Causes, prevention, and management of diabetes-related foot ulcers.

In this Review, we aim to complement the 2023 update of the guidelines of the International Working Group on the Diabetic Foot. We highlight the complexity of the pathological processes that underlie diabetes-related foot ulceration (DFU) and draw attention to the potential implications for clinical management and outcome. Variation observed in the incidence and outcome of DFUs in different communities might result from differences in study populations and the accessibility of care. Comparing differences in incidence, management, and outcome of DFUs in different communities is an essential component of the quality of disease care. Additionally, these comparisons can also highlight the relationship between DFU incidence, management, and outcome and the structure of local clinical services and the availability of staff with the necessary skills. The clinical outcome is, however, also dependent on the availability of multidisciplinary care and the ability of people with DFUs to gain access to that care.

Use of Biodegradable Temporising Matrix (BTM) in the reconstruction of diabetic foot wounds: A pilot study.

Introduction: Complex diabetes-related foot wounds are at high risk of infection and subsequent major amputation unless healed expediently. Biodegradable Temporising Matrix (BTM) is a synthetic matrix that facilitates the organisation of the extracellular matrix, resulting in a neodermis layer over these difficult-to-heal areas. The aim of this study was to evaluate the efficacy of using BTM in the reconstruction of challenging diabetic foot wounds. Methods: Eighteen patients with complex diabetic foot wounds (exposed tendon, fascia, joint, bone), or chronic ulcers at high shear stress locations had BTM applied. Indications for BTM application were high shear stress location (66.6%), exposed bone (16.6%), exposed fascia (5.6%), exposed tendon (5.6%) and chronic non-healing wound (5.6%). The time to complete healing, infection rate and incidence of subsequent wound breakdown was analysed. Discussion: Thirteen of 18 patients completed the BTM treatment regime with all these patients achieving complete wound healing at a median time of 13 weeks. One patient had partial treatment with BTM and four patients were withdrawn from the study following BTM application. The rate of infection and re-ulceration were both 15.4%. Conclusion: This is the first prospective cohort pilot study evaluating the use of BTM for complex diabetic foot wounds. BTM demonstrates potential in healing uninfected, non-ischaemic diabetic foot wounds with exposed deep structures and chronic wounds subject to high shear stress. The re-ulceration and infection rates were relatively low for this high-risk population. BTM may also offer promise as an alternative to free flaps. Lay Summary: The prevalence of diabetes and its complications, including foot ulcers and wounds, have significantly increased worldwide over the last 40 years. Increasingly patients are admitted to hospital for antibiotics, debridements and subsequent amputations from these wounds. Complex diabetes-associated wounds are those at highest risk of these complications or necessitating more extensive, complex operations such as free flaps. These wounds may have exposed deep structures, be at risk of high shear stress or be chronic non-healing wounds.Temporisers are a type of material which integrates into the wound and promotes in-growth of tissue, ideal for healing over these difficult to heal areas. Biodegradable Temporising Matrix (BTM) is a synthetic temporising matrix which has demonstrated positive outcomes in facilitating healing in burns and plastics wounds, but its effectiveness in diabetic foot wounds has not yet been proven. This is the first prospective cohort pilot study evaluating the use of BTM for complex diabetic foot wounds. BTM demonstrates potential in healing uninfected, non-ischaemic complex diabetic foot wounds and potentially avoiding more complex operations.

Factors Associated With Key Outcomes in Diabetes Related Foot Disease: A Prospective Observational Study.

OBJECTIVE: Diabetic foot disease is a serious and common complication of diabetes mellitus. The aim of this study was to assess limb and patient factors associated with key clinical outcomes in diabetic patients with foot ulcers. METHODS: This was a prospective observational study of diabetic patients with foot wounds admitted to a major tertiary teaching hospital in South Australia or seen at associated multidisciplinary foot clinics between February 2017 and December 2018. Patient demographic and clinical data were collected, including limb status severity assessed by the WIfI system and grip strength. Participants were followed up for 12 months. The primary outcomes were major amputation, death, amputation free survival, and completion of healing of the index wound within one year. RESULTS: A total of 153 participants were recruited and outcome data were obtained for 152. Forty-two participants underwent revascularisation during the research period. Eighteen participants (11.8%) suffered major amputation of the index limb and 16 (10.5%) died during follow up. Complete wound healing was achieved in 106 (70%) participants. There was a statistically significant association between WIfI stage and major amputation (subdistribution hazard ratio [SHR] 2.75), mortality (hazard ratio [HR] 2.60), amputation free survival (odds ratio [OR] 0.32), and wound healing (SHR 0.69). There was also a statistically significant association between time to healing and grip strength (SHR 0.50), and previous amputations (major or minor) (SHR 0.57). CONCLUSION: This prospective study supports the ability of the WIfI classification system to predict one year key clinical outcomes in a diabetic population with foot ulcers. It also demonstrated that grip strength may be a useful predictor of wound healing.

Update of a Model to Predict Outcomes after Endovascular Aneurysm Repair.

BACKGROUND: Risk assessment models must be continuously validated and updated to ensure that predictions remain valid. Here, the Endovascular Aneurysm Repair Risk Assessment Model, developed in 2008, is updated and improved. METHODS: We used prospectively collected data from Australian patients who underwent elective endovascular aneurysm repair between 2009 and 2013 (n = 695). Data were provided by treating surgeons and the National Death Index. Key outcomes were early and midterm survival, early complications (endoleak, operative, and graft-related) and late complications (endoleak and graft-related). Multinomial logistic regression determined which preoperative variables best predicted each outcome. Area under Receiver Operating Characteristic curve (AUROC), model P-value and internal validation statistics were used to select the best model. RESULTS: Ten preoperative variables were included in the modeling for 10 key outcomes. The most valid outcomes with AUROC>0.7 were 1- and 3-year survival, 30 and 90-day mortality, early and late endoleak (types I, III and IV) and type II endoleak (with an increase in sac size ≥5 mm). The 10 preoperative variables that contributed to outcome models were self-reported fitness, American Society of Anesthesiologists physical status score, history of stroke/transient ischemic attack, age, aneurysm angle, infrarenal neck length, white cell count, respiratory assessment, diabetes and statin therapy. Fitness alone statistically significantly predicted 30 and 90-day deaths better than any other preoperative variable; achieving high AUROCs (0.78 and 0.80), and high odds ratios (12.8 [95% CI: 1.5-110.4] and 18.1 [95% CI: 2.2-149]). CONCLUSIONS: An updated interactive predictive model of outcomes after endovascular aneurysm repair has been created. Many of the variables used in the 2008 model continued to be significant, however, new variables including fitness and respiratory assessment, improved the model. The new model uses variables routinely collected preoperatively, and hence can better support surgeon-patient discussions prior to operation. Informing patients of potential risks or likely outcomes following elective surgery can assist with preoperative shared decision-making.

Assessment of a smartphone-based application for diabetic foot ulcer measurement.

The accurate measurement of diabetic foot ulcer (DFU) wound size is essential as the rate of wound healing is a significant prognostic indicator of the likelihood of complete wound healing. Mobile phone photography is often used for surveillance and to aid in telemedicine consultations. However, there remains no accurate and objective measurement of wound size integrated into these photos. The NDKare mobile phone application has been developed to address this need and our study evaluates its accuracy and practicality for DFU wound size assessment. The NDKare mobile phone application was evaluated for its accuracy in two- (2D) and three-dimensional (3D) wound measurement. One hundred and fifteen diabetic foot wounds were assessed for wound surface area, depth and volume accuracy in comparison to Visitrak and the WoundVue camera. Thirty five wounds had two assessors with different mobiles phones utilizing both applications to assess the reproducibility of the measurements. The 2D surface area measurements by NDKare showed excellent concordance with Visitrak and WoundVue measurements (ICC: 0.991 [95% CI: 0.988, 0.993]) and between different users (ICC: 0.98 [95% CI: 0.96, 0.99)]. The 3D NDKare measurements had good agreement for depth and fair agreement for volume with the WoundVue camera. The NDKare phone application can consistently and accurately obtain 2D measurements of diabetic foot wounds with mobile phone photography. This is a quick and readily accessible tool which can be integrated into comprehensive diabetic wound care.

Evaluation of a Novel Three-Dimensional Wound Measurement Device for Assessment of Diabetic Foot Ulcers.

Objective: The initial wound measurement and regular monitoring of diabetic foot ulcers (DFU) is critical to assess treatment response. There is no standardized, universally accepted, quick, reliable, and quantitative assessment method to characterize DFU. To address this need, a novel topographic imaging system has been developed. Our study aims at assessing the reliability and practicality of the WoundVue® camera technology in the assessment of DFU. Approach: The WoundVue system is a prototype device. It consists of two infrared cameras and an infrared projector, and it is able to produce a three-dimensional (3D) reconstruction of the wound structure. Fifty-seven diabetic foot wounds from patients seen in a multidisciplinary foot clinic were photographed from two different angles and distances by using the WoundVue camera. Wound area, volume, and maximum depth were measured for assessment of reliability. Thirty-one of these wounds also had area calculated by using the established Visitrak™ system, and a correlation between the area obtained by using both systems was assessed. Results: WoundVue images analysis showed excellent agreement for area (intraclass correlation coefficient [ICC]: 0.995), volume (ICC: 0.988), and maximum depth (ICC: 0.984). Good agreement was found for area measurement by using the WoundVue camera and Visitrak system (ICC: 0.842). The average percentage differences between measures obtained by using the WoundVue from different angles for assessment of different sizes and shapes of wounds were 2.9% (95% confidence interval [CI]: 0.3-5.4), 12.9% (95% CI: 9.6-35.7), and 6.2% (95% CI: 2.3-14.7) for area, maximum depth, and volume, respectively. Innovation: This is the first human trial evaluating this novel 3D wound measurement device. Conclusion: The WoundVue system is capable of recreating a 3D model of DFU and produces consistent data. Digital images are ideal for monitoring wounds over time, and the WoundVue camera has the potential to be a valuable adjunct in diabetic foot wound care.

Micronutrient Status in Diabetic Patients with Foot Ulcers.

Objective: To explore the prevalence of micronutrient deficiencies in patients with diabetic foot ulcers and correlate this with foot disease severity and other clinical factors. Approach: Prospective cohort study of diabetic patients with foot ulcers seen in multidisciplinary foot clinics across Adelaide or admitted to the Vascular Surgery Unit at the Royal Adelaide Hospital between February 2017 and September 2018. A total of 131 patients were included in the study. Plasma serum levels of vitamins A, C, D, and E, copper, zinc, and ferritin were measured. Demographic and clinical data, including BMI, smoking status, duration of diabetes, HbA1c, and WIfI score, were obtained. Results: The most prevalent nutritional deficiency found was vitamin D affecting 55.7% of patients. Suboptimal levels of vitamin C affected 73% of patients, comprising marginal levels in 22.2% and deficient levels in 50.8%. Zinc deficiency, vitamin A deficiency, and low ferritin levels were present in 26.9%, 10.9%, and 5.9% of patients, respectively. There was no correlation between BMI, grip strength, duration of diabetes, HbA1c, or smoking status with micronutrient deficiency. Increased severity of diabetic foot disease was associated with lower vitamin C levels (p = 0.02). Innovation: This study has demonstrated that the deficiency of micronutrients, especially vitamin D, vitamin C, zinc, and vitamin A, is common in diabetic patients with foot ulcers. Conclusions: The prevalence of micronutrient deficiency is high in a diabetic population with foot ulcers/wounds. Special concerns regarding the high prevalence of vitamin C and zinc deficiency, given their roles in wound healing. Although further research needs to be performed to determine the clinical implications of our findings, micronutrient deficiency should be considered in diabetic patients with foot wounds.

Low total psoas area as scored in the clinic setting independently predicts midterm mortality after endovascular aneurysm repair in male patients.

OBJECTIVE: Preoperative sarcopenia is an established risk factor for poor outcomes after surgery. Methods for assessing sarcopenia are either complex, time consuming, or poorly validated. We aimed to assess the interobserver reliability of scoring psoas area at the level of the L3 vertebra and to evaluate whether sarcopenia scored by this simple and rapid method correlated with other fitness scoring methods or impacted on mortality and duration of stay for patients undergoing endovascular aneurysm repair (EVAR). METHODS: We had access to 191 preoperative computed tomography scans of patients who underwent EVAR. For each scan the axial slice at the most caudal level of the L3 vertebra was extracted. Three observers independently calculated the combined cross-sectional area of the left and right psoas muscle at this level. Interobserver variability was calculated as per Band and Altman. Psoas area was normalized for patient height with sarcopenia defined as total psoas area of <500 mm2/m2. The effect of sarcopenia on patient survival was assessed using Cox proportional hazards models. Kaplan-Meier curves are also presented. RESULTS: Interobserver reliability of scoring psoas area was acceptable (reproducibility coefficient as percent of mean for each observer pair: 7.92%, 7.95%, and 14.33%). Sarcopenic patients had poorer survival (hazard ratio, 2.37; P = .011) and an increased hospital duration of stay (4.0 days vs 3.0 days; P = .008) when compared with nonsarcopenic patients. Sarcopenic patients were more likely to self-report as unfit (12.4% vs 33.3%; P = .004). Sarcopenia did not correlate with an increased rate of postprocedure complications. CONCLUSIONS: Psoas area scoring has good interobserver reliability. Preoperative sarcopenia as defined by psoas area was associated with poorer survival and of longer length of stay. As all patients being worked up for an endovascular aortic aneurysm repair will undergo a computed tomography scan, this method is a rapid and effective way to highlight patients in the clinic setting who have an increased risk of morbidity and mortality after EVAR.

Fitness plus American Society of Anesthesiologists grade improve outcome prediction after endovascular aneurysm repair.

BACKGROUND: Although the American Society of Anesthesiologists (ASA) grade was established for statistical purposes, it is often used prognostically. However, older patients undergoing elective surgery are typically ASA III, which limits patient stratification. We look at the prognostic effect on early complications and survival of using ASA and self-reported physical fitness to stratify patients undergoing endovascular repair of abdominal aortic aneurysms. METHODS: Data were extracted from a trial database. All patients were assigned a fitness level (A (fit) or B (unfit)) based on their self-reported ability to walk briskly for 1 km or climb two flights of stairs. Fitness was used to stratify ASA III patients, with fitter patients assigned ASA IIIA and less fit patients ASA IIIB. Outcomes assessed included survival, reinterventions, endoleak, all early and late complications and early operative complications. RESULTS: A combined ASA/fitness scale (II, IIIA, IIIB and IV) correlated with 1- and 3-year survival (1-year P = 0.001, 3-year P = 0.001) and early and late complications (P = 0.001 and P = 0.05). On its own, ASA predicted early complications (P = 0.0004) and survival (1-year P = 0.01, 3-year P = 0.01). Fitness alone was predictive for survival (1-year P = 0.001, 3-year P = 0.001) and late complications (P = 0.009). CONCLUSION: This study shows that even a superficial assessment of fitness is reflected in surgical outcomes, with fitter ASA III patients showing survival patterns similar to ASA II patients. Physicians should be alert to differences in fitness between patients in the ASA III group, despite similarities based on preexisting severe systemic disease.

Type II Endoleak after Endovascular Aneurysm Repair: Natural History and Treatment Outcomes.

BACKGROUND: The natural history of type II endoleaks and linkage to aneurysm rupture is unclear. Likewise, treatment recommendations are controversial. The aim of this study was to examine the incidence, factors associated with type II endoleaks, and outcomes in an Australia cohort of patients who have undergone endovascular aneurysm repair (EVAR). METHODS: Data from 693 patients who underwent EVAR between 2009 and 2013 at multiple institutions across Australia were studied. Patients who developed (1) type II endoleak and (2) type II endoleak with sac expansion were compared for preoperative demographics, mortality, sac expansion, aneurysm rupture, and intervention rates. RESULTS: A total of 225 patients developed type II endoleak over a mean follow-up of 1.9 years (±1.0 years), out of which 133 spontaneously resolved, 37 were untreated unresolved, and 16 underwent intervention. Type I and III endoleaks occurred in 50 and 19 patients, respectively. Smoking (P = 0.002) and warfarin (P = 0.044) were protective factors for development of type II endoleak, whereas age (P = 0.034), right iliac artery tortuosity (P = 0.031), and right (P = 0.008) and left external iliac diameters (P = 0.028) were risk factors for endoleak. Three patients suffered aneurysm ruptures in the entire cohort. All ruptures occurred in type II endoleak patients, of which two occurred after reintervention and in the absence of sac expansion (>5 mm). Late type II endoleak occurred in 117 patients, out of which 26 had sac expansion. Of those without late type II endoleak, 25 have sac expansion. There was no statistically significant difference in survival between those with and without type II endoleak. Age (P < 0.0001) and smoking (P = 0.001) were significant independent predictive factors for survival in this patient sample. Treatment outcomes were encouraging with most cases involving endoleak resolution (15 of 16 patients) and no sac expansion after intervention (0 of 8 patients with complete follow-up info on sac size). CONCLUSIONS: Aneurysm rupture in patients with type II endoleak is uncommon in our series. Type II endoleak with sac expansion does not appear to be associated with aneurysm rupture. In this series, most aneurysm ruptures occurred in the absence of documented sac expansion and after reintervention.

Self-reported fitness of American Society of Anesthesiologists class 3 patients undergoing endovascular aneurysm repair predicts patient survival.

BACKGROUND: Most patients undergoing elective endovascular aneurysm repair (EVAR) are classified American Society of Anesthesiologists (ASA) 3. However, the severity of systemic disease among these patients can vary, resulting in markedly different levels of fitness. In this study, we explored the hypothesis that ASA 3 patients with good self-reported exercise tolerance have better survival after EVAR. METHODS: Data for EVAR patients classified ASA 3 were extracted retrospectively from a prospectively collected registry database. Patients were split into two groups according to fitness level, based on their self-reported ability to climb stairs or to walk briskly for 1 km. Patient survival for each group was assessed by Cox proportional hazards models. RESULTS: During follow-up of 392 patients for a mean of 1.9 years, there were 64 deaths (16.3%), 13.4% in the more physically able group and 21.6% in the less able group. Self-reported inability to walk or to climb stairs was associated with increased risk of all-cause mortality (hazard ratio, 3.55; P < .0001). Following risk adjustment for a number of possible confounding variables, fitness remained significant (hazard ratio, 3.03; P = .0011). CONCLUSIONS: This study has shown that among ASA 3 patients, self-reported exercise capacity is an excellent means of predicting survival. Physicians should consider the physical fitness of their ASA 3 patients when discussing treatment options.

International trends in patient selection for elective endovascular aneurysm repair: sicker patients with safer anatomy leading to improved 1-year survival.

BACKGROUND: To review the trends in patient selection and early death rate for patients undergoing elective endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) in 3 countries. For this study, audit data from 4,163 patients who had undergone elective infrarenal EVAR were amalgamated. The data originated from Australia, Canada (Ontario), and England (London, Cambridge, and Leicester). METHODS: Statistical analyses were undertaken to determine whether patient characteristics and early death rate varied between and within study groups and over time. The study design was retrospective analysis of data collected prospectively between 1999 and 2012. RESULTS: One-year survival improved over time (P = 0.0013). Canadian patients were sicker than those in Australia or England (P < 0.001). American Society of Anesthesiologists classification (ASA) increased over time across all countries although more significantly in Canada. Age at operation remained constant, although older patients were treated more recently in London (P < 0.001). English centers treated larger aneurysms compared with Australia and Canada (P < 0.001). Australian centers treated a much larger proportion of aneurysms that were <55 mm than other countries. Preoperative creatinine levels decreased over time for all countries and centers (P < 0.001). Infrarenal neck angles have significantly decreased over time (P < 0.001). Recent data from London (UK) showed that operations were performed on longer (P < 0.001) and wider (P < 0.001) infrarenal necks than elsewhere. CONCLUSIONS: In this international comparison, several trends were noted including improved 1-year survival despite declining patient health (as measured by increasing ASA status). This may reflect greater knowledge regarding EVAR that centers from different countries have gained over the last decade and improved medical management of patients with aneurysmal disease.

Uroplakin Ib gene transcription in urothelial tumor cells is regulated by CpG methylation.

Uroplakin Ib is a structural protein on the surface of urothelial cells. Levels of uroplakin Ib mRNA are dramatically reduced or absent in many transitional cell carcinomas, but the molecular mechanisms responsible remain undetermined. Previously, we showed that loss of uroplakin Ib expression correlated with CpG methylation of Sp1/NFkappaB-binding motifs within the proximal promoter. In this study, we show that reporter activity was completely blocked by the methylation of three CpG pairs in this promoter region. Gel shift analysis using purified proteins or nuclear extracts showed that Sp1 and NFkappaB bound to motifs encompassing two of the three CpG pairs. Interestingly, the methylation of these two CpG sites did not prevent the binding of proteins to the promoter in gel shift analyses. Additionally, mutation of these two CpGs did not affect reporter activity, but mutation of 6-bp fragment spanning each CpG partially inhibited reporter activity, suggesting that these sites were functional. A requirement for both Sp1 and NFkappaB in regulating reporter activity was confirmed in transfection experiments using plasmids expressing individual proteins. Our data suggest that the methylation of specific CpG sites can silence the uroplakin Ib promoter, at least in part, by blocking the binding of Sp1 and NFkappaB, although other factors may be involved.

Endovascular repair of abdominal aortic aneurysm reduces intraoperative cortisol and perioperative morbidity.

BACKGROUND: The release of catabolic stress hormones because of surgical trauma leads to a breakdown of fats, proteins, and carbohydrate stores and interference with immune function. This can delay wound healing and may increase the risk of systemic inflammatory response syndrome (SIRS)/sepsis and postoperative complications. Minimally invasive surgery can attenuate this response. Our purpose was (1) to compare neuroendocrine responses in patients undergoing open abdominal aneurysm repair with those in patients undergoing endovascular aneurysm repair (EVAR), (2) to compare the incidence of SIRS/sepsis and all complications in these two groups, and (3) to look at the relationship between procedure type, neuroendocrine response, and incidence of SIRS/sepsis and complications. METHODS: Forty-six patients who underwent open repair and 19 who underwent EVAR were studied. A baseline (T1) 24-hour urine save was undertaken in the week before admission, and a second 24-hour save (T2) commenced at anesthetic induction to measure cortisol and catecholamines. The incidences of SIRS/sepsis and complications were recorded. RESULTS: Significant ( P

Methylation of a CpG island within the uroplakin Ib promoter: a possible mechanism for loss of uroplakin Ib expression in bladder carcinoma.

Uroplakin Ib is a structural protein on the surface of urothelial cells. Expression of uroplakin Ib mRNA is reduced or absent in many transitional cell carcinomas (TCCs) but molecular mechanisms underlying loss of expression remain to be determined. Analysis of the uroplakin Ib promoter identified a weak CpG island spanning the proximal promoter, exon 1, and the beginning of intron 1. This study examined the hypothesis that methylation of this CpG island regulates uroplakin Ib expression. Uroplakin Ib mRNA levels were determined by reverse transcription polymerase chain reaction and CpG methylation was assessed by bisulfite modification of DNA, PCR, and sequencing. A correlation was demonstrated in 15 TCC lines between uroplakin Ib mRNA expression and lack of CpG methylation. In support of a regulatory role for methylation, incubating uroplakin Ib-negative lines with 5-aza-2'-deoxycytidine reactivated uroplakin Ib mRNA expression. A trend between uroplakin Ib mRNA expression and CpG methylation was also observed in normal urothelium and bladder carcinomas. In particular, loss of uroplakin Ib expression correlated with methylation of a putative Sp1/NFkappaB binding motif. The data are consistent with the hypothesis that methylation of specific sites within the uroplakin Ib promoter may be an important factor in the loss of uroplakin Ib expression in TCCs.