A prospective,randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers

The aim of this study is to determine if weekly application of dehydrated human amnion/chorion membrane allograft reduce time to heal more effectively than biweekly application for treatment of diabetic foot ulcers. This was an institutional review board‐approved, registered, prospective, randomised, comparative, non‐blinded, single‐centre clinical trial. Patients with non‐infected ulcers of ≥ 4 weeks duration were included for the study. They were randomised to receive weekly or biweekly application of allograft in addition to a non‐adherent, moist dressing with compressive wrapping. All wounds were offloaded. The primary study outcome was mean time to healing. Overall, during the 12‐week study period, 92·5% (37/40) ulcers completely healed. Mean time to complete healing was 4·1 ± 2·9 versus 2·4 ± 1·8 weeks (P = 0·039) in the biweekly versus weekly groups, respectively. Complete healing occurred in 50% versus 90% by 4 weeks in the biweekly and weekly groups, respectively (P = 0·014). Number of grafts applied to healed wounds was similar at 2·4 ± 1·5 and 2·3 ± 1·8 for biweekly versus weekly groups, respectively (P = 0·841). These results validate previous studies showing that the allograft is an effective treatment for diabetic ulcers and show that wounds treated with weekly application heal more rapidly than with biweekly application. More rapid healing may decrease clinical operational costs and prevent long‐term medical complications.     

Amniotic membrane is a potential regenerative option for chronic non‐healing wounds: a report of five cases receiving dehydrated human amnion/chorion membrane allograft

A case series of five patients with a total of six chronic non‐healing wounds (>30 day duration) were non‐randomly selected to evaluate the performance, safety and handling properties of dehydrated human amnion/chorion membrane allograft, an amniotic membrane scaffolding product. The patients had lower extremity wounds that had previously failed standard of care within a university outpatient/inpatient wound healing programme. Five wounds treated with dehydrated amnion/chorion membrane allograft showed a mean 43% area reduction from baseline (51% median) at 3 weeks into treatment and completely healed with a 64‐day median time to closure (SD ±27·6 days). One wound worsened at 3 weeks and was found to have a complete central vein obstruction that was treated with long‐term mild compression but still eventually healed at 6 months. Removing this outlier, the four responding wounds had a 72% mean and 69% median change in area from baseline, at the 3 week point. All five patients received only one application of dehydrated human amnion/chorion membrane allograft, and there were no adverse events. The product was easy to use, administer and handle. In summary, dehydrated human amnion/chorion membrane allograft appears to be a safe, effective and easy to use therapy for chronic non‐healing wounds. This study describes the details of these clinical cases and provides an overview of the current evidence on the use of amniotic tissue in clinical practice.     

A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: A prospective,multicentre, randomised,controlled study of 110 patients from 14 wound clinics

A randomised, controlled multicentre clinical trial was conducted at 14 wound care centres in the United States to confirm the efficacy of dehydrated human amnion/chorion membrane allograft (dHACM) for the treatment of chronic lower extremity ulcers in persons with diabetes. Patients with a lower extremity ulcer of at least 4 weeks duration were entered into a 2‐week study run‐in phase and treated with alginate wound dressings and appropriate offloading. Those with less than or equal to 25% wound closure after run‐in were randomly assigned to receive weekly dHACM application in addition to offloading or standard of care with alginate wound dressings, for 12 weeks. A total of 110 patients were included in the intent‐to‐treat (ITT) analysis, with n = 54 in the dHACM group and n = 56 in the no‐dHACM group. Of the participants, 98 completed the study per protocol, with 47 receiving dHACM and 51 not receiving dHACM. The primary study outcome was percentage of study ulcers completely healed in 12 weeks, with both ITT and per‐protocol participants receiving weekly dHACM significantly more likely to completely heal than those not receiving dHACM (ITT—70% versus 50%, P = 0.0338, per‐protocol—81% versus 55%, P = 0.0093). A Kaplan–Meier analysis was performed to compare the time‐to‐healing performance with/without dHACM, showing a significantly improved time to healing with the use of allograft, log‐rank P < 0.0187. Cox regression analysis showed that dHACM‐treated subjects were more than twice as likely to heal completely within 12 weeks than no‐dHACM subjects (HR: 2.15, 95% confidence interval 1.30–3.57, P = 0.003). At the final follow up at 16 weeks, 95% of dHACM‐healed ulcers and 86% of healed ulcers in the no‐dHACM group remained closed. These results confirm that dHACM is an efficacious treatment for lower extremity ulcers in a heterogeneous patient population.     

An economic evaluation examining the cost‐effectiveness of continuous diffusion of oxygen therapy for individuals with diabetic foot ulcers

Continuous delivery of oxygen therapy has been observed to improve healing for individuals with an advanced diabetic foot ulcer (DFU). However, this intervention requires the purchasing of an oxygen delivery device and moist dressings. It is unknown whether this upfront financial investment represents good value for money. Thus the aim of this project is to evaluate the cost‐effectiveness of treating advanced DFU using continuous delivery of oxygen compared with negative pressure wound therapy from the perspective of the public health care payer in Ontario, Canada. A microsimulation model was constructed with inputs from peer‐reviewed journal publications and publicly available reports. The 5‐year costs and quality‐adjusted life‐years were compared between treatment and comparator. Sensitivity analyses were conducted to evaluate the robustness of results. The model predicted that continuous delivery of oxygen would cost $4800 less compared with negative pressure wound therapy and increased quality‐adjusted life years by 0.025. Lower cost and improved outcomes were observed in most scenario analyses. The results of this economic evaluation suggest that CDO therapy may reduce health care economic burden with a modest increase in quality of life outcomes. Health care decision‐makers should consider the inclusion of CDO for the treatment of DFU.     

A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix®) allograft for the treatment of venous leg ulcers

A randomised, controlled, multicentre clinical trial was conducted to evaluate the efficacy of dehydrated human amnion/chorion membrane (EpiFix) allograft as an adjunct to multilayer compression therapy for the treatment of non‐healing full‐thickness venous leg ulcers. We randomly assigned 109 subjects to receive EpiFix and multilayer compression (n = 52) or dressings and multilayer compression therapy alone (n = 57). Patients were recruited from 15 centres around the USA and were followed up for 16 weeks. The primary end point of the study was defined as time to complete ulcer healing. Participants receiving weekly application of EpiFix and compression were significantly more likely to experience complete wound healing than those receiving standard wound care and compression (60% versus 35% at 12 weeks, P = 0·0128, and 71% versus 44% at 16 weeks, P = 0·0065). A Kaplan–Meier analysis was performed to compare the time‐to‐healing performance with or without EpiFix, showing a significantly improved time to healing using the allograft (log‐rank P = 0·0110). Cox regression analysis showed that subjects treated with EpiFix had a significantly higher probability of complete healing within 12 weeks (HR: 2·26, 95% confidence interval 1·25–4·10, P = 0·01) versus without EpiFix. These results confirm the advantage of EpiFix allograft as an adjunct to multilayer compression therapy for the treatment of non‐healing, full‐thickness venous leg ulcers.     

Use of an aseptically processed,dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective,randomised, multi‐centre clinical trial in 80 patients

Amnion and chorion allografts have shown great promise in healing diabetic foot ulcers (DFUs). Results from an interim analysis of 40 patients have demonstrated the accelerated healing ability of a novel aseptically processed, dehydrated human amnion and chorion allograft (dHACA). The goal of this study was to report on the full trial results of 80 patients where dHACA was compared with standard of care (SOC) in achieving wound closure in non‐healing DFUs. After a 2‐week screening period, during which patients with DFUs were unsuccessfully treated with SOC, patients were randomised to either SOC alone or SOC with dHACA applied weekly for up to 12 weeks. At 12 weeks, 85% (34/40) of the dHACA‐treated DFUs healed, compared with 33% (13/40) treated with SOC alone. Mean time to heal within 12 weeks was significantly faster for the dHACA‐ treated group compared with SOC, 37 days vs 67 days in the SOC group (P = .000006). Mean number of grafts used per healed wound during the same time period was 4.0, and mean cost of the tissue to heal a DFU was $1771. The authors concluded that aseptically processed dHACA heals DFUs significantly faster than SOC at 12 weeks.     

Variations in study outcomes relative to intention‐to‐treat and per‐protocol data analysis techniques in the evaluation of efficacy for treatment of venous leg ulcers with dehydrated human amnion/chorion membrane allograft

Statistical interpretation of data collected in a randomised controlled trial (RCT) is conducted on the intention‐to‐treat (ITT) and/or the per‐protocol (PP) study populations. ITT analysis is a comparison of treatment groups including all patients as originally allocated after randomisation regardless if treatment was initiated or completed. PP analysis is a comparison of treatment groups including only those patients who completed the treatment as originally allocated, although it is often criticised because of its potential to instil bias. A previous report from an RCT conducted to evaluate the efficacy of dehydrated human amnion/chorion membrane allograft (EpiFix) as an adjunct to standard comprehensive wound therapy consisting of moist dressings and multi‐layer compression in the healing of venous leg ulcers (VLUs) only reported PP study results (n = 109, 52 EpiFix and 57 standard care patients), although there were 128 patients randomised: 64 to the EpiFix group and 64 to the standard care group. Primary study outcome was the incidence of healing at 12 weeks. The purpose of the present study is to report ITT results on all 128 randomised subjects and assess if both ITT and PP data analyses arrive at the same conclusion of the efficacy of EpiFix as a treatment for VLU. Rates of healing for the ITT and PP populations were, respectively, 50% and 60% for those receiving EpiFix and 31% and 35% for those in the standard care cohort. Within both ITT and PP analyses, these differences were statistically significant; P = 0.0473, ITT and P = 0.0128, PP. The Kaplan‐Meier plot of time to heal within 12 weeks for the ITT and PP populations demonstrated a superior wound‐healing trajectory for EpiFix compared with VLUs treated with standard care alone. These data provide clinicians and health policymakers an additional level of assurance regarding the effectiveness of EpiFix.     

Efficacy of a topical concentrated surfactant gel on microbial communities in non‐healing diabetic foot ulcers with chronic biofilm infections: A proof‐of‐concept study

This proof‐of‐concept study sought to determine the effects of standard of care (SOC) and a topically applied concentrated surfactant gel (SG) on the total microbial load, community composition, and community diversity in non‐healing diabetic foot ulcers (DFUs) with chronic biofilm infections. SOC was provided in addition to a topical concentrated SG, applied every 2 days for 6 weeks. Wound swabs were obtained from the base of ulcers at baseline (week 0), week 1, mid‐point (week 3), and end of treatment (week 6). DNA sequencing and real‐time quantitative polymerase chain reaction (qPCR) were employed to determine the total microbial load, community composition, and diversity of patient samples. Tissue specimens were obtained at baseline and scanning electron microscopy and peptide nucleic acid fluorescent in situ hybridisation with confocal laser scanning microscopy were used to confirm the presence of biofilm in all 10 DFUs with suspected chronic biofilm infections. The application of SG resulted in 7 of 10 samples achieving a reduction in mean log10 total microbial load from baseline to end of treatment (0.8 Log10 16S copies, ±0.6), and 3 of 10 samples demonstrated an increase in mean Log10 total microbial load (0.6 log10 16S copies, ±0.8) from baseline to end of treatment. Composition changes in microbial communities were driven by changes to the most dominant bacteria. Corynebacterium sp. and Streptococcus sp. frequently reduced in relative abundance in patient samples from week 0 to week 6 but did not disappear. In contrast, Staphylococcus sp., Finegoldia sp., and Fusobacterium sp., relative abundances frequently increased in patient samples from week 0 to week 6. The application of a concentrated SG resulted in varying shifts to diversity (increase or decrease) between week 0 and week 6 samples at the individual patient level. Any shifts in community diversity were independent to changes in the total microbial loads. SOC and a topical concentrated SG directly affect the microbial loads and community composition of DFUs with chronic biofilm infections.     

Retrospective real‐world comparative effectiveness of ovine forestomach matrix and collagen/ORC in the treatment of diabetic foot ulcers

The retrospective pragmatic real‐world data (RWD) study compared the healing outcomes of diabetic foot ulcers (DFUs) treated with either ovine forestomach matrix (OFM) (n = 1150) or collagen/oxidised regenerated cellulose (ORC) (n = 1072) in out‐patient wound care centres. Median time to wound closure was significantly (P = .0015) faster in the OFM group (14.6 ± 0.5 weeks) relative to the collagen/ORC group (16.4 ± 0.7). A sub‐group analysis was performed to understand the relative efficacy in DFUs requiring longer periods of treatment and showed that DFUs treated with OFM healed up to 5.3 weeks faster in these challenging wounds. The percentage of wounds closed at 36 weeks was significantly improved in OFM treated DFUs relative to the collagen/ORC. A Cox proportional hazards analysis showed OFM‐treated wounds had a 18% greater probability of healing versus wounds managed with collagen/ORC, and the probability increased to 21% when the analysis was adjusted for multiple variables. This study represents the first large retrospective RWD analysis comparing OFM and collagen/ORC and supports the clinical efficacy of OFM in the treatment of DFUs.     

A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers

The aim of this study was to determine the safety and effectiveness of dehydrated human umbilical cord allograft (EpiCord) compared with alginate wound dressings for the treatment of chronic, non‐healing diabetic foot ulcers (DFU). A multicentre, randomised, controlled, clinical trial was conducted at 11 centres in the United States. Individuals with a confirmed diagnosis of Type 1 or Type 2 diabetes presenting with a 1 to 15 cm² ulcer located below the ankle that had been persisting for at least 30 days were eligible for the 14‐day study run‐in phase. After 14 days of weekly debridement, moist wound therapy, and off‐loading, those with ≤30% wound area reduction post‐debridement (n = 155) were randomised in a 2:1 ratio to receive a weekly application of EpiCord (n = 101) or standardised therapy with alginate wound dressing, non‐adherent silicone dressing, absorbent non‐adhesive hydropolymer secondary dressing, and gauze bandage roll (n = 54). All wounds continued to have appropriate off‐loading during the treatment phase of the study. Study visits were conducted for 12 weeks. At each weekly visit, the DFU was cleaned and debrided as necessary, with the wound photographed pre‐ and post‐debridement and measured before the application of treatment group‐specific dressings. A follow‐up visit was performed at week 16. The primary study end point was the percentage of complete closure of the study ulcer within 12 weeks, as assessed by Silhouette camera. Data for randomised subjects meeting study inclusion criteria were included in an intent‐to‐treat (ITT) analysis. Additional analysis was conducted on a group of subjects (n = 134) who completed the study per protocol (PP) (EpiCord, n = 86, alginate, n = 48) and for those subjects receiving adequate debridement (EpiCord, n = 67, alginate, n = 40). ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70%) vs 26 of 54 (48%) for EpiCord and alginate dressings, respectively, P = 0.0089. Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81%) for EpiCord‐treated and 26 of 48 (54%) for alginate‐treated DFUs, P = 0.0013. For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96%) of the EpiCord‐treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65%) of adequately debrided alginate‐treated ulcers, P < 0.0001. Seventy‐five subjects experienced at least one adverse event, with a total of 160 adverse events recorded. There were no adverse events related to either EpiCord or alginate dressings. These results demonstrate the safety and efficacy of EpiCord as a treatment for non‐healing DFUs.     

The effect of low‐level laser therapy on diabetic foot ulcers: A meta‐analysis of randomised controlled trials

Our purpose was to perform a meta‐analysis to evaluate the effect of Low‐level laser therapy (LLLT) on diabetic foot ulcers (DFUs). The PubMed, Cochrane, Embase, Web of Science, Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases were searched systematically up to August 27, 2020. Studies that met the inclusion criteria were included in the analysis. A total of 13 randomised controlled trials (RCTs) and 413 patients were analysed. Compared with the control group, LLLT significantly increased the complete healing rate (risk ratio [RR] = 2.10, 95% confidence interval [CI] 1.56‐2.83, P < .00001), reduced the ulcer area (standardised mean difference [SMD] = 3.52, 95% CI 1.65‐5.38, P = .0002), and shortened the mean healing time (SMD = −1.40, 95% CI −1.90 to −0.91, P < .00001) of patients with DFUs. The quality of the evidence was very low according to the GRADE system. LLLT is a promising and effective adjuvant treatment to accelerate the healing of DFUs. Further evidence from larger samples and higher quality RCTs is needed to prove the effect of LLLT and to determine the most appropriate parameters for the healing of DFUs.     

Decreased expression of miR‐204‐3p in peripheral blood and wound margin tissue associated with the onset and poor wound healing of diabetic foot ulcers

To investigate the relationship between small non‐coding RNA‐204‐3p (miR‐204‐3p) and the onset and wound healing of diabetic foot ulcers (DFU) and the underlying molecular mechanism, sixty four newly diagnosed patients with T2DM without DFU (T2DM group), 82 T2DM patients with DFU (DFU group), and 60 controls with normal glucose tolerance (NC group) were included. Quantitative real‐time PCR (qRT‐PCR) method was used to determine miR‐204‐3p expression levels in peripheral blood and wound margin tissue of subjects, and to analyse the relationship between the expression of miR‐204‐3p and wound healing. In vitro experiments were also performed to understand the effect of miR‐204‐3p on high glucose induced injury of HaCaT cells (human keratinocytes). The results showed that miR‐204‐3p expression level of peripheral blood in the T2DM group was marked lower than that in the NC group [2.38 (1.31‐5.04) vs 3.27 (1.51‐6.98)] (P < .05). Similarly, the miR‐204‐3p expression level of peripheral blood in the DFU group was significantly lower than the T2DM group [1.15 (0.78‐2.89) vs 2.38 (1.31‐5.04)] (P < .01). The expression level of miR‐204‐3p in peripheral blood and wound margin tissues of DFU patients was positively correlated with the healing rate of foot ulcers after 8 weeks (P < .05). Multifactorial logistic regression analysis showed that decreased expression of miR‐204‐3p in peripheral blood was an independent risk factor for DFU (OR = 2.95, P < .05). The results of in vitro experiments showed that miR‐204‐3p could improve the proliferation and migration of HKC cells and reduce the proportion of apoptosis of HKC cells by targeted regulation of zinc finger protein Kruppel like factor 6 (KLF6) in high glucose environment. Therefore, the decreased expression of miR‐204‐3p in peripheral blood and wound tissue of T2DM patients is closely related to the occurrence and poor wound healing of DFU. The down‐regulated expression of miR‐204‐3p can reduce its ability to antagonise the functional damage of keratinocytes induced by high‐glucose conditions. These results will provide potential targets for the treatment of DFU.     

Effect of platelet‐rich plasma vs standard management for the treatment of diabetic foot ulcer wounds: A meta‐analysis

We performed a meta‐analysis to evaluate the effect of platelet‐rich plasma vs standard management for the treatment of diabetic foot ulcer wounds. A systematic literature search up to March 2022 was performed and 1435 subjects with diabetic foot ulcer wounds at the baseline of the studies; 723 of them were treated with platelet‐rich plasma, and 712 used control. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to assess the effect of platelet‐rich plasma vs standard management for the treatment of diabetic foot ulcer wounds using the dichotomous method with a random or fixed‐effect model. The use of autologous platelet‐rich plasma resulted in significantly higher complete‐healed diabetic foot ulcer wounds compared with control (OR, 1.95; 95% CI, 1.49‐2.56, P < 0.001). The use of allogeneic platelet‐rich plasma resulted in significantly higher complete‐healed diabetic foot ulcer wounds compared with control (OR, 6.19; 95% CI, 2.32‐16.56, P < 0.001). The use of autologous and allogeneic platelet‐rich plasma resulted in significantly higher complete‐healed diabetic foot ulcer wounds compared with control. Though, the analysis of outcomes should be with caution because of the low number of studies in certain comparisons, for example, allogeneic platelet‐rich plasma compared with control.     

Changes in miroRNA‐103 expression in wound margin tissue are related to wound healing of diabetes foot ulcers

To investigate the relationship between small noncoding microRNA‐103 (miR‐103) and wound healing of diabetic foot ulcers (DFU) and the underlying molecular mechanism, forty type 2 diabetes mellitus with DFU (DFU group), and 20 patients with a chronic skin ulcer of lower limbs and normal glucose tolerance (SUC group) were included. Quantitative real‐time PCR method was used to determine miR‐103 expression levels in the wound margin tissue of subjects, and to analyse the relationship between the expression of miR‐103 and DFU wound healing. In vitro experiments were also performed to understand the effect of miR‐103 on the high glucose‐induced injury of normal human dermal fibroblasts (NHDFs) cells. The results showed that the miR‐103 expression level in the DFU group was significantly higher than that in the SUC group [5.81 (2.25–9.36) vs 2.08 (1.15–5.72)] (P < 0.05). The expression level of miR‐103 in the wound margin tissue of DFU was negatively correlated with the healing rate of foot ulcers after four weeks (P = 0.037). In vitro experiments revealed that miR‐103 could inhibit the proliferation and migration of NHDF cells and promote the apoptosis of NHDF cells by targeted regulation of regulator of calcineurin 1 (RCAN1) gene expression in a high glucose environment. Down‐regulation of miR‐103 could alleviate high glucose‐induced NHDF cell injury by promoting RCAN1 expression. Therefore, the increased expression of miR‐103 is involved in the functional damage of NHDF cells induced by high‐glucose conditions, which is related to poor wound healing of DFU. These research findings will provide potential targets for the diagnosis and treatment of chronic skin wounds in diabetes.     

A prospective,randomised, controlled,multi‐centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft,bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers

A prospective, randomised, controlled, parallel group, multi‐centre clinical trial was conducted at three sites to compare the healing effectiveness of treatment of chronic lower extremity diabetic ulcers with either weekly applications of Apligraf^® (Organogenesis, Inc., Canton, MA), EpiFix^® (MiMedx Group, Inc., Marietta, GA), or standard wound care with collagen‐alginate dressing. The primary study outcome was the percent change in complete wound healing after 4 and 6 weeks of treatment. Secondary outcomes included percent change in wound area per week, velocity of wound closure and a calculation of the amount and cost of Apligraf or EpiFix used. A total of 65 subjects entered the 2‐week run‐in period and 60 were randomised (20 per group). The proportion of patients in the EpiFix group achieving complete wound closure within 4 and 6 weeks was 85% and 95%, significantly higher (all adjusted P‐values ≤ 0·003) than for patients receiving Apligraf (35% and 45%), or standard care (30% and 35%). After 1 week, wounds treated with EpiFix had reduced in area by 83·5% compared with 53·1% for wounds treated with Apligraf. Median time to healing was significantly faster (all adjusted P‐values ≤0·001) with EpiFix (13 days) compared to Apligraf (49 days) or standard care (49 days). The mean number of grafts used and the graft cost per patient were lower in the EpiFix group campared to the Apligraf group, at 2·15 grafts at a cost of $1669 versus 6·2 grafts at a cost of $9216, respectively. The results of this study demonstrate the clinical and resource utilisation superiority of EpiFix compared to Apligraf or standard of care, for the treatment of diabetic ulcers of the lower extremities.     

The effectiveness of a new dried human amnion derived membrane in addition to standard care in treating diabetic foot ulcers: A patient and assessor blind,randomised controlled pilot study

Recent reviews suggest that amniotic membrane products may accelerate healing of diabetic foot ulcers. A new dried human amniotic membrane (dHAM) has been used for ocular ulcers but not for diabetic foot ulcers. This was a multi‐centre, prospective, patient and observer blind, randomised controlled pilot trial, to investigate whether 2 weekly addition of the dHAM to standard care versus standard care alone increased the proportion of healed participants'' index foot ulcers within 12 weeks. Thirty‐one people (mean age 59.8 years, 81% male, 87% type 2 diabetes) were randomised (15 dHAM, 16 usual care). Within 12 weeks, healing occurred in 4 (27%) ulcers in the dHAM group versus 1 (6.3%) usual care group (P = .1). Percentage wound area reduction was higher in the dHAM versus control group. (P = .0057). There was no difference in AEs between the two groups. Six participants allocated to dHAM correctly identified their treatment group, although 5 in usual care incorrectly thought they were in the intervention arm. This pilot trial result is encouraging showing that this dHAM preparation is safe and promising treatment. These results will be used to design a statistically powered, definitive double blind randomised controlled trial.     

Cost‐effectiveness of statins for primary prevention of atherosclerotic cardiovascular disease among people living with HIV in the United States

BackgroundExpanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost‐effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States.MethodsWe developed a microsimulation model that randomly selected (with replacement) individuals from the Data‐collection on Adverse Effects of Anti‐HIV Drugs study with follow‐up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid‐lowering therapy. Direct medical costs and quality‐adjusted life‐years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness‐to‐pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual’s probability of experiencing atherosclerotic cardiovascular disease over 20 years.ResultsPersons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost‐effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost‐effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal.ConclusionsPravastatin was projected to be cost‐effective compared with no statin. With substantial price reduction, pitavastatin may be cost‐effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV‐specific estimates on the efficacy of statins and the quality‐of‐life burden associated with taking an additional daily pill.     

Identification of potential circRNAs and circRNA‐miRNA‐mRNA regulatory network in the development of diabetic foot ulcers by integrated bioinformatics analysis

We aimed to explore the mechanism of circular RNAs (circRNAs) and provide potential biomarkers for molecular therapy of diabetic foot ulcers (DFU). Gene expression profile of {"type":"entrez-geo","attrs":{"text":"GSE114248","term_id":"114248"}}GSE114248, including five normal samples and five DFU samples, was downloaded from GEO database. Differentially expressed circRNAs (DEcircRNAs) between two groups were identified. Then, DEcircRNA‐miRNA and miRNA‐mRNA interaction was revealed, followed by the circRNA‐miRNA‐mRNA network construction. Moreover, functional and pathway analysis were performed based on mRNAs, followed by the DM‐related pathway exploration. Specific binding sites for key circRNAs and associated miRNAs were under investigation. Finally, RT‐qPCR was used to verify the candidate the relative expression level of circRNA between normal tissues and DFU. Totally, 65 DEcircRNAs were revealed between two groups, followed by 113 circRNA‐miRNA‐mRNA interactions explored. The mRNAs in these interactions were mainly assembled in functions like cell proliferation and pathways. Moreover, a total of 11 DM‐related pathways were revealed. Finally, circRNA‐miRNA specific binding‐site analysis revealed two key circRNAs, for example, circRNA_072697 and circRNA_405463, corresponding to their miRNAs. These two circRNAs were novel biomarkers for DFU. circRNA_072697 acted as a sponge of miR‐3150a‐3p in the progression of DFU via regulating KRAS. MAPK signaling pathway might contribute to the development of DFU.     

Human amniotic membrane allograft,a novel treatment for chronic diabetic foot ulcers: A systematic review and meta‐analysis of randomised controlled trials

To evaluate the efficacy and safety of human amniotic membrane (HAM) allograft in treating chronic diabetic foot ulcers (DFUs), a comprehensive search of randomised controlled trials in MEDLINE, EMBASE, PubMed, CENTRAL and Web of Science was conducted to December 7, 2019. Two reviewers independently screened the studies, extracted data, and evaluated the quality of studies. The primary outcome was the proportion of complete healing. The secondary outcomes were mean time to complete healing and adverse events. Statistical analyses were performed using RevMan 5.3. We identified 257 articles, of which 7 articles (465 participants) were included in the meta‐analysis. The proportion of complete wound healing in HAM plus standard of care (SOC) group was 3.88 times as high as that in SOC alone (RR: 3.88 [95% CI: 2.34, 6.44]) at 6 weeks, and 2.01 times at 12 weeks (RR: 2.01 [95%CI: 1.45, 2.77]). The intervention group had a significantly shorter time to complete healing (MD: −30.33 days, [95% CI: −37.95, −22.72]). The number needed to treat within 6 weeks was 2.3 ([95% CI: 1.8, 3.1]). No significant difference was shown in adverse events. Results were consistent in a sensitivity analysis. Hence, HAM plus SOC is effective and safe in treating chronic DFUs.     

Analysis of routine blood markers for predicting amputation/re‐amputation risk in diabetic foot

Diabetic foot is challenging progressive disease which requires multisystemic control. Neuropathy, arteriopathy, and cellular responses should treated collaboratively. Despite all medical advances, diabetic foot can highly resulted with amputation and also re‐amputation can be required because of failed wound healing. In this study, we aimed to investigate the relation between blood parameters and amputation events. Diabetic 323 patients include to the study who referred to orthopaedic clinic for amputation. Amputation levels (amputation levels phalanx, metatarsal, lisfranc, syme, below knee, knee‐disarticulation, above‐knee amputation) and re‐amputations recorded and compared with routine blood parameters. Re‐amputation was observed at 69 patients. The significant difference detected between lower albumin, higher HbA1c, higher CRP levels (P < 0.05) in regards to gross amputation levels, and increased wound depth. Furthermore, lower albumin levels and higher levels of WBC, HbA1c, CRP, and Creatinine were detected in re‐amputation levels. Especially, HbA1c, CRP, and Creatinine levels were found as upper bound of reference line for re‐amputation. The statistically optimal HbA1c cutoff point for diabetes was ≥7.05%, with a sensitivity of 86% and a specificity of 59%. In according to our results, simple blood parameters can be useful for observing the progress of amputation in diabetic foot. Particularly, lower albumin, and higher HbA1c, CRP, and Creatinine levels detected as related with poor prognosis. Besides, screening of HbA1c level seems to be highly sensitive for detecting of re‐amputation possibility.