Diabetic Foot Ulcer Patients Research Articles

Factors Affecting Platelet-Rich Plasma Success in Patients With Diabetic Foot Ulcer.

Introduction Diabetic foot ulcers (DFU) are one of the most common complications of diabetes mellitus (DM). The use of platelet-rich plasma (PRP) in the treatment of DFU has been increasing in recent years. In the current study, we aimed to evaluate the factors affecting the success of PRP in the management of DFU. Methods The present study was planned in a prospective manner, and we enrolled patients with DFU inthe study. Patients' characteristics, DFU properties, and treatment outcomes were recorded. Patients with DFU were classified into two groups according to PRP success: healed DFU patients in Group 1 and non-healed DFU patients in Group 2. Groups were compared according to patient characteristics and treatment outcomes, and multivariate regression analysis was performed to clarify factors that predicted PRP success. Results In total, 182 patients were enrolled in the study, and DFU in 141 (77.5%) patients healed with PRP treatment. The mean body mass index (BMI) was significantly higher in the non-healed patients (p= 0.005). The smoking rate was 58.5% in the non-healed group and 39.7% in the healed group (p= 0.016). The duration of DM (17.9 yearsvs.22.5 years, p= 0.003) was significantly longer, and patients with glomerular filtration rate (GFR) < 60 (44.0%vs.63.4, p= 0.028) were significantly more common in the non-healed group. Multivariate regression analysis demonstrated that BMI ≥30 kg/m2and duration of DM ≥20 years were predictive factors for PRP failure in patients with DFU (p= 0.019 and p= 0.005). Smoking and GFR <60 were significantly associated with PRP failure (p= 0.040 and p= 0.044). Conclusion In our study, it was found that PRP was an effective treatment that improved DFU in 141 out of 182 patients. Moreover, the present study demonstrated for the first time that higher BMI, longer duration of DM, smoking, and lower GFR were significantly related to PRP failure in patients with DFU.

1000-P: The Economic Impact of Reducing Hospitalizations and Amputations in Patients with Diabetic Foot Ulcers

The purpose of this real-word evidence (RWE) cohort study was to evaluate whether utilization of Cyclical Pressurized Topical Oxygen (TWO2) therapy had any impact on the incidence of Diabetic Foot Ulcer related hospitalizations and amputations over a 12-month period in patients with hard to heal Diabetic foot Ulcers (DFU). An IRB approved retrospective review of deidentified DFU patient medical records was conducted at 2 US Veterans Affairs Medical Centers in Illinois and Virginia, which included demographic information on wound characteristics, clinical characteristics, neuropathy, cardiovascular disease (CVD), peripheral vascular disease (PVD), pain levels and kidney disease etc. Within the unmatched cohorts of the 202 DFU patients (91 TWO2, 111 NO TWO2)there was an 88% reduction in hospitalizations and a 71% reduction in amputations over a 12-month period for the patients treated with TWO2 therapy compared to those that did not receive TWO2 therapy. Propensity score matching was conducted showing similar outcomes and a regression analysis as preformed along with a budget impact model which demonstrated significant cost saving to the payor system. This large RWE study demonstrates the TWO2 therapy positively impacts patients quality of life and the costs associated with treating their DFU by forcing them into remission, resulting in significantly reduced rates of hospitalizations, amputations and cost outlay. Disclosure M.G.Garoufalis: Consultant; Uluru, Employee; AOT Inc., Speaker's Bureau; 3M/KCI, Horizon Therapeutics plc.

100-OR: A Novel Macrophage-Regulation Drug for Treating Diabetic Foot Ulcer—A Phase III MRCT Study and Taiwan Experience

Macrophage regulation plays an essential role in Diabetic foot ulcer (DFU) healing. By recognizing the therapeutic potential in M1/M2-macrophage-regulation for DFUs, we aim to investigate the efficacy and safety of ON101, a topical new drug with a M1/M2-macrophage-regulating mechanism in phase 3 MRCT across the US, China, and Taiwan (NCT01898923). There are 236 eligible subjects with Wagner Grade 1 or 2 DFU(s), randomized 1:1 to receive ON101 or comparator for up to 16 weeks, followed by a 12-week follow-up. The incidence of complete healing was 60.7% by ON101 and 35.1% by the comparator (P=0.0001). The time to complete ulcer healing was faster in the ON101 group (P=0.002). Since the high levels of HbA1C, ulcer persistence, ulcer location, and amputation history as the risk factors leading to poor DFU outcomes, ON101 also showed demonstrated robust efficacy and safety in hard-to-heal ulcers. ON101, approved by Taiwan FDA in 2021, was shown with excellent therapeutic efficacy and safety in the treatment of DFUs. In a real-world scenario, case collation from 133 patients, ulcer severity with Wagner grade 1 to 4, after applying ON101, the average ulcer complete healing rate is 71%, no adverse events were related to ON101, which validates the drug safety of ON101. ON101 further supports its excellent ability to promote wound healing in DFU patients with various severities (Wagner grade 1 to 4). All those patients who applied ON101 alone or with other therapies reached ulcer healing under infection control and with necessary debridement. Macrophage-regulating drug achieved superior therapeutic efficacy in a large Phase 3 MRCT and has demonstrated excellent therapeutic efficacy in the real-world scenario where Wagner grade 3 and 4 DFUs reached ulcer healing when ON101 was combined with other therapies. This enlightens the future treatment in Wagner grade 1 to 4 DFUs by macrophage immunomodulation new drug as a promising solution. Disclosure S.Chen: Employee; Oneness Biotech Co., Ltd. S.Chu: None. C.Pu: None. J.Chen: Employee; Oneness Biotech Company. Y.Wu: Employee; Oneness Biotech Co., Ltd.

Deep Learning-Based Classification and Feature Extraction for Predicting Pathogenesis of Foot Ulcers in Patients with Diabetes.

The World Health Organization (WHO) has identified that diabetes mellitus (DM) is one of the most prevalent disease worldwide. Individuals with DM have a higher risk of mortality, and it is crucial to prioritize the treatment of foot ulcers, which is a significant complication associated with the disease, as they lead to the development of plantar ulcers, which results in the need to amputate part of the foot or leg. People with diabetes are at risk of experiencing various complications, such as heart disease, eye problems, kidney dysfunction, nerve damage, skin issues, foot ulcers, and dental diseases. Unawareness of the risk associated with diabetic foot ulcers (DFU) is a significant contributing factor to the mortality of diabetic patients. Evolving technological advancements such as deep learning techniques can be used to predict the symptoms of diabetic foot ulcers as early as possible, which helps to provide effective treatment to DM patients. This research introduces a methodology for analyzing images of foot ulcers in diabetic patients, focusing on feature extraction and classification. The dataset used in this study was collected from historical medical records and foot images of patients with diabetes, who commonly experience foot ulcers as a major complication. The dataset was pre-processed and segmented, and features were extracted using a deep recurrent neural network (DRNN). Image and numerical/text data were extracted separately, and the normal and abnormal diabetes ranges were identified. Foot images of patients with abnormal diabetes ranges were separated and classified using a pre-trained fast convolutional neural network (PFCNN) with U++net. The classification procedure involves the analysis of foot ulcers to predict their pathogenesis. To assess the effectiveness of the proposed technique, the study presented simulation results, including a confusion matrix and receiver operating characteristic curve. These results specifically focused on predicting two classes: normal and abnormal diabetes foot ulcerations. The analysis yielded various parameters, including accuracy, precision, recall curve, and area under the curve. The main goal of the study was to introduce an novel technique for assessing the risk of foot ulceration development in patients with diabetes, leveraging the analysis of foot ulcer images. The researchers collected a dataset of foot images and medical data from historical records of patients with diabetes and pre-processed and segmented the data. They then used a deep recurrent neural network to extract features from the segmented data and identified normal and abnormal diabetes ranges based on numerical and text data. Foot images of patients with abnormal diabetes ranges were classified using a pre-trained fast convolutional neural network with U++net to examine foot ulcers and forecast the development of the risk of diabetic foot ulcers (DFU). The study assessed the accuracy of the proposed technique as 99.32% by simulating results for feature extraction and the classification of diabetic foot ulcers. A comparison was made between this proposed technique and existing approaches.

Interspecies interactions in mixed-species biofilms formed by Enterococcus faecalis and gram-negative bacteria isolated from polymicrobial diabetic foot ulcers

Diabetic foot ulcers (DFU) are exacerbated by bacterial colonisation. Here, a high prevalence of Enterococcus faecalis was observed in DFU patients from an Argentinean hospital. E. faecalis was frequently co-isolated with Escherichia coli, Morganella morganii, and Pseudomonas aeruginosa. The effect of interspecies interactions on bacterial growth was investigated in mixed-species macrocolony biofilms developed in Lubbock-Glc-agar. Similar cell counts were found for E. faecalis and M. morganii growing in mixed and single-species biofilms. An E. faecalis strain showed 1 Log higher cell counts in mixed biofilms with E. coli. Remarkably, E. faecalis strains showed 2 to 4 Log higher cell counts in mixed biofilms with P. aeruginosa. This effect was not observed in planktonic growth or biofilms developed in tryptic soy agar. The present findings reveal bacterial interactions that benefit E. faecalis in mixed-species biofilms, mainly with P. aeruginosa, in a medium that partially mimics the nutrients found in DFU.

Proteomics and transcriptomics explore the effect of mixture of herbal extract on diabetic wound healing process

BackgroundThe annual incidence of diabetic foot ulcers (DFUs) has been reported to vary from 0.2% to 11% in diabetes-specific clinical settings and less than 0.1% to 8% in community- and population-based cohorts. According to the International Diabetes Foundation, approximately 40 million to 60 million people worldwide are affected by DFUs, and a recent meta-analysis indicates a global prevalence of 6.3% among adults with diabetes, or about 33 million individuals. The cost of diabetes care is significant, amounting to $273 billion in direct and $90 billion in indirect expenses annually, in America. Foot complications in diabetes care excess annual expenditures ranging from 50% to 200% above the baseline cost of diabetes-related care. The cost of advanced-stage ulcers can be more than $50,000 per wound episode, and the direct expenses of major amputation are even higher. DFUs can be treated using various methods, including wound dressings, antibiotics, pressure-off loading, skin substitutes, stem cells, debridement, topical oxygen therapy, gene therapy and growth factors. For severe DFUs patients are at risk of amputation if treatment is not timely or appropriate. Amputating limbs not only causes physical pain to patients, but also brings economic burden due to lost productivity, and decreased employment linked to DFUs. Currently, long-term use of local antibiotics in clinical practice is prone to induce drug resistance, while growth factors do not effectively inhibit bacterial growth and control inflammation in wounds. Stem cell and gene therapies are still in the experimental stage. The method of local debridement combined with negative pressure therapy is expensive. Therefore, we urgently need an affordable, non-surgical method to treat diabetic ulcers. Extracts of bark of Bauhinia purpurea, Paeoniae rubrae, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Acorus calamus L, and Radix Angelicae biseratae have been used as traditional remedies to treat inflammation-related diseases and cutaneous wounds due to their anti-inflammatory properties and their ability to promote vascular renewal. However, there have been few studies on the mixture of these five herbal extracts on diabetic wound healing. PurposeThis study was designed to assess the healing effect of a mixture of five aforementioned herbal extracts on diabetic ulcer wounds in rats, and to reveal the potential mechanisms behind any potential wound healing using transcriptomics and proteomics. Study designWe designed the experiment to explore the effects of five herbal extracts on diabetic wound healing process through in vivo experiments and to investigate the underlying mechanisms through proteomics and transcriptomics. MethodsWe used a mixture of five aforementioned herbal extract to treat rat model of diabetic established by intraperitoneal injection of streptozotocin, and a 2 × 2 cm round full-thickness skin defect was created on the back of the rat. Staphylococcus aureus (1 ml of 1.5 × 109 cfu/ml) was evenly applied to the wound. The wound was then observed for 72 h. The infected ulcer model of diabetic rats was considered to be successfully established if the wound was found to be infected with S. aureus. According to different medications, the rats were divided into three groups, namely mixture of herbal extract (MHE), Kangfuxin solution (KFS) and control (Ctrl). The effects of the medicine on wound healing were observed. HE staining and Masson staining were performed to evaluate the histopathological changes and collagen synthesis. IHC staining was used to assess the neovascularization, and M2 macrophage proliferation was determined by immunofluorescence staining. Proteomic and transcriptomic studies were performed to explore potential mechanism of five herbal extracts to promote wound healing. UHPLC-QE-MS was performed to identify the chemical composition of mixture of herbal extract. ResultsThe study show that the mixed herbal extract promotes angiogenesis, proliferation of M2 macrophages, and collagen synthesis. Transcriptomics showed that rno-miR-1298, rno-miR-144-5p, and rno-miR-92a-1-5p are vital miRNAs which also play a significant role in role in regulating wound healing. Proteomics results showed that the following proteins were important in wounds treated with MHE: Rack1, LOC100362366, Cops2, Cops6, Eif4e, Eif3c, Rpl12, Srp54, Rpl13 and Lsm7. Autophagy, PI3-Akt and mTOR signaling pathways were enriched after treatment with MHE compared to other groups. ConclusionHerein, we have shown that MHE containing extracts of bark of Bauhinia purpurea, P. rubrae, A. dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., A. calamus L, and R. A. biseratae has significant wound healing effects in the diabetic ulcer wound rat model. These results suggest that local application of MHE in diabetic wounds can accelerate the wound healing process. Moreover, in vivo experiments revealed that the diabetic wound healing process was primarily mediated by angiogenesis and M2 macrophage transition. Therefore, this study may provide a promising and non-surgical therapeutic strategy to accelerate diabetic wound healing, thereby decreasing the number of limb amputations in diabetic patients.

Digital Image Analysis of Diabetic Foot Ulcer Areas Using ImageJ Software (National Institute of Health, USA) in Patients Treated with Autologous Activated Platelet-rich Plasma Injection

Background: In this cross-sectional study, we investigated three diabetic foot ulcer (DFU) patients. DFU is a serious diabetes complication affecting general health and social life. Autologous regenerative therapies, such as autologous activated platelet-rich plasma (aaPRP), have been proposed for DFU management. However, precise instruments are required to measure the wound size to evaluate wound closure after treatment. Objectives: This study aimed to evaluate the DFU healing process treated by aaPRP through digital image analysis using ImageJ software (National Institute of Health, USA). Methods: The DFU patients were administered aaPRP and followed up on days 7 and 14. The healing process was analyzed through ImageJ software. Paired t-test was used to assess the wound healing process. Results: The results showed that ImageJ was useful for wound area measurement. Granulation and sloughy tissue development can be evaluated and calculated as a part of wound healing progress. Conclusions: We conclude that ImageJ facilitates DFU analysis not only about the size but also on the healing time process through visualization of granulation and sloughy tissue formation, which can represent the healing progress.

Evaluation of Peripheral Arterial Disease in Patients Presenting with Diabetic Foot Ulcer to Endocrine Clinic

Background and Aim: Diabetes mellitus is an increase in blood glucose levels results in altered fat, protein metabolism, and carbohydrate which leads to cardiac, eye, nervous system dysfunction, and kidney. The major cause of hospitalizations in patients with diabetes mellitus (DM) is diabetic foot ulcers (DFU). The purpose of the present study was to evaluate the peripheral arterial disease in diabetic foot ulcer patients presented to endocrine clinic. Patients and Methods: This descriptive cross-sectional study was carried out on 206 diabetic foot ulcers patients presented to the endocrine clinic in Peshawar from January 2021 to December 2022. Patients were enrolled after taking written informed consent from each individual. Patient’s details such as gender, age, peripheral artery disease (PAD), diabetes types, heart failure, wound size, diabetes duration, end-stage renal disease, DFU history, prior history of amputation, and peripheral neuropathy were recorded. Angiography and revascularization may be required if arterial Doppler ultrasound confirmed PAD. Additionally, wound debridement and topical dressings were applied. In the treatment of wound ischemia, pentoxifylline, and calcium blockers were recommended along with diabetes control procedures and appropriate antibiotics. SPSS version 27 was used for data analysis. Results: Of the total 206 DFU patients, there were 142 (68.9%) male and 64 (31.1%) females. The prevalence of peripheral artery disease (PAD) was 58.3% (n=120). Age-wise distribution of patients were as follows: 31 (15%) in 25-45 years, 107 (52%) in 46-65 years, 60 (29.1%) in 66-85 years, and 8 (3.9%) &gt;85 years. Out of 206 DFU patients, the prevalence of type-I diabetes mellitus and type-II diabetes mellitus was 8 (3.9%) and 198 (96.1%) respectively. PAD prevalence was significantly associated with Type 2 diabetes. The incidence of PAD in plantar foot, non-plantar foot, and heel was 66 (55%), 42 (35%), and 12 (10%) respectively among 120 cases. Out of 206 DFU cases, the incidence of peripheral neuropathy, DFU history, amputation history, heart failure, and chronic renal failure was 142 (68.9%), 104 (50.5%), 54 (26.2%), 46 (22.3%), and 42 (20.4%) respectively. Conclusion: The present study concluded that the prevalence of peripheral artery disease (PAD) was 58.3% among diabetic foot ulcers. Results indicate that DFU and PAD are significantly related. It has been found that male patients with DFU were more likely to suffer from PAD as compared to women with statistically insignificant association. Keywords: Peripheral artery disease, diabetic foot ulcers, type-II diabetes mellitus

Foot Care Knowledge and Education In An Effort To Prevent The Recurrent Of Diabetic Foot Ulcer (Dfu)

Diabetic Foot Ulcer (DFU) is a complication of Diabetes Mellitus (DM), which is a major health problem throughout the world with a high recurrence rate. It is estimated that approximately 40% of patients have a recurrence within one year of ulcer healing, nearly 60% within three years, and 65% within five years. One of the efforts to prevent DFU recurrence can be made with foot care which is preceded by knowledge of foot care. This study aimed to compare the knowledge of DFU patients before and after being given education. This study is a pre-post-test with 21 respondents who routinely received wound care at Rumah Perawatan ETN CENTER. Measurement of initial knowledge using a questionnaire consists of 11 questions that have been tested for content validity (CVI &gt; 80%). Then the patient is given foot care education using a video, and after that, the video link is distributed to the patient; patient knowledge was measured again after three weeks using the same questionnaire. There is a comparison of knowledge before and after being given foot care education with a p-value = 0.000. Foot care is one of the efforts to prevent recurrent DFU. There was an increase in patient knowledge after being given an education

A cross-sectional survey and analysis of the pain status and its influencing factors in diabetic foot ulcer patients

Objective: To investigate the pain status in diabetic foot ulcer (DFU) patients and analyze its influencing factors. Methods: A single-center cross-sectional survey research method was used. From May 2021 to February 2022, DFU patients who were admitted to the Fourth Medical Center of PLA General Hospital and met the inclusion criteria were selected and investigated. The scores of the heaviest pain, the least pain, the average pain, and the current pain in pain degree and the total score and the scores of influence on patients' daily life, mood, walking ability, daily work, relationship with others, sleep, and life interest in pain-related effects and the total score of patients were evaluated by the brief pain inventory. A self-designed general data questionnaire was used to collect the data including patients' gender, age, education level, body mass index, self-care ability, diabetes course, wound Wagner grade, bacterial culture result of wound specimen, and the levels of glycated hemoglobin, albumin, prealbumin, hemoglobin, and leukocyte count. Patients were classified according to general data, and the total scores of pain degree and pain-related effects were counted. Data were statistically analyzed with Kruskal-Wallis test and Mann-Whitney U test. The indicators with statistically significant differences in univariate analysis were selected for generalized linear model analysis to screen the independent risk factors of pain severity and pain-related effects in DFU patients. Results: A total of 44 questionnaires were sent out, and 42 valid questionnaires were collected, with effective recovery of 95.45%. The scores of the heaviest pain, the least pain, the average pain, and the current pain in DFU patients were 5 (0, 10), 2 (0, 6), 3 (0, 8), and 2 (0, 8), respectively, and the total score of the pain severity was 11 (0, 24); the scores of pain-related effects on patients' daily life, mood, walking ability, daily work, relationship with others, sleep, and life interest were 4 (0, 10), 4 (0, 10), 5 (0, 10), 5 (0, 10), 3 (0, 10), 4 (0, 10), and 4 (0, 10), respectively, and the total score of pain-related effects was 30 (0, 63). In 42 DFU patients, most patients were male, aged 39-87 (67±10) years, most patients had education level of junior high school, most patients had diabetes for more than 20 years, half of patients' wounds were Wagner grade 4, most patients had body mass index and leukocyte count within normal limits, most patients had partial dependence on self-care ability, the bacterial culture results of wound specimen in the vast majority of patients were positive, about half of the patients had abnormal level of albumin, and most patients had abnormal levels of glycosylated hemoglobin, prealbumin, and hemoglobin. Univariate analysis of the above general data showed that total scores of pain severity among patients with different hemoglobin levels and leukocyte counts were statistically significant different (with Z values of -2.05 and -2.55, respectively, P<0.05), and the total scores of pain-related effects on patients with different hemoglobin levels, leukocyte counts, and bacterial culture results of wound specimen were statistically significant different (with Z values of -2.66, -2.02, and -2.12, respectively, P<0.05). Generalized linear model analysis showed that leukocyte count was an independent risk factor for pain severity and pain-related effects in 42 DFU patients (with 95% confidence intervals of 0.28-11.87 and 5.67-36.99, respectively, standardized regression coefficient values of 6.17 and 21.33, respectively, both P values <0.05). The bacterial culture result of wound specimen was an independent risk factor for pain-related effects in 42 DFU patients (with 95% confidence interval of 2.92-39.09, standardized regression coefficient value of 21.00, P<0.05). Conclusions: DFU patients often suffer pain, and the bacterial culture results of wound specimen and leukocyte count are the main factors affecting the pain of DFU patients.

Clinical characteristics and risk factors of lower extremity amputation in the diabetic inpatients with foot ulcers.

To analyze clinical characteristics of the diabetic inpatients with foot ulcers and explore the risk factors of lower extremity amputation (LEA) in West China Hospital of Sichuan University. A retrospective analysis was performed based on the clinical data of the patients with diabetic foot ulcer (DFU) hospitalized in West China Hospital of Sichuan University from January 1, 2012 to December 31, 2020. The DFU patients were divided into three groups: non-amputation, minor amputation, and major amputation groups. The ordinal logistic regression analysis was used to identify the risk factors for LEA. 992 diabetic patients (622 males and 370 females) with DFU were hospitalized in the Diabetic Foot Care Center of Sichuan University. Among them, 72 (7.3%) (55 minor amputations and 17 major amputations) cases experienced amputation, and 21(2.1%) refused amputation. Excluding the patients who refused amputation, the mean age and duration of diabetes of and HbA1c the 971 patients with DFU, were 65.1 ± 12.3 years old, 11.1 ± 7.6 years, and 8.6 ± 2.3% respectively. The patients in the major amputation group were older and had longer course of diabetes for a longer period of time than those in the non-amputation and minor amputation groups. Compared with the non-amputation patients (55.1%), more patients with amputation (minor amputation (63.5%) and major amputation (88.2%)) suffered from peripheral arterial disease (P=0.019). The amputated patients had statistically lower hemoglobin, serum albumin and ankle brachial index (ABI), but higher white blood cell, platelet counts, fibrinogen and C-reactive protein levels. The patients with amputation had a higher incidence of osteomyelitis (P = 0.006), foot gangrene (P < 0.001), and a history of prior amputations (P < 0.001) than those without amputation. Furthermore, a history of prior amputation (odds ratio 10.194; 95% CI, 2.646-39.279; P=0.001), foot gangrene (odds ratio 6.466; 95% CI, 1.576-26.539; P=0.010) and ABI (odds ratio 0.791; 95% CI, 0.639-0.980; P = 0.032) were significantly associated with LEAs. The DFU inpatients with amputation were older with long duration of diabetes, poorly glycemic control, malnutrition, PAD, severe foot ulcers with infection. A history of prior amputation, foot gangrene and a low ABI level were the independent predictors of LEA. Multidisciplinary intervention for DFU is essential to avoid amputation of the diabetic patients with foot ulcer.

MALAT1 participates in the role of platelet-rich plasma exosomes in promoting wound healing of diabetic foot ulcer

Exosomes isolated from platelet-rich plasma (PRP-exos) have been recently deemed as an optimized therapeutic strategy in diabetic foot ulcer (DFU) treatment. Herein, we aimed to explore whether MALAT1 participates in DFU wound healing by PRP-exos treatment and the related preliminary mechanism. Fibroblasts were isolated from healthy donors and DFU patients, and the expression of MALAT1, miR-374a-3p and DNMT3A were detected by RT-PCR. The effect of MALAT1 and miR-374a-3p on DFU fibroblast function was verified by gain/loss of function experiment. The targeted binding of MALAT and miRNA was verified by double luciferase reporter gene assay. PRP-exos were isolated from normal human blood and characterized, and then co-cultured with DFU fibroblasts. The MALAT1 expression was donwregulated while the miR-374a-5p expression was upregulated in DFU fibroblasts. Double luciferase reporter gene assay demonstrated the targeted binding of MALAT and miR-374a-5p. Overexpression of MALAT1 or knockdown of miR-374a-5p could increase viability and inhibit apoptosis and pyroptosis of DFU fibroblast. And overexpression of miR-374a-5p reversed the effect of PRR-exos or MALAT1 overexpression on cell viability, apoptosis and pyroptosis. Collectively, MALAT1 mediated signal axis participates in the role of PRP-exos in promoting DFU wound healing, which may help identify optimal targets and effective therapies for DFU treatment.

Application of extracorporeal shockwave therapy to improve microcirculation in diabetic foot ulcers: A prospective study.

Extracorporeal shockwave therapy (ESWT) can induce wound healing by increasing tissue microcirculation. However, studies on the effect of ESWT on enhancing tissue microcirculation in diabetic foot ulcer (DFU), particularly on when the microcirculation increases after ESWT application, are still lacking. Therefore, we aimed to examine the effectiveness of ESWT in promoting microcirculation in DFU patients in a time-dependent manner. We included 50 feet of 25 patients with type 2 diabetes mellitus and Wagner grade I to II DFU in this study. The affected feet were used as the ESWT group and the unaffected contralateral feet were used as the control group. ESWT was performed in 3 sessions per week for a total of 3 weeks. Transcutaneous partial oxygen pressure (TcPO2) was used to evaluate the tissue microcirculation. The TcPO2 level (>43 mm Hg) in the ESWT group was recovered by the 2nd week of treatment, and statistical significance (P < .05) was demonstrated at the same time. From the 2nd week of ESWT, a significant increase in TcPO2 was observed in Wagner grade I and II DFU. These findings imply that the ESWT may improve microcirculation in patients with Wagner grades I to II DFU. However, this impact requires at least 2 weeks or more than 6 sessions. For better comparison, further studies with larger clinical groups and extended period are needed.

SNHG12/NFYC-AS1 Acted as the Sponge for hsa-miR-199a-5p to Promote the Expression of S100A8/S100A7/XDH and was Involved in the Progression of Diabetic Foot Ulcers.

Traditional Chinese medicine has been used to treat diabetic foot ulcer (DFU) for a long time. However, the underlying mechanism of Radix arnebiae seu lithospermi ointment (RAS-ointment) has not been revealed. Effects of RAS-ointment treatment were observed in DFU patients. The endogenous competitive RNA mechanism was constructed based on micro-arraysequencing and bioinformatics analysis. RT-PCR was used to detected the expression of genes in DFU ulcerated skins and non-ulcerated skins. Dual luciferase and RT-PCR experiments were used to investigate the endogenous competitive RNA mechanism. Based on micro-array sequencing and bioinformatics analysis, we found that SNHG12/NFYC-AS1, hsa-miR-199a-5p and S100A8/S100A7/XDH might form an endogenous competitive RNA mechanism. RT-PCR assay shown that SNHG12, NFYC-AS1, S100A8, S100A7 and XDH were significantly up-regulated, while hsa-miR-199a-5p was significantly down-regulated in DFU ulcerated skins (N = 10) compared with non-ulcerated skins (N = 10). Dual luciferase and RT-PCR experiments showed that SNHG12 or NFYC-AS1 up-regulated the expression of S100A8, S100A7 and XDH by inhibiting hsa-miR-199a-5p in a direct binding way. After 35days of RAS-ointment treatment, the wound healing of DFU patients was substantially improved and the expression of S100A7 and XDH were reduced expression in DFU patients. In addition, the monomer composition of RAS-ointment, 49070_FLUKA or auraptenol inhibited the expression of S100A7 and XDH in Te317.sk cells. In conclusion, RAS-ointment may be used as an adjunctive therapy for DFU patients.

Quality of life in patients with recurrent diabetic foot ulcers

Aim: The study aimed to evaluate the association between quality of life and wound severity in patients with recurrent diabetic foot ulcers (DFUs). Design: A cross-sectional study. Methods: The total sample comprised 86 DFU patients. The Diabetic Foot Ulcer Scale &#8211; Short Form scale was used to collect quality of life data, and Wagner grading was used to assess wound severity. Statistical analyses were conducted using the Mann-Whitney U-test and Kruskal-Wallis test. Results: The results showed that quality of life (QOL) in all domains was low. There were no significant differences between demographic and wound characteristics and QOL of patients. Significant differences were found between diabetes mellitus (DM) duration and Leisure / enjoying life (p = 0.020); Trigger and Worried about ulcers (p = 0.002); Trigger and Dependence / daily life (p = 0.006); Trigger and Negative emotions (p = 0.006); and Trigger and Bothered by ulcer care (p = 0.000). However, there were no significant differences between demographic and wound characteristics and physical health. Conclusion: The study showed that QOL of patients with recurrent diabetic ulcers was low. There was no correlation between quality of life or wound severity and recurrent DFUs. However, there was a correlation between DM duration and Leisure / enjoying life; Trigger and Worried about the ulcer; Trigger and Dependency / daily life; Trigger and Negative emotions; and Trigger and Bothered by ulcer care.

Level of 25-hydroxyvitamin D and vitamin D receptor in diabetic foot ulcer and factor associated with diabetic foot ulcers

BackgroundAt present, there is no clinical study to elucidate the correlation between vitamin D deficiency and the incidence of diabetic foot osteomyelitis (DFO).This study aims to clarify levels of 25-hydroxyvitamin D [25(OH)VD] in peripheral blood and vitamin D receptor (VDR) expression in wound margin tissues (T-VDR) of patients with type 2 diabetes mellitus (T2DM) with diabetic foot ulcer (DFU) and DFO, and to determine its correlation with treatment outcomes of DFU and DFO, and and its value as a potential biomarker for the diagnosis of DFU and DFO.Methods156 T2DM patients with DFU (DFU group), 100 T2DM patients without DFU (T2DM group), and 100 healthy controls (NC group). The DFU group patients were subdivided into DFO (n = 80) and NDFO groups (n = 76). The level of serum 25(OH)VD was measured via chemiluminescence immunoassay, and T-VDR expression level was determined by quantitative real-time PCR.ResultsThe levels of serum 25(OH)VD in the DFU group were significantly lower than the T2DM group [(10.3 (5.8, 18.7) vs 15.7 (8.6, 24.6) ng/mL, P = 0.002)]. Similarly, the levels of serum 25(OH)VD and T-VDR expression in the DFO group were statistically lower than the NDFO group [9.2 (5.2, 20.5) vs 12.8 (6.9, 22.1) ng/mL, P = 0.006)], [1.96 (0.61, 3.97) vs 3.11 (1.36, 5.11), P = 0.004)], respectively. Furthermore, the levels of serum 25(OH)VD and T-VDR expression in DFU patients were positively correlated with the ulcer healing rate of foot ulcer after 8 weeks of treatment ( P = 0.031, P = 0.016, respectively). Multivariate logistic regression analysis showed that low level of serum 25(OH)VD was an independent risk factor for DFU and DFO (ORDFU = 2.42, ORDFO = 3.05, P = 0.008, 0.001, respectively), and decreased T-VDR expression level was an independent risk factor for DFO (OR = 2.83, P = 0.004). Meanwhile, the ROC curve analysis indicated that the AUC of serum 25(OH)VD level for the diagnosis of DFU and DFO was 0.821 (95% CI, 0.754–0.886, P < 0.001) and 0.786 (95%CI, 0.643–0.867, P < 0.001), respectively. When establishing a diagnosis of DFO, the AUC of T-VDR expression level was 0.703 (95%CI: 0.618–0.853, P < 0.001).ConclusionsThe levels of serum 25(OH)VD and T-VDR expression in DFU and DFO decreased. Serum 25(OH)VD and T-VDR are potentially valuable biomarkers for diagnosis and prognosis of DFU and DFO..

Development and Validation of a Risk Prediction Model for Foot Ulcers in Diabetic Patients.

The current study analyzed the status and the factors of foot ulcers in diabetic patients and developed a nomogram and web calculator for the risk prediction model of diabetic foot ulcers. This was a prospective cohort study that used cluster sampling to enroll diabetic patients in the Department of Endocrinology and Metabolism in a tertiary hospital in Chengdu from July 2015 to February 2020. The risk factors for diabetic foot ulcers were obtained by logistic regression analysis. Nomogram and web calculator for the risk prediction model were constructed by R software. The incidence of foot ulcers was 12.4% (302/2432). Logistic stepwise regression analysis showed that BMI (OR: 1.059; 95% CI 1.021-1.099), abnormal foot skin color (OR: 1.450; 95% CI 1.011-2.080), foot arterial pulse (OR: 1.488; 95% CI: 1.242-1.778), callus (OR: 2.924; 95%: CI 2.133-4.001), and history of ulcer (OR: 3.648; 95% CI: 2.133-5.191) were risk factors for foot ulcers. The nomogram and web calculator model were developed according to risk predictors. The performance of the model was tested, and the testing data were as follows: AUC (area under curve) of the primary cohort was 0.741 (95% CI: 0.7022-0.7799), and AUC of the validation cohort was 0.787 (95% CI: 0.7342-0.8407); the Brier score of the primary cohort was 0.098, and the Brier score of the validation cohort was 0.087. The incidence of diabetic foot ulcers was high, especially in diabetic patients with a history of foot ulcers. This study presented a nomogram and web calculator that incorporates BMI, abnormal foot skin color, foot arterial pulse, callus, and history of foot ulcers, which can be conveniently used to facilitate the individualized prediction of diabetic foot ulcers.

Identification of signalling downstream of the transcription factor forkhead box protein M1 that protects against endoplasmic reticulum stress in a diabetic foot ulcer model.

Diabetic foot ulcer (DFU) has a significant impact on the quality of life of diabetic mellitus (DM) patients. Here, we aimed to explore the molecules with aberrant expression and their regulatory mechanisms in DFU. The expression of gene and protein was examined using quantitative polymerase chain reaction (qPCR) and western blot. Pearson's correlation analysis was used to analyse interactions among FOXM1, GAS5 and SDF4. Immunofluorescence was used to detect PDI and GRP78 expression. Flow cytometry was used to assess cell apoptosis. Tube formation assay was used to determine angiogenic capacity. Fluorescence in situ hybridization (FISH) assay was employed to determine the cellular localization of GAS5 and SDF4 in human umbilical vein endothelial cells (HUVECs). The interactions among FOXM1, GAS5 and SDF4 were validated by chromatin immunoprecipitation (ChIP), luciferase, RNA pull-down and RNA immunoprecipitation (RIP) assays. FOXM1, GAS5 and SDF4 were decreased in the skin tissues of DFU patients. High glucose (HG) stimulation induced endoplasmic reticulum (ER) stress and cell apoptosis but suppressed angiogenesis in HUVECs, which were abolished by FOXM1 overexpression. FOXM1 promoted GAS5 transcriptional activity, resulting in increased GAS5 expression, and GAS5 knockdown reversed the effects of FOXM1 overexpression in HG-treated HUVECs. Moreover, GAS5 recruited TAF15 to promote SDF4 expression in HUVECs. GAS5 overexpression inhibited ER stress, cell apoptosis and induced angiogenesis in HG-treated HUVECs which could be reversed by silencing SDF4. Our results revealed that FOXM1 suppressed ER stress, cell apoptosis and promoted angiogenesis in HG-induced HUVECs via mediating GAS5/TAF15/SDF4 axis, providing a novel therapeutic molecule mechanism for DFU.

Evaluation of Sciatic Nerve Stiffness Using Shear Wave Elastography in Patients with Unilateral Diabetic Foot Ulcers.

To evaluate the stiffness of the sciatic nerve by shear wave elastography (SWE) and to determine whether SWE can be used to predict diabetic foot ulcer (DFU) in a patient with diabetic peripheral neuropathy (DPN). Sixteen patients (thirty-two lower limbs) with unilateral DFU were studied retrospectively. The ultrasonographic parameters including cross-sectional area (CSA) of sciatic nerve, intraneural blood flow, peak systolic velocity (Vmax) and resistive index (RI) in the intraneural artery of the sciatic nerve, and the SWE stiffness value of the sciatic nerve were measured. The examinations of arteries of the lower limbs were also performed by ultrasound. According to the presence or absence of DFU, the 32 lower limbs were divided into two groups: the DFU group and the non-DFU group. The ultrasonographic parameters were compared between these two groups. There was no significant difference (p > 0.05) between the two groups for CSA, intraneural blood flow, Vmax and RI in the intraneural artery of the sciatic nerve, and numbers of severe artery stenosis or full occlusion of the artery in the lower limbs. However, SWE stiffness values in the sciatic nerve in the DFU group are higher than the non-DFU group (p < 0.05). When the SWE stiffness values were used for prediction of DFU in patients with DPN, the area under the ROC curve (AUC) was 0.727 (95% CI: 0.541-0.868). When the best SWE stiffness value of 24.48 kPa was taken as a cutoff for prediction of DFU, the sensitivity was 62.50% (95% CI: 35.4-84.8%), and the specificity was 75% (95% CI: 47.6-92.7%). Sciatic nerve stiffness is significantly higher in lower limbs with DFU. SWE is a noninvasive imaging method that may be used to evaluate sciatic nerve stiffness, then potentially predict DFU in patients with DPN.

Vitamin D as adjuvant therapy for diabetic foot ulcers: Systematic review and meta-analysis approach

Diabetic Foot Ulcer (DFU) is a combination of neuropathy and ischaemia on diabetic patient's lower limbs. It has a high burden of limb amputation rate, mortality rate, disability, economic burden, and lower quality of life on diabetic patients. It took mostly 3-6 months and up to 1 year for DFU to heal. DFU patients also have an increased risk of vitamin D deficiency. Meanwhile vitamin D has effects on immune response, insulin secretion, and sensitivity. The long duration of DFU healing is a problem for the patient's health, job, income, quality of life, economy and healthcare. Therefore, we aim to conduct a meta-analysis to assess reliability of vitamin D supplementation on diabetic foot ulcer clinical outcome. We conducted systematic literature search according to PRISMA guideline on Cochrane Library, PubMed, Google Scholar, ProQuest, EBSCO and ScienceDirect from 16 until 24 June 2022. Effect of vitamin D supplementation on diabetic foot ulcer patients was analyzed with a comprehensive meta-analysis tool. Pooled ulcer area, total cholesterol, triglyceride, C-reactive protein, HbA1c, and fasting plasma glucose assessed with 95% confidence intervals were estimated using fixed-effects or random-effects models. We included 4 papers with 197 people as sample reporting vitamin D capability as treatment for DFU patients. The pooled analysis showed significant differences in ulcer area, serum Vitamin D, Total Cholesterol, Fasting Plasma Glucose, Triglyceride, C-Reactive Protein, and HbA1c. Insignificant results on Erythrocyte Sedimentation Rate and High Density Lipoprotein levels. Vitamin D supplementation is beneficial to be given as adjuvant treatment for diabetic foot ulcer. It may fasten the wound healing and decrease the burden caused by diabetic foot ulcers.