Use of Serum Protein Measurements as Biomarkers that Can Predict the Outcome of Diabetic Foot Ulceration.

Objectives: To identify proteins that are prognostic for diabetic foot ulcer (DFU) healing and may serve as biomarkers for its management, serum samples were analyzed from diabetic mellitus (DM) patients. Approach: The serum specimens that were evaluated in this study were obtained from DM patients with DFU who participated in a prospective study and were seen biweekly until they healed their ulcer or the exit visit at 12 weeks. The group was divided into Healers (who healed their DFU during the study) and Non-Healers. Results: Interleukin (IL)-10, IL-4, IL-5, IL-6, and IL-13 and interferon-gamma were higher in the Healers while Fractalkine, IL-8, and TNFα were higher in the Non-Healers. The trajectory of IL-10 levels remained stable over time within and across groups, resulting in a strong prognostic ability for the prospective DFU healing course. Classification and Regression Tree analysis created an 11-node decision tree with healing status as the categorical response. Innovation: Consecutive measurements of proteins associated with wound healing can identify biomarkers that can predict DFU healing over a 12-week period. IL-10 was the strongest candidate for prediction. Conclusion: Measurement of serum proteins can serve as a successful strategy in guiding clinical management of DFU. The data also indicate likely superior performance of building a multiprotein biomarker score instead of relying on single biomarkers.

Use of hyperspectral imaging to predict healing of diabetic foot ulceration.

Our main objective was to validate that hyperspectral imaging via a new portable camera carries the potential to provide a reliable clinical biomarker that can predict DFU healing. We recruited patients with diabetic foot ulceration (DFU) without peripheral arterial disease, infection or other serious illness. Using an hyperspectral imaging (HSI) apparatus, post-debridement hyperspectral images were taken evaluating the ulcer size, periwound oxyhemoglobin (OxyHb), deoxyhemoglobin level (DeoxyHb) and oxygen saturation (O2 Sat) for four consecutive visits. Twenty-seven patients were followed, out of whom seven healed their DFU while the remaining 20 failed to heal their DFU. The average time between each visit was 3 weeks. Binary logistic regression of healers versus non-healers on Visit 1 oxyHb and on Visit 2 showed a significant inverse association, OR = 0.85 (95% CI: 0.73-0.98, p < 0.001). An inverse correlation was observed between the Visit 1 oxyHb and the percentage of ulcer size reduction between Visit 1 and Visit 4 (r = -0.46, p = 0.02) and between the Visit 2 oxyHb and the percentage of ulcer size reduction between Visits 2 and 4 (r = -0.65, p = 0.001). Using oxyHb 50 as the cut-off point to predict DFU complete healing, Visit 1 oxyHb measurement provided 85% sensitivity, 70% specificity, 50% positive predictive value and 93% negative predictive value. For Visit 2, oxyHb had 85% sensitivity, 85% specificity, 66% positive predictive value and 94% negative predictive value. We conclude that this preliminary study, which involved a relatively small number of patients, indicates that hyperspectral imaging is a simple exam that can easily be added to daily clinical practice and has the potential to provide useful information regarding the healing potential of DFU over a short period of time.

12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2023.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

More Specialties, Fewer Problems: Using Collaborative Competency Between Infectious Diseases, Podiatry, and Pathology to Improve the Care of Patients with Diabetic Foot Osteomyelitis.

BACKGROUND: Diabetic foot osteomyelitis is a common infection where treatment involves multiple services, including infectious diseases, podiatry, and pathology. Despite its ubiquity in the hospital, consensus on much of its management is lacking. METHODS: Representatives from infectious diseases, podiatry, and pathology interested in quality improvement developed multidisciplinary institutional recommendations culminating in an educational intervention describing optimal diagnostic and therapeutic approaches to diabetic foot osteomyelitis (DFO). Knowledge acquisition was assessed by preintervention and postintervention surveys. Inpatients with forefoot DFO were retrospectively reviewed before and after intervention to assess frequency of recommended diagnostic and therapeutic maneuvers, including appropriate definition of surgical bone margins, definitive histopathology reports, and unnecessary intravenous antibiotics or prolonged antibiotic courses. RESULTS: A postintervention survey revealed significant improvements in knowledge of antibiotic treatment duration and the role of oral antibiotics in managing DFO. There were 104 consecutive patients in the preintervention cohort (April 1, 2018, to April 1, 2019) and 32 patients in the postintervention cohort (November 5, 2019, to March 1, 2020), the latter truncated by changes in hospital practice during the coronavirus disease 2019 pandemic. Noncategorizable or equivocal disease reports decreased from before intervention to after intervention (27.0% versus 3.3%, respectively; P = .006). We observed nonsignificant improvement in correct bone margin definition (74.0% versus 87.5%; P = .11), unnecessary peripherally inserted central catheter line placement (18.3% versus 9.4%; P = .23), and unnecessary prolonged antibiotics (21.9% versus 5.0%; P = .10). In addition, by working as an interdisciplinary group, many solvable misunderstandings were identified, and processes were adjusted to improve the quality of care provided to these patients. CONCLUSIONS: This quality improvement initiative regarding management of DFO led to improved provider knowledge and collaborative competency between these three departments, improvements in definitive pathology reports, and nonsignificant improvement in several other clinical endpoints. Creating collaborative competency may be an effective local strategy to improve knowledge of diabetic foot infection and may generalize to other common multidisciplinary conditions.

A Case Report and Literature Review: Intraneural Ganglion Cyst Causing Tarsal Tunnel Syndrome.

Intraneural ganglion cysts are benign mucinous lesions that form within joints and enter adjacent nerves via an articular branch. Despite being morphologically characterized as benign, they can demonstrate considerable intrafascicular destruction and expansion, resulting in worsening compressive neuropathies or nerve injury. There have been several suggested theories of pathogenesis, but the most widely accepted articular (synovial) theory describes a capsular defect in a neighboring joint that allows joint fluid to egress and track along the epineurium of the innervating articular branch. In this case report, we describe an intraneural ganglionic cyst located in the tarsal tunnel with extensive involvement of the tibial nerve. We describe the symptoms, diagnosis, and treatment as well as review the current literature on intraneural ganglionic cysts.

Methicillin-Resistant Staphylococcus aureus Endocarditis from a Diabetic Foot Ulcer Understanding and Mitigating the Risk.

Diabetic foot infections are a common cause of morbidity and mortality in the United States, and successful treatment often requires an aggressive and prolonged approach. Recent work has elucidated the importance of appropriate therapy for a given severity of diabetic foot infection, and highlighted the ongoing risk such patients have for subsequent invasive life-threatening infection should diabetic foot ulcers fail to heal. The authors describe the case of a man with diabetes who had prolonged, delayed healing of a diabetic foot ulcer. The ulcer subsequently became infected by methicillin-resistant Staphylococcus aureus (MRSA). The infection was treated conservatively with oral therapy and minimal debridement. Several months later, he experienced MRSA bloodstream infection and complicating endocarditis. The case highlights the ongoing risk faced by patients when diabetic foot ulcers do not heal promptly, and emphasizes the need for aggressive therapy to promote rapid healing and eradication of MRSA.

Invasive Systemic Infection After Hospital Treatment for Diabetic Foot Ulcer: Risk of Occurrence and Effect on Survival.

BACKGROUND: Diabetic foot ulcers (DFUs) threaten limbs and prompt hospitalization. After hospitalization, remote-site invasive systemic infection related to DFU (DFU-ISI) may occur. The characteristics of DFU-ISIs and their effect on mortality risk have not been defined. METHODS: We conducted a retrospective cohort study of 819 diabetic patients hospitalized for treatment of 1212 unique DFUs during a 9-year period. We defined the index ulcer as that present at the first (index) DFU admission to our hospital. We defined DFU-ISI as a nonfoot infection that occurred after the index hospitalization and was caused by a microorganism concomitantly or previously cultured from the index ulcer. We determined the frequency, risk factors, and mortality risk associated with DFU-ISIs. RESULTS: After 1212 index DFU hospitalizations, 141 patients had 172 DFU-ISIs. Of the initial 141 DFU-ISIs, 64% were bacteremia, 13% deep abscesses, 10% pneumonia, 7% endocarditis, and 6% skeletal infections. Methicillin-resistant Staphylococcus aureus (MRSA) caused 57% of the ISIs. Patients with initial DFU cultures yielding MRSA and protracted open ulcers had a high 24-month cumulative probability of DFU-ISI (31%) and all-cause mortality rate (13%). Analysis with Cox regression modeling showed that complicated ulcer healing (hazard ratio, 3.812; 95% confidence interval, 2.434-5.971) and initial DFU culture yielding MRSA (2.030; 1.452-2.838) predicted DFU-ISIs and that DFU-ISIs were associated with increased mortality risk (1.987; 1.106-3.568). CONCLUSIONS: DFU-ISIs are important late complications of DFUs. Prevention of DFU-ISIs should be studied prospectively. Meanwhile, clinicians should aggressively incorporate treatment to accelerate ulcer healing and address MRSA into the care of diabetic patients with foot ulcers.

Treatment of tophaceous gout: When medication is not enough.

OBJECTIVES: To review the literature concerning surgical intervention of tophaeceous gout and propose clinical circumstances for when it may be considered. INTRODUCTION: Tophi develop in approximately 12-35% of patients with gout. Tophaceous disease is usually preventable given the availability of effective urate lowering therapies (ULT) including allopurinol, febuxostat, probenecid, lesinurad, and pegloticase. Despite medical therapy, there remains a subset of patients who develop significant complications of tophi including infection, ulceration, and entrapment neuropathy. Tophi in close proximity to joints can cause joint instability, severely limited range of motion, and significant functional impairment. For the rare circumstance when a tophus is causing an urgent complication or if a patient has a contraindication to all available ULTs, surgery may be an appropriate option. This review summarizes the published experience with surgical interventions for tophaceous gout and offers recommendations for its consideration. METHODS: Using Medline and Google Scholar, all available series of surgery for tophaceous gout were reviewed. RESULTS: Overall, 7 published surgical series were identified. In all, 6 of these 7 series were published between 2002 and 2014. The reported outcomes of surgical interventions for tophaceous gout were generally positive without major post-surgical complications. CONCLUSION: Although medical therapy with ULTs should be the first-line approach to tophaceous gout, surgery should be considered for the rare patient with impending or severe, debilitating complications including infections, entrapment neuropathy or those at risk for permanent joint destruction. In these selected clinical circumstances, surgical intervention for tophaceous gout may be appropriate.

Mechanisms involved in the development and healing of diabetic foot ulceration.

We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.

Foot muscle energy reserves in diabetic patients without and with clinical peripheral neuropathy.

OBJECTIVE To investigate changes in the foot muscle energy reserves in diabetic non-neuropathic and neuropathic patients. RESEARCH DESIGN AND METHODS We measured the phosphocreatinine (PCr)/inorganic phosphate (Pi) ratio, total (31)P concentration, and the lipid/water ratio in the muscles in the metatarsal head region using MRI spectroscopy in healthy control subjects and non-neuropathic and neuropathic diabetic patients. RESULTS The PCr/Pi ratio was higher in the control subjects (3.23 +/- 0.43) followed by the non-neuropathic group (2.61 +/- 0.36), whereas it was lowest in the neuropathic group (0.60 +/- 1.02) (P < 0.0001). There were no differences in total (31)P concentration and lipid/water ratio between the control and non-neuropathic groups, but both measurements were different in the neuropathic group (P < 0.0001). CONCLUSIONS Resting foot muscle energy reserves are affected before the development of peripheral diabetic neuropathy and are associated with the endothelial dysfunction and inflammation.

Diabetes: the latest trends in glycemic control.

The increasing pervasiveness of diabetes mellitus on a global stage has been well documented. Many groundbreaking studies have detailed the consequences of inadequate glycemic control, but only recently have data supported evidence that demonstrates benefits in the acute setting. Consensus is lacking with regard to how to achieve glycemic control in the hospital setting. This article discusses glycemic control, with special emphasis on the perioperative patient. Emerging therapeutic treatments and less frequently encountered protocols such as insulin pump management and insulin infusion are considered.

The use of medical hyperspectral technology to evaluate microcirculatory changes in diabetic foot ulcers and to predict clinical outcomes.

OBJECTIVE: Foot ulceration is a serious complication of diabetes, and new techniques that can predict wound healing may prove very helpful. We tested the ability of medical hyperspectral technology (HT), a novel diagnostic scanning technique that can quantify tissue oxy- and deoxyhemoglobin to predict diabetic foot ulcer healing. RESEARCH DESIGN AND METHODS: Ten type 1 diabetic patients with 21 foot ulcer sites, 13 type 1 diabetic patients without ulcers, and 14 nondiabetic control subjects were seen up to 4 times over a 6-month period. HT measurements of oxyhemoglobin (HT-oxy) and deoxyhemoglobin (HT-deoxy) were performed at or near the ulcer area and on the upper and lower extremity distant from the ulcer. An HT healing index for each site was calculated from the HT-oxy and -deoxy values. RESULTS: Hyperspectral tissue oxygenation measurements observed changes in tissue immediately surrounding the ulcer when comparing ulcers that heal and ulcers that do not heal (P < 0.001). The sensitivity, specificity, and positive and negative predictive values of the HT index for predicting healing were 93, 86, 93, and 86%, respectively, when evaluated on images taken at the first visit. Changes in HT-oxy among the three risk groups were noted for the metatarsal area of the foot (P < 0.05) and the palm (P < 0.01). Changes in HT-deoxy and the HT healing index were noted for the palm only (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: HT has the capability to identify microvascular abnormalities and tissue oxygenation in the diabetic foot and predict ulcer healing. HT can assist in the management of foot ulceration.

Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial.

OBJECTIVE: To assess the ability of the 4-week healing rate to predict complete healing over a 12-week period in a large prospective multicenter trial of diabetic patients with foot ulceration. RESEARCH DESIGN AND METHODS: We examined the change in ulcer area over a 4-week period as a predictor of wound healing within 12 weeks in patients who were seen weekly in a prospective, randomized controlled trial. RESULTS: Wound area measurements at baseline and after 4 weeks were performed in 203 patients. The midpoint between the percentage area reduction from baseline at 4 weeks in patients healed versus those not healed at 12 weeks was found to be 53%. Subjects with a reduction in ulcer area greater than the 4-week median had a 12-week healing rate of 58%, whereas those with reduction in ulcer area less than the 4-week median had a healing rate of only 9% (P < 0.01). The absolute change in ulcer area at 4 weeks was significantly greater in healers versus nonhealers (1.5 versus 0.8 cm2, P < 0.02). The percent change in wound area at 4 weeks in those who healed was 82% (95% CI 70-94), whereas in those who failed to heal, the percent change in wound area was 25% (15-35; P < 0.001). CONCLUSIONS: The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This simple tool may serve as a pivotal clinical decision point in the care of diabetic foot ulcers for early identification of patients who may not respond to standard care and may need additional treatment.

Diabetic foot disorders. A clinical practice guideline (2006 revision).

The prevalence of diabetes mellitus is growing at epidemic proportions in the United States and worldwide. Most alarming is the steady increase in type 2 diabetes, especially among young and obese people. An estimated 7% of the US population has diabetes, and because of the increased longevity of this population, diabetes-associated complications are expected to rise in prevalence. Foot ulcerations, infections, Charcot neuroarthropathy, and peripheral arterial disease frequently result in gangrene and lower limb amputation. Consequently, foot disorders are leading causes of hospitalization for persons with diabetes and account for billion-dollar expenditures annually in the US. Although not all foot complications can be prevented, dramatic reductions in frequency have been achieved by taking a multidisciplinary approach to patient management. Using this concept, the authors present a clinical practice guideline for diabetic foot disorders based on currently available evidence, committee consensus, and current clinical practice. The pathophysiology and treatment of diabetic foot ulcers, infections, and the diabetic Charcot foot are reviewed. While these guidelines cannot and should not dictate the care of all affected patients, they provide evidence-based guidance for general patterns of practice. If these concepts are embraced and incorporated into patient management protocols, a major reduction in diabetic limb amputations is certainly an attainable goal.

Early changes in the skin microcirculation and muscle metabolism of the diabetic foot.

BACKGROUND: Changes in the large vessels and microcirculation of the diabetic foot are important in the development of foot ulceration and subsequent failure to heal existing ulcers. We investigated whether oxygen delivery and muscle metabolism of the lower extremity were factors in diabetic foot disease. METHODS: We studied 108 patients (21 control individuals who did not have diabetes, 36 patients with diabetes who did not have neuropathy, and 51 patients with both diabetes and neuropathy). We used medical hyperspectral imaging (MHSI) to investigate the haemoglobin saturation (S(HSI)O2; % of oxyhaemoglobin in total haemoglobin [the sum of oxyhaemoglobin and deoxyhaemoglobin]) in the forearm and foot; we also used 31P-MRI scans to study the cellular metabolism of the foot muscles by measuring the concentrations of inorganic phosphate and phosphocreatine and calculating the ratio of inorganic phosphate to phosphocreatine (Pi/PCr). FINDINGS: The forearm S(HSI)O2 during resting was different in all three groups, with the highest value in controls (mean 42 [SD 17]), followed by the non-neuropathic (32 [8]) and neuropathic (28 [8]) groups (p<0.0001). In the foot at resting, S(HSI)O2 was higher in the control (38 [22]) and non-neuropathic groups (37 [12]) than in the neuropathic group (30 [12]; p=0.027). The Pi/PCr ratio was higher in the non-neuropathic (0.41 [0.10]) and neuropathic groups (0.58 [0.26]) than in controls (0.20 [0.06]; p<0.0001). INTERPRETATION: Our results indicate that tissue S(HSI)O2 is reduced in the skin of patients with diabetes, and that this impairment is accentuated in the presence of neuropathy in the diabetic foot. Additionally, energy reserves of the foot muscles are reduced in the presence of diabetes, suggesting that microcirculation could be a major reason for this difference.

Diabetic foot complications: diagnosis and management.

Foot complications in patients with diabetes mellitus are a challenge to the health care industry. A great deal of expenditure is due to the management of diabetic foot complications. This places a great burden on the health care industry. It also places a great burden on those diabetic patients with foot complications and their families. Therefore, their effective management in an efficient manner is crucial to our patients. To deal with these problems, a dedicated, knowledgeable, and experienced multidisciplinary team is key. Intervention at the earliest possible time yields the best outcome. Prevention is the focus for those with no ulcerations. For those with ulcerations, prompt recognition and treatment is key. The importance of classifying ulcerations according to size, depth, presence or absence of infection, and vascular status can not be overstated. Proper offloading is vital for those with neuropathic lesions. Recognition of patients with a component of ischemia and vascular intervention to increase perfusion will aid in wound healing. Of course deep infection requires immediate drainage. All efforts of those in the multidisciplinary team are directed at the restoration and maintenance of an ulcer-free foot which is important in enabling our patients to maintain their ambulatory status.

Foot small muscle atrophy is present before the detection of clinical neuropathy.

OBJECTIVE: To characterize structural changes and the metabolic profile of foot muscles and correlate them with diabetic neuropathy measurements using phosphorus-31 ((31)P) rapid acquisition with relaxation enhancement (RARE) magnetic resonance imaging (MRI). RESEARCH DESIGN AND METHODS: We studied 12 control subjects, 9 non-neuropathic diabetic patients, and 12 neuropathic diabetic patients using (31)P RARE and proton ((1)H) MRI at 3 Tesla. The ratio of the total cross-sectional area of the foot to that of the muscle tissue was calculated from transaxial (1)H and (31)P images. The average (31)P concentration across the metatarsal head region was measured from the (31)P images. RESULTS: The muscle area-to-total area ratio differed among all three groups (means +/- SD): 0.55 +/- 0.04 vs. 0.44 +/- 0.05 vs. 0.06 +/- 0.06 for control, non-neuropathic, and neuropathic subjects, respectively (P < 0.0001). The average (31)P concentration also differed among all groups: 27.7 +/- 3.8 vs. 21.7 +/- 4.8 vs. 7.9 +/- 8.8 mmol/l for control, non-neuropathic, and neuropathic subjects (P < 0.0001). The muscle area-to-total area ratio strongly correlated with clinical measurements: Neuropathy Disability Score, r = -0.83, P < 0.0001; vibration perception threshold, r = -0.79, P < 0.0001; and Semmes-Weinstein monofilaments, r = -0.87, P < 0.0001. CONCLUSIONS: Small muscle atrophy is present in diabetes before clinical peripheral neuropathy can be detected using standard clinical techniques. The (31)P RARE MRI method evaluates the severity of muscle atrophy, even in the early stages when neuropathy is absent. This technique may prove to be a useful diagnostic tool in identifying early-stage diabetic foot problems.