Impact of case-mix adjustment on observed variation in the healing of diabetic foot ulcers at 12 weeks using data from the National Diabetes Foot Care Audit of England and Wales: A cohort study.

AIM: This cohort study investigates the extent to which variation in ulcer healing between services can be explained by demographic and clinical characteristics. METHODS: The National Diabetes Foot Care Audit collated data on people with diabetic foot ulcers presenting to specialist services in England and Wales between July 2014 and March 2018. Logistic regression models were created to describe associations between risk factors and a person being alive and ulcer-free 12 weeks from presentation, and to investigate whether variation between 120 participating services persisted after risk factor adjustment. RESULTS: Of 27,030 people with valid outcome data, 12,925 (47.8%) were alive and ulcer-free at 12 weeks, 13,745 (50.9%) had an unhealed ulcer and 360 had died (1.3%). Factors associated with worse outcome were male sex, more severe ulcers, history of cardiac or renal disease and a longer time between first presentation to a non-specialist healthcare professional and first expert assessment. After adjustment for these factors, four services (3.3%) were more than 3SD above and seven services (5.8%) were more than 3SD below the national mean for proportions that were alive and ulcer-free at follow-up. CONCLUSIONS/INTERPRETATIONS: Variation in the healing of diabetic foot ulcers between specialist services in England and Wales persisted after adjusting for demographic characteristics, ulcer severity, smoking, body mass index and co-morbidities. We conclude that other factors contribute to variation in healing of diabetic foot ulcers and include the time to specialist assessment.

Which diagnostic tests in everyday clinical practice are (not) useful in the management of diabetic foot disease?

This commentary reviews the use of a small number of tests used in the routine management of foot disease in diabetes. The aim is to consider some of the evidence underlying the use of these tests and the difficulties that can be encountered in interpretation. All tests have their limitations and it is important for these to be understood by the clinicians who request them. There are few test results which are categorically diagnostic in the field of the diabetic foot and the majority merely provide supporting evidence for a diagnosis that is either less or more strongly suspected on other grounds.

Rat bite as a cause of diabetic foot ulcer in sub-Saharan Africa.

There have been relatively few reports of foot ulcers in diabetes resulting from rat bite. The findings were derived from people attending a single specialist service in Dar es Salaam for diabetic foot ulcers (DFUs) between 1 January 1999 and 31 December 2016. Details from people presenting for the first time with an ulcer judged to be caused by rat bite were compared with those with from other causes of foot ulcer. There were 426 first recorded foot ulcer episodes (in 179 people) judged to be caused by rat bite. The affected population was significantly younger (mean 55.9 vs 57.5 years, P = .037) and had a lower body mass index (26.5 vs 27.9, P = .008) than controls with other types of foot ulcer. They also presented significantly sooner (7.8 vs 18.2 days, P < .001) and were more likely to heal (85.8 vs 5.5%, P < .001), even though there was also a trend towards an increased risk of death (9.1% vs 5.3%, P = .032). Rat bite is an uncommon cause of DFU, but is not rare. Although the incidence of ulcer healing is higher than in a general foot ulcer population, the incidence of death is also higher.

Osteomyelitis of the foot: non-surgical management, SPECT/CT scanning and minimising the duration of antibiotic use.

In a paper in this issue of Diabetologia (DOI: https://doi.org/10.1007/s00125-017-4417-x ), Vouillarmet and colleagues have explored the use of single-photon emission computed tomography (SPECT)/computed tomography (CT) to define remission during non-surgical management of osteomyelitis of the foot. Their experience in a non-controlled observational study of 45 individuals was that a negative white blood cell-SPECT/CT scan is a reliable marker of remission, while a positive scan at the end of antibiotic treatment may be relatively useful in the prediction of future short- to medium-term relapse. These findings and conclusions are discussed in the light of current uncertainties relating to the diagnosis of bone infection and the lack of any tested measure that can be used to indicate either its presence or its persistence. In this respect, it is concluded that the value of this approach, and in which population, remains to be clearly established.

Using image J to document healing in ulcers of the foot in diabetes.

The aim of the study was to assess the reliability of measuring the cross-sectional area of diabetic foot ulcers using Image J software. The inter- and intra-rater reliability of ulcer area measures were assessed using digital images of acetate tracings of ulcers of the foot affecting 31 participants in an off-loading randomised trial. Observations were made independently by five specialist podiatrists, one of whom was experienced in the use of Image J software and educated the other four in a single session. The mean (±SD) of the mean cross-sectional areas of the 31 ulcers determined independently by the five observers was 1386·7 (±22·7) mm2 . The correlation between all pairs of observers was >0·99 (P < 0·001). There was no significant difference overall between the five observers (ANOVA F1.538; P = 0·165) and no difference between any two (paired samples test t = -0·787-1·396; P ≥ 0·088). The correlation between the areas determined by two observers on two occasions separated by not less than 1 week was very high (0·997 and 0·999; P < 0·001 and <0·001, respectively). The inter- and intra-reliability of the Image J software is very high, with no evidence of a difference either between or within observers. This technique should be considered for both research and clinical use in order to document changes in ulcer area.

Who was first to diagnose and report neuropathic arthropathy of the foot and ankle: Jean-Martin Charcot or Herbert William Page?

In November 1883, Jean-Martin Charcot and Charles Féré reported on bone and joint disease of the foot in cases of tabes dorsalis, and referred to the condition as 'pied tabétique'--a disabling neuropathic osteoarthropathy that we usually now refer to as the Charcot foot. Charcot had originally described neuropathic osteoarthropathy in more proximal joints in 1868, and in his 1883 paper with Féré stated that involvement of the short bones and small joints of the foot had not yet been described. They emphasised in the paper that one of their cases was the first ever observed, two years earlier, in 1881. It is relevant, however, that it was in this same year that involvement of the foot by tabetic arthropathy was presented to the International Medical Congress in London by an English surgeon, Herbert William Page. We believe that Page was the first to diagnose and to report a case of tabetic neuropathic osteoarthropathy in which the bones of the foot and ankle were involved. He was also the first to propose a link between the tabetic foot and disease of the peripheral nerves, as opposed to the central nervous system.

Protocol for a systematic review and individual patient data meta-analysis of prognostic factors of foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS).

BACKGROUND: Diabetes-related lower limb amputations are associated with considerable morbidity and mortality and are usually preceded by foot ulceration. The available systematic reviews of aggregate data are compromised because the primary studies report both adjusted and unadjusted estimates. As adjusted meta-analyses of aggregate data can be challenging, the best way to standardise the analytical approach is to conduct a meta-analysis based on individual patient data (IPD).There are however many challenges and fundamental methodological omissions are common; protocols are rare and the assessment of the risk of bias arising from the conduct of individual studies is frequently not performed, largely because of the absence of widely agreed criteria for assessing the risk of bias in this type of review. In this protocol we propose key methodological approaches to underpin our IPD systematic review of prognostic factors of foot ulceration in diabetes.Review questions;1. What are the most highly prognostic factors for foot ulceration (i.e. symptoms, signs, diagnostic tests) in people with diabetes?2. Can the data from each study be adjusted for a consistent set of adjustment factors?3. Does the model accuracy change when patient populations are stratified according to demographic and/or clinical characteristics? METHODS: MEDLINE and EMBASE databases from their inception until early 2012 were searched and the corresponding authors of all eligible primary studies invited to contribute their raw data. We developed relevant quality assurance items likely to identify occasions when study validity may have been compromised from several sources. A confidentiality agreement, arrangements for communication and reporting as well as ethical and governance considerations are explained.We have agreement from the corresponding authors of all studies which meet the eligibility criteria and they collectively possess data from more than 17000 patients. We propose, as a provisional analysis plan, to use a multi-level mixed model, using "study" as one of the levels. Such a model can also allow for the within-patient clustering that occurs if a patient contributes data from both feet, although to aid interpretation, we prefer to use patients rather than feet as the unit of analysis. We intend to only attempt this analysis if the results of the investigation of heterogeneity do not rule it out and the model diagnostics are acceptable. DISCUSSION: This review is central to the development of a global evidence-based strategy for the risk assessment of the foot in patients with diabetes, ensuring future recommendations are valid and can reliably inform international clinical guidelines.

Wound healing--a practical algorithm.

The decision-making process involved in the management of diabetic foot wounds is complex but hinges on certain simple principles. The first is to agree the actual aim of management with the patient or their representative - and healing of an open wound may be only a part of this. The agreed plan should be discussed and reviewed if the wound is unresponsive to intervention. Management depends otherwise on regular debridement and cleansing, treatment of any infection, consideration of revascularisation and protection of the wound by dressings and off-loading. The evidence to justify the use of advanced wound care therapies is not strong, and outcome depends more on the organisation of the wound care process than on the choice of a particular wound care product. The introduction of an expert multidisciplinary team has been shown to lead to a very significant reduction in the incidence of major amputation and it is likely that it is the availability or otherwise of prompt expert advice which is the principal explanation of the major variations that are known to exist in the incidence of amputation even within single countries.

Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers.

Diabetic foot ulcers remain a major health care problem. They are common, result in considerable suffering, frequently recur, and are associated with high mortality, as well as considerable health care costs. While national and international guidance exists, the evidence base for much of routine clinical care is thin. It follows that many aspects of the structure and delivery of care are susceptible to the beliefs and opinion of individuals. It is probable that this contributes to the geographic variation in outcome that has been documented in a number of countries. This article considers these issues in depth and emphasizes the urgent need to improve the design and conduct of clinical trials in this field, as well as to undertake systematic comparison of the results of routine care in different health economies. There is strong suggestive evidence to indicate that appropriate changes in the relevant care pathways can result in a prompt improvement in clinical outcomes.

Assessing the outcome of the management of diabetic foot ulcers using ulcer-related and person-related measures.

OBJECTIVE: The purpose of this study was to compare different outcome measures in the audit of management of diabetic foot ulcers RESEARCH DESIGN AND METHODS: Data collected prospectively in a consecutive cohort of patients referred to a specialist multidisciplinary foot care clinic between 1 January 2000 and 31 December 2003 were analyzed. A single index ulcer was selected for each patient and classified according to both the Size (Area and Depth), Sepsis, Arteriopathy, and Denervation [S(AD)SAD] and University of Texas (UT) systems. Ulcer-related outcomes (healing, resolution by ipsilateral amputation or by death, and persisting unhealed) were determined at 6 and 12 months and compared with patient-related outcomes (survival, any amputation, and being free from any ulcer) at 12 months. RESULTS: In 449 patients (63.7% male, mean age 66.7 +/- 13.2 years), 352 (78.4%) ulcers were superficial [S(AD)SAD/UT grade 1] and 134 of these (38.1% of 352) were neither ischemic nor infected. A total of 183 (40.8% of 449) ulcers were clinically infected, and peripheral arterial disease was present in 216 patients (48.1%). Seventeen patients (3.8%) were lost to follow-up and were excluded from analysis. Of the ulcers, 247 (55.0% of 449) and 295 (65.7%) healed without amputation by 6 and 12 months, respectively. Median (range) time to healing was 78 (7-364) days. Of all index ulcers, 5.8 and 8.0% were resolved by amputation, and 6.2 and 10.9% by death by the same time points; 27.8 and 11.6% persisted unhealed. In contrast, patient-related outcomes revealed that of 449 patients only 202 (45.0%) were alive, without amputation, and ulcer free at 12 months. This group had had 272 (1-358) days without any ulcer. A total of 48 (10.7%) patients had undergone some form of amputation, and 75 (16.7%) had died. CONCLUSIONS: These data illustrate the extent to which ulcer-related outcomes may underestimate the true morbidity and mortality associated with diabetic foot disease. It is suggested that when attempts are made to compare the effectiveness of management in different centers, greater emphasis should be placed on patient-related outcome measures.

The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes.

The pathogenesis of the acute Charcot foot of diabetes remains unclear. All patients with this condition have evidence of peripheral neuropathy, with loss of protective sensation and abnormal foot biomechanics. However, the acute Charcot foot is also characterised by a pronounced inflammatory reaction and the pathogenic significance of this inflammation has received little attention. We suggest that an initial insult--which may or may not be detected--is sufficient to trigger an inflammatory cascade through increased expression of proinflammatory cytokines, including TNFalpha and interleukin 1beta. This cascade then leads to increased expression of the nuclear transcription factor, NF-kappaB, which results in increased osteoclastogenesis. Osteoclasts cause progressive bone lysis, leading to further fracture, which in turn potentiates the inflammatory process. The potential role of proinflammatory cytokines suggests the possibility of new treatments for this sometimes devastating complication of diabetes.

Dressing and Diabetic Foot Ulcers: A Current Review of the Evidence.

BACKGROUND: The outcome of ulcers of the foot in diabetes is generally poor with around 1 in 10 resulting in the loss of a limb. There is an urgent need for the development of interventions to improve the outcome for patients. To date, however, the evidence base to support many of the interventions in common use, including wound dressings, is poor. METHODS: This article summarizes the findings of systematic reviews of the subject published between 2006 and 2014 and covers all relevant articles in any language, as well as comments on certain newer publications. RESULTS: The 3 consecutive systematic reviews selected a total of 207 articles that met the predefined criteria from a total of 5,632 identified. These included articles on a very wide range of interventions designed to be applied to ulcers of the foot in diabetes to promote wound healing. CONCLUSIONS: The available data suggest that although some newer therapies show promise, few published studies were of high quality, and the majority were susceptible to bias. More work is needed to substantiate the role of available dressings and wound care products in day-to-day clinical practice. Future work will require studies to be performed to a higher standard than many of those reviewed here and should establish not just clinical effectiveness but cost-effectiveness. The conclusions drawn from the studies of diabetic foot ulcers (DFUs) might apply to the management of other types of chronic wounds.

Reporting standards of studies and papers on the prevention and management of foot ulcers in diabetes: required details and markers of good quality.

The evidence base for many aspects of the management of foot ulcers in people with diabetes is weak, and good-quality research, especially relating to studies of direct relevance to routine clinical care, is needed. In this paper, we summarise the core details required in the planning and reporting of intervention studies in the prevention and management of diabetic foot ulcers, including studies that focus on off-loading, stimulation of wound healing, peripheral artery disease, and infection. We highlight aspects of trial design, conduct, and reporting that should be taken into account to minimise bias and improve quality. We also provide a 21-point checklist for researchers and for readers who assess the quality of published work.

Abnormalities of vasomotor regulation in the pathogenesis of the acute charcot foot of diabetes mellitus.

The acute Charcot foot complicates distal symmetrical neuropathy but is remarkably rare. This article reviews the multiple processes that may complicate both diabetes and neuropathy and might, in turn, explain the association of features that are typical of this disorder: osteolysis, vascular calcification in association with intact lower limb blood flow, and uncontrolled inflammation. Specifically, it is suggested that the disorder arises because of abnormal expression of the nuclear transcription factor, NFkappaB, in diabetic neuropathy and that this is further enhanced at the onset of the acute arthropathy as a result of the release of proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1. These proinflammatory cytokines and RANKL may then enter a cycle of mutual augmentation, and this is a factor that underlies the continuing inflammation that characterizes the disorder. If this hypothesis is confirmed, it would suggest the option of new effective treatments for this sometimes devastating disorder.

Controversies in diagnosing and managing osteomyelitis of the foot in diabetes.

The optimal approach to diagnosing and managing osteomyelitis of the foot in diabetes is unclear. Diagnosis is based on clinical signs, supplemented by a variety of imaging tests. Bone biopsy is the accepted criterion standard for diagnosis but is not used by many. Management traditionally involves surgical removal of infected bone, combined with antibiotic therapy. However, recent studies have shown that antibiotics alone may apparently eliminate bone infection in many cases. There is also evidence that early amputation of infected digits is frequently noncurative. Agreement on criteria for diagnosing osteomyelitis is required, and randomized trials are urgently needed, to determine the relative benefits of various surgical interventions and the optimal deployment of antibiotics. We review the microbiology of osteomyelitis of the foot in diabetes, the benefits and limitations of various diagnostic procedures, and the evidence for the effectiveness of both surgical and nonsurgical approaches to management.

Evidence for the use of biological therapies in ulcers of the foot in diabetes.

Because the chronic ulcer of the foot in diabetes is often unresponsive to standard care, there has been considerable interest in the potential benefit of so-called "advanced wound therapies"--many of which have a biological basis. This article summarizes the findings of earlier systematic reviews, together with the findings of more recent publications. The available evidence suggests that while some biological therapies offer promise, more work is needed to substantiate their role in clinical practice. This conclusion needs to be placed in the context of very strong observational data demonstrating the major improvements that can accompany changes to the way in which wound care is delivered with, in particular, the introduction of multidisciplinary team work and more rapid referral for expert assessment.