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The goal of this multicentre study was to evaluate whether circulating endothelial precursor cells and microparticles can predict diabetic foot ulcer healing by the 16th week of care. We enrolled 207 subjects, and 40.0% (28.4, 41.5) healed by the 16th week of care. Using flow cytometry analysis, several circulating endothelial precursor cells measured at the first week of care were associated with healing after adjustment for wound area and wound duration. For example, CD34+CD45dim, the univariate odds ratio was 1.19 (95% confidence interval: 0.88, 1.61) and after adjustment for wound area and wound duration, the odds ratio was (1.67 (1.16, 2.42) p = 0.006). A prognostic model using CD34+ CD45dim, wound area, and wound duration had an area under the curve of 0.75 (0.67, 0.82) and CD34+ CD45dim per initial wound area, an area under the curve of 0.72 (0.64, 0.79). Microparticles were not associated with a healed wound. Previous studies have indicated that circulating endothelial precursor cells measured at the first office visit are associated with a healed diabetic foot ulcer. In this multicentred prospective study, we confirm this finding, show the importance of adjusting circulating endothelial precursor cells measurements by wound area, and show circulating endothelial precursor cells per wound area is highly predictive of a healed diabetic foot ulcer by 16th week of care. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFU) are a critical problem for those with diabetes mellitus. Predicting the healing likelihood of a DFU is important to implementing appropriate care, allocating resources, having access to advanced therapies, having successful clinical trials, calibrating clinical trial results, and providing information to administrative entities on patient and provider outcomes. Prognostic modelling can also be important when attempting to compare results across trials or care centres. In a prospective cohort study, we demonstrate and replicate that simple wound characteristics like wound area and wound duration can be used to predict wound healing by the 16th week of care. The models were based on previous literature and replicated using a machine learning algorithm. The use of wound duration and wound area in a prognostic model continues to be important when comparing study results, centre‐based outcomes, as well as designing clinical trials. [ABSTRACT FROM AUTHOR]

Chronic, nonhealing wounds consume a great deal of healthcare resources and are a major public health problem, associated with high morbidity and significant economic costs. Skin grafts are commonly used to facilitate wound closure. The grafts can come from the patient's own skin (autograft), a human donor (allograft), or from a different species (xenograft). A fish skin xenograft from cold‐water fish (Atlantic cod, Gadus morhua) is a relatively recent option that shows promising preclinical and clinical results in wound healing. Chronic wounds vary greatly in etiology and nature, requiring large cohorts for effective comparison between therapeutic alternatives. In this study, we attempted to imitate the status of a freshly debrided chronic wound by creating acute full‐thickness wounds, 4 mm in diameter, on healthy volunteers to compare two materials frequently used to treat chronic wounds: fish skin and dHACM. The purpose is to give an indication of the efficacy of the two therapeutic alternatives in the treatment of chronic wounds in a simple, standardized, randomized, controlled, double‐blind study. All volunteers were given two identical punch biopsy wounds, one of which was treated with a fish skin graft and the other with dehydrated human amnion/chorion membrane allograft (dHACM). In the study, 170 wounds were treated (85 wounds per group). The primary endpoint was defined as time to heal (full epithelialization) by blinded assessment at days 14, 18, 21, 25, and 28. The superiority hypothesis was that the fish skin grafts would heal the wounds faster than the dHACM. To evaluate the superiority hypothesis, a mixed Cox proportional hazard model was used. Wounds treated with fish skin healed significantly faster (hazard ratio 2.37; 95% confidence interval: (1.75–3.22; p = 0.0014) compared with wounds treated with dHACM. The results show that acute biopsy wounds treated with fish skin grafts heal faster than wounds treated with dHACM. [ABSTRACT FROM AUTHOR]

It is unclear why many with diabetes develop foot ulcers (DFU) and why some do not heal. It could be associated with genetic variation. We have previously shown that NOS1AP variation is associated with lower extremity amputation in those with diabetes and that circulating stem progenitor cell concentration (SPC) is associated with impaired foot ulcer healing in those with diabetes. The goal of this study was to determine if NOS1AP variation is associated with impaired wound healing and with SPC mobilization in those with DFU. In longitudinal cohort study we demonstrate that NOS1AP variants rs16849113 and rs19649113 are associated with impaired wound healing and with SPC mobilization in those with DFU. We believe that further study of NOS1AP is merited and that it NOS1AP might be associated with a functional impairment. [ABSTRACT FROM AUTHOR]

The present status of clinical leg ulcer healing research was reviewed by 25 experts over 2 days on September 28 and 29, 2015. Multiple clinical effectiveness reviews were presented suggesting that published clinical wound healing research often does not meet present (2015) evidence based standards. Specific areas requiring remediation were highlighted and approaches to overcoming existing challenges were proposed. Participants using anonymous voting technology developed an action plan to resolve perceived deficiencies. Statements were accepted if 75% of participants agreed. Older patients with a high frequency of comorbid conditions posed particular difficulties in designing clinical research protocols and better diagnostic categorization is necessary A standardized model template for collecting information about diagnosis and evaluation of the effect of interventions on healing of all types of leg ulcers was considered a high priority. Such a model template could be modified depending on the specific etiology of the leg ulcers. Generally agreed on quantifiable standards to establish degree of morbidity was considered a high priority. There was universal agreement that sources of funding and conflicts of interest needed to be disclosed in presentations and all publications. All clinical research studies should be registered with appropriate authorities. There was substantial enthusiasm for a clinical research network with quality standards for membership and an advisory research core available to investigators. Such a network should be funded and actively managed to insure long-term viability. The governance of such an entity needs to be established by the wound care community. The present trend to integrate patients into the clinical research process was endorsed and there was enthusiasm to develop patient advocacy for wound healing research. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers (DFUs) affect 1.5 million Americans annually, of which only a minority heal with standard care, and they commonly lead to amputation. To improve care, investigations are underway to better understand DFU pathogenesis and develop more effective therapies. Some currently used medications may improve healing. One small, randomized clinical trial found statins improve DFU healing. In this secondary analysis of a large multisite prospective observational cohort of 139 patients with DFUs receiving standard care, we investigated whether there was an association between 6-week DFU wound size reduction and use of a variety of medications including alpha-blockers, beta-blockers, angiotensin converting enzyme inhibitors (ACEi) and statins. We found no significant ( p < 0.05) association between six-week wound reduction and use of any of the evaluated drugs; however, statins did trend toward an association ( p = 0.057). This suggests a potential benefit of statins on DFU healing, and larger, targeted studies are warranted. [ABSTRACT FROM AUTHOR]

Management of neuropathic foot ulcers in patients with diabetes (DFUs) has changed little over the past decade, and there is currently no objective method to gauge probability of successful healing. We hypothesized that studies of stem/progenitor cells (SPCs) in the early weeks of standard wound management could predict who will heal within 16 weeks. Blood and debrided wound margins were collected for 8 weeks from 100 patients undergoing weekly evaluations and treatment. SPC number and intracellular content of hypoxia-inducible factors (HIFs) were evaluated by flow cytometry and immunohistochemistry. More SPCs entered the bloodstream in the first 2 weeks of care in patients who healed (n = 37) than in those who did not (n = 63). Logistic regression demonstrated that the number of blood-borne SPCs and the cellular content of HIFs at study entry and the first-week follow-up visit predicted healing. Strong correlations were found among week-to-week assessments of blood-borne SPC HIF factors. We conclude that assays of SPCs during the first weeks of care in patients with DFUs can provide insight into how well wounds will respond and may aid with decisions on the use of adjunctive measures. [ABSTRACT FROM AUTHOR]

Diabetic patients undergoing hyperbaric oxygen therapies (HBOT) for refractory lower extremity neuropathic ulcers exhibit more than a twofold elevation ( p=0.004) in circulating stem cells after treatments and the post-HBOT CD34 cell population contains two- to threefold higher levels of hypoxia inducible factors-1, -2, and -3, as well as thioredoxin-1 ( p<0.003), than cells present in blood before HBOT. Skin margins obtained from 2-day-old abdominal wounds exhibit higher expression of CD133, CD34, hypoxia inducible factor-1, and Trx-1 vs. margins from refractory lower extremity wounds and expression of these proteins in all wounds is increased due to HBOT ( p<0.003). HBOT is known to mobilize bone marrow stem cells by stimulating nitric oxide synthase. We found that nitric oxide synthase activity is acutely increased in patients' platelets following HBOT and remains elevated for at least 20 hours. We conclude that HBOT stimulates vasculogenic stem cell mobilization from bone marrow of diabetics and more cells are recruited to skin wounds. [ABSTRACT FROM AUTHOR]

This is a randomized factorial design clinical trial that investigates the efficacy and feasibility of providing prognostic information on wound healing. Prognostic information was provided based on baseline or 4-week wound characteristics. Healing rates were then determined at 24 weeks for venous leg ulcers and 20 weeks for diabetic neuropathic foot ulcers. Centers that had access to baseline information for venous leg ulcer prognosis had an odds ratio (OR) of healing of 1.42 (95% confidence interval [CI]: 1.03, 1.95) while centers that had access to information at 4 weeks had an OR of healing of 1.43 (95% CI: 1.05, 1.95) compared with controls. Diabetic neuropathic foot ulcer patients treated in centers that had been randomized to receive only 4-week prognostic information were more likely to heal than individuals seen in centers randomized to receive no intervention (OR 1.50, 95% CI: 1.05, 2.14). Our study found that it is feasible and efficacious to provide prognostic information on venous leg ulcers and diabetic neuropathic foot ulcers in a wound care setting using an existing administrative database. This intervention was easy to administer and likely had low associated costs. This method of dispersing prognostic information to healthcare providers should be expanded to include recently published treatment algorithms. [ABSTRACT FROM AUTHOR]

To evaluate the ability of research nurses to identify pressure ulcers, the authors assembled digital photographs of the skin of 160 consenting elderly patients (80% African American, 63% women). The series included 39 photos of pressure ulcers, 109 of normal skin, and 12 of other skin conditions, determined by consensus by two experts (D.J.M. and S.H.K.). Photos were packaged electronically into eight blocks of 20, with pressure ulcer prevalence ranging from 20% to 30% per block. The eight blocks were duplicated to create two sets of 160 photos each. Each of six raters (experienced clinical research nurses), working independently, evaluated the 320 photos as if each photo depicted a different patient. For analysis, the ratings were collapsed into binary determinations (any pressure ulcer vs. none). The overall sensitivity and specificity of the ratings were 0.97 (95% confidence interval: 0.94, 0.98) and 0.81 (95% confidence interval: 0.77, 0.86), respectively. Rater-specific prevalence (range: 31.8–47.5%) exceeded the true prevalence (24.4%). Inter- and intrarater reliability coefficients were 0.69 and 0.84, respectively. Trained research nurses can accurately classify pressure ulcers from photographs, even when patients are largely non-White and the photographs depict pressure ulcers spanning all pressure ulcer stages. [ABSTRACT FROM AUTHOR]

The objective of this study was to undertake a retrospective analysis of claims data of diabetic foot ulcer (DFU) patients to determine the rates of amputation and identify the risk and protective factors. Rates of amputation were calculated in patients diagnosed with DFU in the MEDSTAT Marketscan database between January 2000 and December 2002, who had prediagnosis coverage of 90 days. A nested case–control study was conducted using a 1 : 10 ratio of amputee cases to randomly selected nonamputee controls matched on follow-up days. The association of co-morbid conditions, demographic factors, and severity (5+ outpatient claims for DFU) on amputation was estimated by adjusted odds ratios (AOR) with 95% confidence intervals (CIs). The 5911 eligible patients yielded an incidence density rate of 2.30 amputations per 100 person years (95% CI = 1.91, 2.77). The 116 cases and 1153 controls averaged 307.3 and 308.5 observation days, respectively. Amputation was significantly increased by male gender (AOR 1.98), Charlson co-morbidity scores of 4–5 and 6+ (AOR = 2.89 and 5.36, respectively), renal disease (AOR = 2.11), peripheral vascular disease (AOR = 2.67), and 5+ outpatient DFU services (AOR = 2.17). Practitioners may consider more aggressive care and earlier referral to specialists for DFU patients who fit risk profiles for amputation, which include peripheral vascular disease, multiple co-morbid conditions, and repeated outpatient DFU services. [ABSTRACT FROM AUTHOR]

Venous leg ulcers are among the most common chronic wounds. Treatment is commonly with a limb compression bandage. Previous small, often single-center, studies have shown that it is possible to predict which wounds are likely to respond to compression therapy. We designed this cohort study using a dataset of over 20,000 individuals with a venous leg ulcer to investigate the accuracy of several prognostic models. Creating complex models using logistic regression, as well as simply counting prognostic factors, we show that initial measures of wound size and duration accurately predict, as measured by area under the receiver operator curve and Brier score, who will heal by the 24th week of care. For example, a wound that is less than 10 cm2 and less than 12 months old at the first visit has a 29 percent chance of not healing by the 24th week of care, while a wound greater than 10 cm2 and greater than 12 months old has a 78 percent chance of not healing. Ultimately, these models can be applied by a clinician to help determine whom to continue to treat with standard care and perhaps whom to treat with adjuvant therapies. They may also aid in the design of clinical trials. [ABSTRACT FROM AUTHOR]

PURPOSE: The objective of this study was to estimate the period prevalence and incidence of pressure ulcer among those 65 years of age and older.METHODS: We used a patient-record database called the General Practice Research Database (GPRD). Subjects were 65 years of age and older and cases were ascertained based on strict inclusion and exclusion criteria. The accuracy of the ascertainment strategy was estimated using mailed physician-answered questionnaires. Annual period prevalence and age-specific incidence were estimated per 100 person-years with exact 95% confidence intervals (CI).RESULTS: The accuracy of our ascertainment strategy was excellent, with a positive predictive value of 100% (95% CI: 92%,100%) and negative predictive value of 95% (85%, 95%). Over 200,000 person-years of data were analyzed. The annual period prevalence of pressure ulcer among those 65 years of age and older varied from 0.31% to 0.70%. The incidence varied significantly with advancing patient age from 0.18 to 3.36 per 100-person years (p < 0.001) but was not associated with gender (p = 0.95).CONCLUSIONS: Pressure ulcers are seen in the general practice setting. They are most likely to occur in those over 85 years of age. Preventative strategies within the general practice setting should concentrate on the oldest of the elderly. [Copyright &y& Elsevier]

Prognostic models are increasingly common in the biomedical literature. These models are frequently evaluated with respect to their ability to discriminate between those with and without an outcome. The area under the receiver-operating curve (AROC) is often used to assess discrimination. In this study, we introduce a bootstrap method, and, using Monte Carlo simulation, we compare three different bootstrap approaches with four commonly used methods in their ability to accurately estimate 95% confidence intervals (CIs) around the AROC for a simple prognostic model. We also evaluated the power of a bootstrap method and the commonly used trapezoid rule to compare different prognostic models. We show that several good methods exist for calculating 95% CIs of AROC, but the maximum likelihood estimation method should not be used with small sample sizes. We further show that for our simple prognostic model a bootstrap z-statistic approach is preferred over the trapezoidal method when comparing the AROCs of two related models. [Copyright &y& Elsevier]

Objective: To estimate the effect of various risk factors on the probability that neuropathic diabetic foot ulcers will heal within 20 weeks of care. Design and Setting: A pooled or meta-analysis of individual patient data from the standard care arms of 5 randomized clinical trials was conducted. We analyzed 586 subjects with diabetes mellitus who had a neuropathic diabetic foot ulcer. All patients received good wound care, debridement, and 'off-loading' of the wound. Main Outcome Measure: Multivariable logistic regression was used to calculate the magnitude of the association of each risk factor with patients having healed wounds. Results: Logistic regression odds ratios (ORs; 95% confidence intervals [95% CIs]) revealed that those patients with a diabetic neuropathic foot ulcer that healed within 20 weeks using standard care were more likely to have a smaller wound (OR=0.67; 95% CI, 0.55-0.81), a wound that existed for a shorter period (OR=0.73; 95% CI, 0.61-0.87), and be nonwhite (OR=0.64; 95% CI, 0.43-0.96) compared with patients whose wounds did not heal within 20 weeks. The patient's age (OR=0.99; 95% CI, 0.89-1.01), serum level of glycosylated hemoglobin at the start of the study (OR=1.03; 95% CI, 0.97-1.10), and sex (OR=1.02; 95% CI, 0.69-1.50) were unassociated with the probability of wound healing. Substantial heterogeneity was not found among the studies. Conclusions: A standard care regimen for diabetic neuropathic foot ulcers is most likely to be effective for patients who have wounds that are small and of brief duration. This information should help dermatologists decide initially whether to use standard care, to try a new treatment, or to refer the patient to a specialty center. [ABSTRACT FROM AUTHOR]

Most patients with chronic wounds fail to heal in a reasonable period of time. Despite considerable advances in elucidating the molecular basis of wound repair, attempts at developing new therapies have been disappointing. In fact, in the few studies where cytokine growth factors have been efficacious, their effect has been dramatically less than would have been predicted from animal studies. We hypothesize that platelet-derived growth factor-BB, a growth factor associated with wound healing, when produced in large quantities within the wound bed due to adenovirus mediated gene overexpression by the cells of the wound bed will dramatically enhance wound healing. Simply stated, we plan to insure the delivery of the growth factor by using gene therapy techniques so that cells locally involved in the wound healing process will temporarily increase their production of platelet-derived growth factor-BB. We present the first step in the series of human investigations to test this hypothesis which is a phase I clinical trial. Our proposed study is designed to assess local and systemic toxicity, and the feasibility of using the maximum tolerated dose of H5.020CMV.PDGF-b associated with in vivo platelet-derived growth factor-BB gene transduction via an intraulcer injection of H5.020CMV.PDGF-b in patients with a diabetic insensate foot ulcer. [ABSTRACT FROM AUTHOR]

ABSTRACT The adherence by patients to diabetic foot ulcer therapy is often difficult. The goal of this study was to begin to understand how a patient's health literacy affects their foot ulcer management decisions. Initially using a cross-sectional study design, we evaluated diabetics with foot ulcers within 4 weeks of being asked to participate in a longitudinal study. We assessed health literacy using measures of general health literacy, diabetes health literacy, diabetes self-efficacy, and diabetes numeracy. Individuals enrolled in the study had higher health literacy based on the Short Test of Functional Health Literacy in Adults [33.8 (SD 2.3) versus 27.3 (SD 9.6); p = 0.009] as compared to individuals who previously declined an invitation to enroll in the study. Furthermore, patients with lower Short Test of Functional Health Literacy in Adults scores had larger ( p = 0.04) and older ( p = 0.125) wounds (markers for poorer prognosis). Other measures of literacy showed similar results. In conclusion, those with diminished health literacy were less likely to enroll in an investigational study and had wounds that were less likely to heal. [ABSTRACT FROM AUTHOR]

The article discusses research being done on diabetes mellitus (DM). It references the study "Association of Statin Use and Reduced Risk of Lower-Extremity Amputation Among Patients with Diabetes: A Nationwide Population-Based Cohort Observation," by T.-L. Yang et al. in the 2016 issue of "Diabetes Care." The variables considered include the percentage of relative risk reduction for lower-extremity amputation, medications used and wound healing.

Lower-extremity wounds are a major complication of diabetes. Hemoglobin A1c (HbA1c) reflects glycemia over 2-3 months and is the standard measure used to monitor glycemia in diabetic patients, but results from studies have not shown a consistent association of HbA1c with wound healing. We hypothesized that elevated HbA1c would be most associated with poor wound healing. To test this hypothesis, we conducted a retrospective cohort study of 183 diabetic individuals treated at the Johns Hopkins Wound Center. Our primary outcome was wound-area healing rate (cm2 per day). Calibrated tracings of digital images were used to measure wound area. We estimated coefficients for healing rate using a multiple linear regression model controlling for clustering of wounds within individuals and other common clinic variables. The study population was 45% female and 41% African American, with a mean age of 61 years. Mean HbA1c was 8.0%, and there were 2.3 wounds per individual (310 wounds total). Of all measures assessed, only HbA1c was significantly associated with wound-area healing rate. In particular, for each 1.0% point increase in HbA1c, the daily wound-area healing rate decreased by 0.028 cm2 per day (95% confidence interval: 0.003, 0.0054, P=0.027). Our results suggest that glycemia, as assessed by HbA1c, may be an important biomarker in predicting wound-healing rate in diabetic patients.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub [ABSTRACT FROM AUTHOR]

Surrogate markers are endpoints that occur early in the course of treatment and are intended to predict the true, meaningful clinical endpoint. Surrogate markers have been used to study treatments for a wide range of diseases in which the true outcome is delayed. The evaluation of therapies for venous leg ulcers is challenged by the prolonged observation period necessary to reach the endpoint of healing. We have performed a large cohort study to examine wound healing characteristics as candidate surrogate markers of venous leg ulcer healing using the Curative Health Services population. A total of 58,038 wounds met our definition of venous leg ulcer; however, 1550 wounds were excluded based on size, depth, site, and/or involvement of tendon or bone, leaving 56,488 wounds in 29,189 patients for analysis. The median wound size was 189 mm2 , with a median wound duration of 3 mo. Using a large cohort of diverse venous leg ulcer patients, we demonstrate that after only 4 wk of treatment the wound parameters log healing rate, log wound area ratio, and percentage change in wound area can be valid surrogate markers of healing at 12 or 24 wk of care. Based on the area under the receiver operator characteristic curve log rate, log area ratio, and percentage change in area can discriminate which patients will heal at 12 or 24 wk of care (receiver operator characteristic 0.72–0.80). These surrogates were further validated by demonstrating that established risk factors for not healing such as wound size and wound duration are also important risk factors for not achieving the surrogate endpoint. These surrogate markers for venous leg ulcer healing may allow for early clinical trials to be more efficient, and can allow clinicians to identify patients unlikely to heal early in the course of treatment in order to expedite referral to specialty centers or for the selection of stepped treatment algorithms. [ABSTRACT FROM AUTHOR]