Can the introduction of a 12-lead ECG help reduce mortality in those presenting with foot ulceration to multidisciplinary diabetic foot clinics? An observational evaluation of a real-world implementation pilot in England.

AIMS/HYPOTHESIS: The risk of dying within 2 years of presentation with diabetic foot ulceration is over six times the risk of amputation, with CVD the major contributor. Using an observational evaluation of a real-world implementation pilot, we aimed to assess whether for those presenting with diabetic foot ulceration in England, introducing a 12-lead ECG into routine care followed by appropriate clinical action was associated with reduced mortality. METHODS: Between July 2014 and December 2017, ten multidisciplinary diabetic foot services in England participated in a pilot project introducing 12-lead ECGs for new attendees with foot ulceration. Inception coincided with launch of the National Diabetes Footcare Audit (NDFA), whereby all diabetic footcare services in England were invited to enter data on new attendees with foot ulceration. Poisson regression models assessed the mortality RR at 2 and 5 years following first assessment of those receiving care in a participating pilot unit vs those receiving care in any other unit in England, adjusting for age, sex, ethnicity, deprivation, type and duration of diabetes, ulcer severity, and morbidity in the year prior to first assessment. RESULTS: Of the 3110 people recorded in the NDFA at a participating unit during the pilot, 33% (1015) were recorded as having received an ECG. A further 25,195 people recorded in the NDFA had attended another English footcare service. Unadjusted mortality in the pilot units was 16.3% (165) at 2 years and 37.4% (380) at 5 years for those who received an ECG, and 20.5% (430) and 45.2% (950), respectively, for those who did not receive an ECG. For people included in the NDFA at other units, unadjusted mortality was 20.1% (5075) and 42.6% (10,745), respectively. In the fully adjusted model, mortality was not significantly lower for those attending participating units at 2 (RR 0.93 [95% CI 0.85, 1.01]) or 5 years (RR 0.95 [95% CI 0.90, 1.01]). At participating units, mortality in those who received an ECG vs those who did not was lower at 5 years (RR 0.86 [95% CI 0.76, 0.97]), but not at 2 years (RR 0.87 [95% CI 0.72, 1.04]). Comparing just those that received an ECG with attendees at all other centres in England, mortality was lower at 5 years (RR 0.87 [95% CI 0.78, 0.96]), but not at 2 years (RR 0.86 [95% CI 0.74, 1.01]). CONCLUSIONS/INTERPRETATION: The evaluation confirms the high mortality seen in those presenting with diabetic foot ulceration. Overall mortality at the participating units was not significantly reduced at 2 or 5 years, with confidence intervals just crossing parity. Implementation of the 12-lead ECG into the routine care pathway proved challenging for clinical teams-overall a third of attendees had one, although some units delivered the intervention to over 60% of attendees-and the evaluation was therefore underpowered. Nonetheless, the signals of potential mortality benefit among those who had an ECG suggest that units in a position to operationalise implementation may wish to consider this. DATA AVAILABILITY: Data from the National Diabetes Audit can be requested through the National Health Service Digital Data Access Request Service process at: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/national-diabetes-audit-nda.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Site-Specific, Critical Threshold Barefoot Peak Plantar Pressure Associated with Diabetic Foot Ulcer History: A Novel Approach to Determine DFU Risk in the Clinical Setting.

Background and Objectives: Barefoot peak plantar pressures (PPPs) are elevated in diabetes patients with neuropathic foot ulcer (DFU) history; however, there is limited reported evidence for a causative link between high barefoot PPP and DFU risk. We aimed to determine, using a simple mat-based methodology, the site-specific, barefoot PPP critical threshold that will identify a plantar site with a previous DFU. Materials and Methods: In a cross-sectional study, barefoot, site-specific PPPs were measured with normal gait for patients with DFU history (n = 21) and healthy controls (n = 12), using a validated carbon footprint system. For each participant, PPP was recorded at twelve distinct plantar sites (1st-5th toes, 1st-5th metatarsal heads (MTHs), midfoot and heel), per right and left foot, resulting in the analysis of n = 504 distinct plantar sites in the diabetes group, and n = 288 sites in the control group. Receiver operator characteristic curve analysis determined the optimal critical threshold for sites with DFU history. Results: Median PPPs for the groups were: diabetes sites with DFU history (n = 32) = 5.0 (3.25-7.5) kg/cm2, diabetes sites without DFU history (n = 472) = 3.25 (2.0-5.0) kg/cm2, control sites (n = 288) = 2.0 (2.0-3.25) kg/cm2; (p < 0.0001). Diabetes sites with elevated PPP (>6 kg/cm2) were six times more likely to have had DFU than diabetes sites with PPP ≤ 6 kg/cm2 (OR = 6.4 (2.8-14.6, 95% CI), p < 0.0001). PPP > 4.1 kg/cm2 was determined as the optimal critical threshold for identifying DFU at a specific plantar site, with sensitivity/specificity = 100%/79% at midfoot; 80%/65% at 5th metatarsal head; 73%/62% at combined midfoot/metatarsal head areas. Conclusions: We have demonstrated, for the first time, a strong, site-specific relationship between elevated barefoot PPP and previous DFU. We have determined a critical, highly-sensitive, barefoot PPP threshold value of >4.1 kg/cm2, which may be easily used to identify sites of previous DFU occurrence and, therefore, increased risk of re-ulceration. This site-specific approach may have implications for how high PPPs should be investigated in future trials.

Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes-ProNOx1 study.

The aim of this multicenter, prospective, observer-blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting "real world" clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25-2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12-week follow-up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110-75; Control-73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention-to-treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice.

FMLP-, thapsigargin-, and H2O2-evoked changes in intracellular free calcium concentration in lymphocytes and neutrophils of type 2 diabetic patients.

Type 2 diabetic (T2DM) patients are immune-compromised having a higher susceptibility to infections and long-term complications in different parts of the body contributing to increased morbidity and mortality. A derangement in the homeostasis of intracellular free calcium concentration [Ca²âº](i) is known to be associated with several diseases in the body including T2DM. Both neutrophils and lymphocytes play active protective roles in host immune response to infection showing impairment in microbicidal functions including phagocytosis and chemotaxis which are calcium-dependent processes. This study evaluated the process of [Ca²âº]i mobilization from both neutrophils and lymphocytes taken from blood of both T2DM patients and healthy age-matched control subjects investigating the effect of N-formyl-methionyl-leucyl-phenylalanine (fMLP), thapsigargin (TG), and hydrogen peroxide (H2O2) on [Ca²âº](i) homeostasis. This study employed isolated peripheral blood neutrophils and lymphocytes from 24 T2DM patients and 24 healthy volunteers. Either neutrophils or lymphocytes were stimulated separately with fMLP, TG, or H2O2. Induced changes in [Ca²âº] in both neutrophils and lymphocytes were evaluated using spectrofluorometric methods. Stimulation of human neutrophils and lymphocytes with fMLP, TG, or H2O2 in the presence of [Ca²âº]o resulted in significant decreases in [Ca²âº](i) mobilization from T2DM patients compared with healthy controls. These data indicate that neutrophils and lymphocytes from T2DM patients are less responsive to calcium mobilizing agents compared with granulocytes from healthy controls and this is possibly due to the hyperglycemia. The results suggest that agonist-evoked decrease in [Ca²âº](i) in immune cells might be one of the possible mechanisms of impaired immunity in diabetic patients.

Not So Innocent Indapamide.

A 58-year-old asymptomatic man was referred by his general practitioner for abnormal blood results. Routine blood tests to monitor blood count and kidney functions showed neutropenia and hyponatremia. He was euvolemic on examination. A further detailed investigation did not reveal any cause of neutropenia and hyponatremia. After careful assessment of their drug history, it transpired he recently started Indapamide for uncontrolled hypertension. Hyponatraemia is a common side effect of Indapamide and in addition, it can rarely cause agranulocytosis and leukopenia. Indapamide was stopped and the blood counts started to improve and became normal after two weeks.

Diabetic foot problem in Nepal.

Introduction: Nepal is a developing country where diabetes is becoming a major health challenge due to its high prevalence of 8.5% affecting around 2 million people. Due to limited resources, there are many barriers to providing affordable and convenient diabetes care or regular screening for complications. There is no reliable data on incidence, prevalence, and complications of diabetic foot problems in Nepal. Methods: We conducted an online survey amongst senior physicians, who were members of 'Diabetes & Endocrine Association of Nepal' to assess their perception of diabetic foot problems in Nepal. Results: Thirty-Eight physicians responded to the survey who saw a total of 17597 patients in the preceding month. They recalled seeing 647 with 'Diabetic Foot Ulcers', giving a crude Diabetic Foot Ulcer prevalence rate of 3.7%. They recalled seeing 2522 patients with painful neuropathy that required medical treatment, giving a crude painful neuropathy prevalence rate of 14.3%. A history of foot ulcer was present in an additional 578 patients. Previous minor amputation had been performed in 215 patients (1.2%) and major amputation in 135 patients (0.8%). Discussion: Despite having expertise in various fields there is no dedicated multi-disciplinary diabetic foot clinic in Nepal. This survey shows that diabetic foot problems are abundant in Nepal and there is a need for structured multi-disciplinary approach for screening and treatment.

The Real-Life Outcome of VACOped Boot in the Management of Diabetic Foot Ulcers.

The total contact cast (TCC) is considered the gold standard treatment to off-load diabetic foot ulcers (DFUs); however, the use of TCC can be limited due to various reasons such as underlying infections, ischemia, and patient's reluctance. Removable cast walkers are used in such cases, and the VACOped boot is one such device. The aim of this study was to analyze the results of the VACOped boot in the treatment of DFUs in real life. Case records of all patients with DFUs treated with a VACOped from 2011 to 2017 were reviewed retrospectively. Eighty-three episodes of ulcerations in 42 subjects were identified, of which 48 (57.8%) healed in a median duration of 17.5 (95% confidence interval = 15-33) weeks with the use of the VACOped and 35 (42.2%) discontinued its use. The median duration of healing with the VACOped of 17.5 weeks appears to be longer, but this cohort included patients with underlying infection and ischemia, which are often excluded in the clinical trials of off-loading. Our data show that the VACOped application is preferred by many patients and seems to be equally effective to other removable cast walkers.

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

An intelligent insole system with personalised digital feedback reduces foot pressures during daily life: An 18-month randomised controlled trial.

AIMS: High plantar pressure is a major risk factor in the development of diabetic foot ulcers (DFUs) and recent evidence shows plantar pressure feedback reduces DFU recurrence. This study investigated whether continued use of an intelligent insole system by patients at high-risk of DFUs causes a reduction in plantar pressures. METHODS: Forty-six patients with diabetic peripheral neuropathy and previous DFU were randomised to intervention (IG) or control groups (CG). Patients received an intelligent insole system, consisting of pressure-sensing insoles and digital watch. Patients wore the device during all daily activity for 18-months or until ulceration, and integrated pressure was recorded continuously. The device provided high-pressure feedback to IG only via audio-visual-vibrational alerts. High-pressure parameters at the whole foot, forefoot and rearfoot were compared between groups, with multilevel binary logistic regression analysis. RESULTS: CG experienced more high-pressure bouts over time than IG across all areas of the foot (P < 0.05). Differences between groups became apparent >16 weeks of wearing the device. CONCLUSIONS: Continuous plantar pressure feedback via an intelligent insole system reduces number of bouts of high-pressure in patients at high-risk of DFU. These findings suggest that patients were learning which activities generated high-pressure, and pre-emptively offloading to avoid further alerts.

The DFUC 2020 Dataset: Analysis Towards Diabetic Foot Ulcer Detection.

Every 20 seconds a limb is amputated somewhere in the world due to diabetes. This is a global health problem that requires a global solution. The International Conference on Medical Image Computing and Computer Assisted Intervention challenge, which concerns the automated detection of diabetic foot ulcers (DFUs) using machine learning techniques, will accelerate the development of innovative healthcare technology to address this unmet medical need. In an effort to improve patient care and reduce the strain on healthcare systems, recent research has focused on the creation of cloud-based detection algorithms. These can be consumed as a service by a mobile app that patients (or a carer, partner or family member) could use themselves at home to monitor their condition and to detect the appearance of a DFU. Collaborative work between Manchester Metropolitan University, Lancashire Teaching Hospitals and the Manchester University NHS Foundation Trust has created a repository of 4,000 DFU images for the purpose of supporting research toward more advanced methods of DFU detection. This paper presents a dataset description and analysis, assessment methods, benchmark algorithms and initial evaluation results. It facilitates the challenge by providing useful insights into state-of-the-art and ongoing research.

Recognition of ischaemia and infection in diabetic foot ulcers: Dataset and techniques.

Recognition and analysis of Diabetic Foot Ulcers (DFU) using computerized methods is an emerging research area with the evolution of image-based machine learning algorithms. Existing research using visual computerized methods mainly focuses on recognition, detection, and segmentation of the visual appearance of the DFU as well as tissue classification. According to DFU medical classification systems, the presence of infection (bacteria in the wound) and ischaemia (inadequate blood supply) has important clinical implications for DFU assessment, which are used to predict the risk of amputation. In this work, we propose a new dataset and computer vision techniques to identify the presence of infection and ischaemia in DFU. This is the first time a DFU dataset with ground truth labels of ischaemia and infection cases is introduced for research purposes. For the handcrafted machine learning approach, we propose a new feature descriptor, namely the Superpixel Colour Descriptor. Then we use the Ensemble Convolutional Neural Network (CNN) model for more effective recognition of ischaemia and infection. We propose to use a natural data-augmentation method, which identifies the region of interest on foot images and focuses on finding the salient features existing in this area. Finally, we evaluate the performance of our proposed techniques on binary classification, i.e. ischaemia versus non-ischaemia and infection versus non-infection. Overall, our method performed better in the classification of ischaemia than infection. We found that our proposed Ensemble CNN deep learning algorithms performed better for both classification tasks as compared to handcrafted machine learning algorithms, with 90% accuracy in ischaemia classification and 73% in infection classification.

Survival at 10 years following lower extremity amputations in patients with diabetic foot disease.

BACKGROUND: Amputations are associated with markedly reduced long-term survival in patients with diabetic foot disease. However, there is paucity of long-term survival data in published literature. METHODS: We searched the electronic case records and laboratory details of patients who underwent amputations between 1997 and 2006 to obtain at least 10 years of follow up data after the surgery to assess the survival rates and possible risk factors reducing survival in the year 2016. Amputation level below ankle was considered as minor and above ankle as major amputations. RESULTS: Of the 233 cases (159 males; median age 68 years), 161 had major amputations. Of the 72 cases who had minor amputations initially, 63 needed a further amputation or contralateral amputation on follow up. One hundred seventy-seven patients (76%) were not alive after 10 years of follow up. The survival rates at 1, 3, 5, 7, and ≥10 years were 64%, 50%, 40%, 34%, and 24%, respectively. Maximum number of deaths occurred within 4 months of amputations. There was no difference between survival rates following major or minor amputations and among males or females. The only statistically significant parameter affecting lower survival rate was age ≥70 years, with each additional year of age increasing the hazard by a factor of 1.039 (95% CI: 1.024-1.054) or 3.9% (2.4-5.4%). CONCLUSIONS: Five-year and 10-year survival rates were 40% and 24%, respectively, following diabetic foot amputations. Higher age ≥70 years was associated with lower survival rate compared with younger age groups after lower extremity amputations.

Robust Methods for Real-Time Diabetic Foot Ulcer Detection and Localization on Mobile Devices.

Current practice for diabetic foot ulcers (DFU) screening involves detection and localization by podiatrists. Existing automated solutions either focus on segmentation or classification. In this work, we design deep learning methods for real-time DFU localization. To produce a robust deep learning model, we collected an extensive database of 1775 images of DFU. Two medical experts produced the ground truths of this data set by outlining the region of interest of DFU with an annotator software. Using five-fold cross-validation, overall, faster R-CNN with InceptionV2 model using two-tier transfer learning achieved a mean average precision of 91.8%, the speed of 48 ms for inferencing a single image and with a model size of 57.2 MB. To demonstrate the robustness and practicality of our solution to real-time prediction, we evaluated the performance of the models on a NVIDIA Jetson TX2 and a smartphone app. This work demonstrates the capability of deep learning in real-time localization of DFU, which can be further improved with a more extensive data set.

Combined exercise and visual gaze training improves stepping accuracy in people with diabetic peripheral neuropathy.

INTRODUCTION: Patients with diabetes and diabetic peripheral neuropathy (DPN) place their feet with less accuracy whilst walking, which may contribute to the increased falls-risk. This study examines the effects of a multi-faceted intervention on stepping accuracy, in patients with diabetes and DPN. METHODS: Forty participants began the study, of which 29 completed both the pre and post-intervention tests, 8 patients with DPN, 11 patients with diabetes but no neuropathy (D) and 10 healthy controls (C). Accuracy of stepping was measured pre- and post-intervention as participants walked along an irregularly arranged stepping walkway. Participants attended a one-hour session, once a week, for sixteen weeks, involving high-load resistance exercise and visual-motor training. RESULTS: Patients who took part in the intervention improved stepping accuracy (DPN: +45%; D: +36%) (p < 0.05). The diabetic non-intervention (D-NI) group did not display any significant differences in stepping accuracy pre- to post- the intervention period (-7%). DISCUSSION: The improved stepping accuracy observed in patients with diabetes and DPN as a result of this novel intervention, may contribute towards reducing falls-risk. This multi-faceted intervention presents promise for improving the general mobility and safety of patients during walking and could be considered for inclusion as part of clinical treatment programmes.

Innovative intelligent insole system reduces diabetic foot ulcer recurrence at plantar sites: a prospective, randomised, proof-of-concept study.

BACKGROUND: Prevention of diabetic foot ulcer recurrence in high risk patients, using current standard of care methods, remains a challenge. We hypothesised that an innovative intelligent insole system would be effective in reducing diabetic foot ulcer recurrence in such patients. METHODS: In this prospective, randomised, proof-of-concept study, patients with diabetes, and with peripheral neuropathy and a recent history of plantar foot ulceration were recruited from two multidisciplinary outpatient diabetic foot clinics in the UK, and were randomly assigned to either intervention or control. All patients received an insole system, which measured plantar pressure continuously during daily life. The intervention group received audiovisual alerts via a smartwatch linked to the insole system and offloading instructions when aberrant pressures were detected; the control group did not receive any alerts. The primary outcome was plantar foot ulcer occurrence within 18 months. This trial is registered with ISRCTN, ISRCTN05585501, and is closed to accrual and complete. FINDINGS: Between March 18, 2014, and Dec 20, 2016, 90 patients were recruited and consented to the study, and 58 completed the study. At follow-up, ten ulcers from 8638 person-days were recorded in the control group and four ulcers from 11 835 person-days in the intervention group: a 71% reduction in ulcer incidence in the intervention group compared with the control group (incidence rate ratio 0·29, 95% CI, 0·09-0·93; p=0·037). The number of patients who ulcerated was similar between groups (six of 26 [control group] vs four of 32 [intervention group]; p=0·29); however, individual plantar sites ulcerated more often in the control group (ten of 416) than in the intervention group (four of 512; p=0·047). In an exploratory analysis of good compliers (n=40), ulcer incidence was reduced by 86% in the intervention group versus control group (incidence rate ratio 0·14, 95% CI 0·03-0·63; p=0·011). In the exploratory analysis, plantar callus severity (change from baseline to 6 months) was greater in re-ulcerating patients (6·5, IQR 4·0-8·3) than non-re-ulcerating patients (2·0, 0·0-4·8; p=0·040). INTERPRETATION: To our knowledge, this study is the first to show that continuous plantar pressure monitoring and dynamic offloading guidance, provided by an innovative intelligent insole system, can lead to a reduction in diabetic foot ulcer site recurrence. FUNDING: Diabetes UK and Orpyx Medical Technologies.

A New Mobile Application for Standardizing Diabetic Foot Images.

BACKGROUND: We describe the development of a new mobile app called "FootSnap," to standardize photographs of diabetic feet and test its reliability on different occasions and between different operators. METHODS: FootSnap was developed by a multidisciplinary team for use with the iPad. The plantar surface of 30 diabetic feet and 30 nondiabetic control feet were imaged using FootSnap on two separate occasions by two different operators. Reproducibility of foot images was determined using the Jaccard similarity index (JSI). RESULTS: High intra- and interoperator reliability was demonstrated with JSI values of 0.89-0.91 for diabetic feet and 0.93-0.94 for control feet. CONCLUSIONS: Similarly high reliability between groups indicates FootSnap is appropriate for longitudinal follow-ups in diabetic feet, with potential for monitoring pathology.

Achilles Tendon in Diabetes.

INTRODUCTION: Diabetes mellitus is one of the most common metabolic problems and is characterized by persistent hyperglycaemia. Exposure to chronic hyperglycaemia can affect many tissues including the Achilles Tendon, which is one of the largest tendons in the body. The current literature on the effects of hyperglycaemia on tendons is sparse, though evidence on rat models does suggest a process of chronic degeneration, which is increased in the presence of neuropathy and deformity. There is no epidemiological data on rupture of Achilles tendon in diabetes. Similarly, the knowledge of the best treatments for this condition in people with diabetes is also lacking. CONCLUSION: In this review we have systematically analysed current literature in this area and suggested future studies.

Diabetic Neuropathy and Gait: A Review.

Diabetic peripheral neuropathy (DPN) is a major sequela of diabetes mellitus and may have a detrimental effect on the gait of people with this complication. DPN causes a disruption in the body's sensorimotor system and is believed to affect up to 50% of patients with diabetes mellitus, dependent on the duration of diabetes. It has a major effect on morbidity and mortality. The peripheral nervous system controls the complex series of events in gait through somatic and autonomic functions, careful balancing of eccentric and concentric muscle contractions and a reliance on the sensory information received from the plantar surface. In this literature review focussing on kinetics, kinematics and posture during gait in DPN patients, we have identified an intimate link between DPN and abnormalities in gait and demonstrated an increased risk in falls for older patients with diabetes. As such, we have identified a need for further research on the role of gait abnormalities in the development of diabetic foot ulceration and subsequent amputations.