c change was substantially greater at 6 months for intensifiers than for non-intensifiers (- 0.81% vs. - 0.35%), with no additional benefit at 12 months (- 0.81% vs. - 0.49%, respectively). Compared with non-intensifiers, a greater proportion of intensifiers achieved target HbA1c at 6 months (25.1% vs. 18.8%) and at 12 months (33.4% vs. 28.2%).

Conclusions: Many real-world patients with T2D suboptimally controlled with BI do not have their therapy intensified. The results of this study suggest that in this patient population, therapy intensification achieves significant reductions in HbA1c at 6 months post intensification, with little additional clinical benefit at 12 months. This suggests that, for patients who fail to achieve their glycemic targets at 6 months, since no meaningful additional clinical benefit is observed at 12 months when continuing the same therapy, further therapy intensification or change should be promptly considered.

Funding: This study and the Rapid Service Fees were funded by Sanofi.

Trial Registration: 17THIN068.
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http://dx.doi.org/10.1007/s13300-019-0667-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778546PMC
October 2019

Endothelial Progenitor Cells Biology in Diabetes Mellitus and Peripheral Arterial Disease and their Therapeutic Potential.

Stem Cell Rev Rep 2019 04;15(2):157-165

Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

Endothelial progenitors are a population of cells with the inherent capacity to differentiate into mature endothelial cells and proangiogenic paracrine action. These characteristics have led to extensive studies being performed and tested in the treatment of tissue ischemia. The natural course of diabetes mellitus (DM) results in multiple areas of vascular damage. Thus endothelial progenitor cells'(EPCs) beneficial potential is particularly desirable in diabetic patients. In this review, we summarize contemporary knowledge of EPC biology in DM. It has been shown that EPC functions are considerably impaired by DM. The presence of peripheral arterial disease (PAD) seems to further exacerbate the deficiencies of EPCs. However, studies examining EPC counts in PAD and DM observed disparate results, which can be due to a lack of consensus on precise EPC immunotype used in the different studies. Nevertheless, the results of EPC-based autologous cell therapy (ACT) are promising. In addition, EPCs have been shown to bean independent predictor of cardiovascular risk and diabetic foot ulcer healing.
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http://dx.doi.org/10.1007/s12015-018-9863-4DOI Listing
April 2019

Advancements in improving health-related quality of life in patients living with diabetic foot ulcers.

Expert Rev Endocrinol Metab 2018 11 1;13(6):307-316. Epub 2018 Nov 1.

b Department of Medicine, Diabetes Centre , Tameside Hospital NHS Foundation Trust , Ashton-under-Lyne , UK.

Introduction: Diabetic foot ulcer (DFU) constitutes a burden to patients with diabetes deteriorating their quality of life. Health related quality of life (HRQoL) can now be quantified with the use of specific tools; some of them provide a holistic approach to patients' well-being, while others are disease specific or even region specific. Many of these tools are applicable to patients with DFU. This review will present current data about the impact different interventions in the management of DFU on quality of life related parameters.

Areas Covered: We performed a search of literature using keywords 'diabetes mellitus', 'diabetic foot ulcer', 'diabetic foot', 'health related quality of life', 'quality of life' and 'SF-36' to identify studies that contained data about the relationship between different interventions and quality of life of patients with diabetic foot ulcers.

Expert Commentary: Available data are not sufficient to conclude on the impact of interventions aimed to heal DFU on HRQoL. There is need for more, better designed studies and meta-analysis to estimate the effect of treatments on HRQoL in patients with DFUs. The development of new, diabetic foot specific tools will help to improve our knowledge in this field.
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http://dx.doi.org/10.1080/17446651.2018.1541403DOI Listing
November 2018

Relationship Between Vitamin D Status and Vitamin D Receptor Gene Polymorphisms With Markers of Metabolic Syndrome Among Adults.

Front Endocrinol (Lausanne) 2018 16;9:448. Epub 2018 Aug 16.

Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland.

Recent studies have demonstrated that vitamin D deficiency contributes to the development of metabolic disorders, including obesity and type 2 diabetes mellitus (T2DM). Several vitamin D receptor (VDR) gene polymorphisms had been described to play a role in these conditions since vitamin D receptors were found in many tissues. The aim of this study was to assess the relationship between vitamin D status and VDR gene polymorphisms with metabolic syndrome (MS) parameters in Russian middle-aged women. A total of 697 women aged between 30 to 55 years were included in this cross-sectional study. Serum 25-hydroxyvitamin D (25(OH)D) level and four VDR gene polymorphisms rs1544410 (), rs7975232 (), rs731236 (), and rs2228570 () were measured. We applied the International Diabetes Federation (IDF) criteria to identify subjects with MS. 9.3% of subjects had normal vitamin D level, while 90.7% were insufficient or deficient. Abdominal obesity (AO) was seen in 75.5%, impaired glucose tolerance (IGT) or T2DM was observed in 33.3%, reduced high-density lipoprotein cholesterol (HDL-C) level in 32.2% and hypertriglyceridemia in 23.4%. Serum 25(OH)D level in women with or without MS did not differ (48.6 ± 1.8 and 51.1 ± 1.5 nmol/l, > 0.05). Subjects with vitamin D deficiency showed an increased risk of AO [CI 95% 2.23; 1.15-4.30] and low HDL-C [CI95% 2.60; 1.04-6.49] compared to subjects with normal 25(OH)D level. IGT and T2DM risk was increased only when 25(OH)D concentration was less than 39.0 nmol/l [CI 95% 7.17; 2.99-17.7], but risk of MS did not differ in normal vitamin D status subjects and insufficient/deficient ones ( > 0.05). T allele carriers () of rs7975232 had higher total cholesterol and low-density lipoprotein cholesterol levels compared with the GG () genotypes. Similarly, GG ( genotype carriers of rs1544410 had higher triglyceride levels than subjects with A ( allele carriers. However VDR gene polymorphisms did not seem to be associated with an increased risk of MS. Vitamin D deficiency, rs7975232, and rs1544410 VDR gene variants are associated with MS parameters in Russian middle-aged women.
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http://dx.doi.org/10.3389/fendo.2018.00448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106967PMC
August 2018

Difference in Serum Endostatin Levels in Diabetic Patients with Critical Limb Ischemia Treated by Autologous Cell Therapy or Percutaneous Transluminal Angioplasty.

Cell Transplant 2018 09 4;27(9):1368-1374. Epub 2018 Jun 4.

3 Diabetes Centre, Tameside Hospital NHS Foundation Trust and University of Manchester, Lancashire, UK.

The aim of this study was to compare the serum levels of the anti-angiogenic factor endostatin (S-endostatin) as a potential marker of vasculogenesis after autologous cell therapy (ACT) versus percutaneous transluminal angioplasty (PTA) in diabetic patients with critical limb ischemia (CLI). A total of 25 diabetic patients with CLI treated in our foot clinic during the period 2008-2014 with ACT generating potential vasculogenesis were consecutively included in the study; 14 diabetic patients with CLI who underwent PTA during the same period were included in a control group in which no vasculogenesis had occurred. S-endostatin was measured before revascularization and at 1, 3, and 6 months after the procedure. The effect of ACT and PTA on tissue ischemia was confirmed by transcutaneous oxygen pressure (TcPO) measurement at the same intervals. While S-endostatin levels increased significantly at 1 and 3 months after ACT (both P < 0.001), no significant change of S-endostatin after PTA was observed. Elevation of S-endostatin levels significantly correlated with an increase in TcPO at 1 month after ACT ( r = 0.557; P < 0.001). Our study showed that endostatin might be a potential marker of vasculogenesis because of its significant increase after ACT in diabetic patients with CLI in contrast to those undergoing PTA. This increase may be a sign of a protective feedback mechanism of this anti-angiogenic factor.
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http://dx.doi.org/10.1177/0963689718775628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168989PMC
September 2018

Social deprivation modifies the association between incident foot ulceration and mortality in type 1 and type 2 diabetes: a longitudinal study of a primary-care cohort.

Diabetologia 2018 04 21;61(4):959-967. Epub 2017 Dec 21.

Salford Royal NHS Foundation Trust, Diabetes and Endocrinology, Stott Lane, Salford, UK.

Aims/hypothesis: The aim of this study was to determine whether social deprivation in the presence of diabetes is an independent predictor of developing a foot ulcer and separately of mortality.

Methods: This was a primary-care-based retrospective analysis of 13,955 adults with type 1 (n = 1370) or type 2 (n = 12,585) diabetes after a median follow-up of 10.5 years. Demographic characteristics, indices of social deprivation and clinical variables were assessed at baseline. The primary outcomes were new foot ulceration (in those without a previous history of foot ulcers) and all-cause mortality. Cox proportional hazard models were used to describe the associations among foot ulceration, social deprivation and mortality.

Results: The mean age of the population was 69.4 (range: 16-89) years. The incidence of foot ulceration was greater in individuals with type 2 (8.6%) compared with type 1 diabetes (4.8%). Occurrence was similar by sex, but increased with age and deprivation index. Individuals in the highest quintile of deprivation were 77% more likely to develop a foot ulcer compared with those in the lowest quintile (OR 1.77 [95% CI 1.45, 2.14], p < 0.0001). Overall, 2946 (21.1%) deaths were recorded. Compared with individuals without a foot ulcer, the development of a foot ulcer was associated with a higher age- and sex-adjusted mortality rate (25.9% vs 14.0%), and a 72% (HR 1.72 [95% CI 1.56, 1.90], p < 0.001) increased risk of mortality in those with type 2 diabetes. Risk of death increased by 14% per quintile of deprivation in a univariable analysis (HR 1.14 [95% CI 1.10, 1.17]). In multivariable Cox regression analyses, there was a 48% increased risk of mortality in individuals with a foot ulcer (HR 1.48 [95% CI 1.33, 1.66]) independent of the Townsend index score (HR 1.13 [95% CI 1.10, 1.17], per quintile), baseline age, sex, diabetes type, smoking status, hypertension, statin use, β-blocker use, metformin use, HbA levels and insulin use.

Conclusions/interpretation: This study confirms the high mortality rate in individuals with diabetes-related foot ulcers. In addition, socioeconomic disadvantage was found to be an independent effect modifier, contributing to an increased burden of mortality in people with diabetes who develop foot ulceration. In light of this, and as diabetes service configurations are orientated for the next 5-10 years, modelling of foot ulceration risk needs to take socioeconomic disadvantage into account.
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http://dx.doi.org/10.1007/s00125-017-4522-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448990PMC
April 2018

Diabetic complications do not hamper improvement of health-related quality of life over the course of treatment of diabetic foot ulcers - the Eurodiale study.

J Diabetes Complications 2017 Jul 13;31(7):1145-1151. Epub 2017 Apr 13.

Division of Endocrinology, Department of Internal Medicine and Research School CAPHRI, Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: Diabetic complications, and in particular diabetic foot ulcers (DFUs), are associated with low health-related quality of life (HRQoL). We evaluated whether the presence of diabetic complications also influenced the improvement of HRQoL during DFU treatment.

Methods: 1088 patients presenting for DFU treatment at the centers participating in the Eurodiale study were followed prospectively up to one year. HRQoL was measured both at presentation and after healing or at end of follow up, using EQ-5D: a standardized instrument consisting of five domains and a summary index. The influence of diabetic comorbidity on the course of HRQoL was evaluated for each of the EQ-5D outcomes in multi-level linear regression analyses, adjusting for baseline characteristics.

Results: HRQoL improved in all EQ-5D outcomes over the course of treatment for those DFUs that healed. The few significant differences in the development of HRQoL between patients with and without comorbidity showed a more beneficial development for patients with comorbidity in DFUs that did not heal or healed slowly.

Conclusions: Comorbidity does not hamper improvement of HRQoL in DFU treatment. On the contrary, HRQoL improved sometimes more in patients with certain comorbidity with hard-to-heal ulcers.
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http://dx.doi.org/10.1016/j.jdiacomp.2017.04.008DOI Listing
July 2017

Cell therapy of critical limb ischemia in diabetic patients - State of art.

Diabetes Res Clin Pract 2017 Apr 27;126:263-271. Epub 2017 Feb 27.

Diabetes Centre, Tameside Hospital NHS Foundation Trust and University of Manchester, Lancashire, UK.

In this review we report on the state of cell therapy of critical limb ischemia (CLI) with respect to differences between diabetic and non-diabetic patients mainly from the clinical point of view. CLI is the most severe form of peripheral arterial disease and its diagnosis and treatment in diabetic patients is very difficult. The therapeutic effect of standard methods of CLI treatment is only partial - more than one third of diabetic patients are not eligible for standard revascularization; therefore, new therapeutic techniques such as cell therapy have been studied in clinical trials. Presence of CLI in patients with diabetic foot disease is associated with worse clinical outcomes such as lack of healing of foot ulcers, major amputations and premature mortality. A revascularization procedure cannot be successful as the only method in contrast to patients without diabetes, but it must always be part of a complex therapy focused not only on ischemia, but also on treatment of infection, off-loading, metabolic control of diabetes and nutrition, local therapy, etc. Therefore, the main criteria for cell therapy may vary in diabetic patients and non-diabetic persons and results of this treatment method should always be assessed in the context of ensuring comprehensive therapy. This review carries out an analysis of the source of precursor cells, route of administration and brings a brief report of published data with respect to diabetic and non-diabetic patients and our experience with autologous cell therapy of diabetic patients with CLI. Analysis of the studies in terms of diabetes is difficult, because in most of them sub-analysis for diabetic patients is not performed separately. The other problem is that it is not clear if diabetic patients received adequate complex treatment for their foot ulcers which can strongly affect the rate of major amputation as an outcome of CLI treatment.
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http://dx.doi.org/10.1016/j.diabres.2017.02.028DOI Listing
April 2017

Diabetic Foot Infections: an Update in Diagnosis and Management.

Curr Diab Rep 2017 01;17(1)

First Department of Propaedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 33 Lakonias Street, 115 27, Athens, Greece.

Foot infections are a common problem in patients with diabetes and a risk factor for limb amputation. They occur as a result of skin ulceration, which facilitates penetration of pathogens to deeper tissues. The diagnosis of infection is clinical. Aerobic gram-positive cocci are the most common pathogens. Ulcers which are chronic, preceded by administration of antibiotics and hospitalization or complicated by severe infection are polymicrobial. Antibiotic therapy is initially empiric based on the severity of the infection. Definitive therapy is modified according to the results of the microbiological culture and the response to empiric treatment. The optimal duration of antibiotic therapy ranges from 1-2 weeks for mild infections to 2-4 weeks and even longer for severe infections and osteomyelitis. Surgical consultation should be sought for infections complicated with abscesses, necrotizing fasciitis or osteomyelitis. With appropriate care, infection resolves in about 80-90% of non-limb threatening and in about 60% of severe infections.
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http://dx.doi.org/10.1007/s11892-017-0831-1DOI Listing
January 2017

Concordance in diabetic foot ulceration: a cross-sectional study of agreement between wound swabbing and tissue sampling in infected ulcers.

Health Technol Assess 2016 11;20(82):1-176

Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

Background: There is inadequate evidence to advise clinicians on the relative merits of swabbing versus tissue sampling of infected diabetic foot ulcers (DFUs).

Objectives: To determine (1) concordance between culture results from wound swabs and tissue samples from the same ulcer; (2) whether or not differences in bacterial profiles from swabs and tissue samples are clinically relevant; (3) concordance between results from conventional culture versus polymerase chain reaction (PCR); and (4) prognosis for patients with an infected DFU at 12 months' follow-up.

Methods: This was a cross-sectional, multicentre study involving patients with diabetes and a foot ulcer that was deemed to be infected by their clinician. Microbiology specimens for culture were taken contemporaneously by swab and by tissue sampling from the same wound. In a substudy, specimens were also processed by PCR. A virtual 'blinded' clinical review compared the appropriateness of patients' initial antibiotic regimens based on the results of swab and tissue specimens. Patients' case notes were reviewed at 12 months to assess prognosis.

Results: The main study recruited 400 patients, with 247 patients in the clinical review. There were 12 patients in the PCR study and 299 patients in the prognosis study. Patients' median age was 63 years (range 26-99 years), their diabetes duration was 15 years (range 2 weeks-57 years), and their index ulcer duration was 1.8 months (range 3 days-12 years). Half of the ulcers were neuropathic and the remainder were ischaemic/neuroischaemic. Tissue results reported more than one pathogen in significantly more specimens than swabs {86.1% vs. 70.1% of patients, 15.9% difference [95% confidence interval (CI) 11.8% to 20.1%], McNemar's -value < 0.0001}. The two sampling techniques reported a difference in the identity of pathogens for 58% of patients. The number of pathogens differed in 50.4% of patients. In the clinical review study, clinicians agreed on the need for a change in therapy for 73.3% of patients (considering swab and tissue results separately), but significantly more tissue than swab samples required a change in therapy. Compared with traditional culture, the PCR technique reported additional pathogens for both swab and tissue samples in six (50%) patients and reported the same pathogens in four (33.3%) patients and different pathogens in two (16.7%) patients. The estimated healing rate was 44.5% (95% CI 38.9% to 50.1%). At 12 months post sampling, 45 (15.1%) patients had died, 52 (17.4%) patients had a lower-extremity ipsilateral amputation and 18 (6.0%) patients had revascularisation surgery.

Limitations: We did not investigate the potential impact of microbiological information on care. We cannot determine if the improved information yield from tissue sampling is attributable to sample collection, sample handling, processing or reporting.

Conclusions: Tissue sampling reported both more pathogens and more organisms overall than swabbing. Both techniques missed some organisms, with tissue sampling missing fewer than swabbing. Results from tissue sampling more frequently led to a (virtual) recommended change in therapy. Long-term prognosis for patients with an infected foot ulcer was poor.

Future Work: Research is needed to determine the effect of sampling/processing techniques on clinical outcomes and antibiotic stewardship.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta20820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116580PMC
November 2016
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