Functional ambulatory status as a potential adjunctive decision-making tool following wound, level of ischemia, and severity of foot infection assessment.

The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System has been developed to stratify amputation risk on the basis of extent of the wound, level of ischemia, and severity of foot infection (WIfI). However, there are no currently validated metrics to assess, grade, and consider functional status, especially ambulatory status, as a major consideration during limb salvage efforts. Therefore, we propose an adjunct to the current WIfI system to include the patient's ambulatory functional status after initial assessment of limb threat. We propose a functional ambulatory score divided into grade 0, ambulation outside the home with or without an assistive device; grade 1, ambulation within the home with or without an assistive device; grade 2, minimal ambulation, limbs used for transfers; and grade 3, a person who is bed-bound. Adding ambulatory function as a supplementary assessment tool can guide clinical decision making to achieve optimal future functional ambulatory outcome, a patient-centered goal as critical as limb preservation. This adjunct may aid limb preservation teams in rapid, effective communication and clinical decision making after initial WIfI assessment. It may also improve efforts toward patient-centered care and functional ambulatory outcome as a primary objective. We suggest a score of functional ambulatory status should be included in future trials of patients with chronic limb-threatening ischemia.

Predictors of Major Adverse Limb Events after Open Forefoot Amputation in Patients with Chronic Limb-Threatening Ischemia.

BACKGROUND: Management of patients with chronic limb-threatening ischemia (CLTI) and extensive foot necrosis presents a challenge for limb salvage. Our study evaluates preoperative risk factors that contributed to durability and efficacy of limb salvage after open transmetatarsal amputation (TMA) in patients with critical limb-threatening ischemia. METHODS: We abstracted data from patients who underwent open TMA at Los Angeles County-University of Southern California Medical Center and Keck Hospital of University of Southern California from 2009 to 2018. Multivariable logistic regression analysis, adjusting for preoperative risk factors, was used to examine predictors of major adverse limb events (MALE). The aim was to evaluate outcomes following open TMA with MALE as the primary outcome. Our hypotheses were that outcomes would be worse for patients with foot infections and renal failure. RESULTS: Forty-three open TMAs were done in 39 patients during the study period. The cohort had a mean age of 63 ± 11.6 years, 89% had a history of diabetes, 95% hypertension (HTN), 54% had end-stage renal disease (ESRD), and 26% were current smokers. MALE occurred in 39% of the cohort. Sex, race, indication, HTN, smoking status, and history of prior ipsilateral revascularization or minor amputations were not associated with MALE (P > 0.05). Multivariate logistic regression found ESRD to be an independent predictor of MALE (odds ratio 7.43, 95% confidence interval 1.12-49.17, P = 0.038) after adjusting for clinically significant covariates. CONCLUSIONS: Open TMA provides acceptable rates of limb salvage for complex patients with CLTI. ESRD is an independent risk factor for MALE following open TMA in these patients. Vigilant follow-up is essential for this morbid patient population given poorer outcomes after forefoot amputation.

Reconstructive Limb Salvage After COVID-19-Induced Gangrene and Amputation.

This case series describes the clinical course and reconstructive methods utilized for patients with diabetes and significant gangrene and necrosis following coronavirus disease 2019 (COVID-19) infection. COVID-19 produces mainly respiratory symptoms but has a variety of atypical presentations and sequelae. Serious complications are increased in patients with underlying medical conditions such as diabetes mellitus. By generating a prothrombotic milieu, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increases the risk for arterial and venous thromboses. Inflammatory damage and micro-thromboses are thought to contribute to acro-ischemia, colloquially known as 'COVID toes,' which presents cutaneously as chilblain-like lesions. Necrosis can be severe and devastating, often resulting in major amputation. Two exemplary case reports are presented herein: first, a 57-year-old female presented for vascular evaluation with pedal gangrene to the midfoot one month after developing painful discoloration in her right toe. After angioplasty restored pedal blood flow, she received a transmetatarsal amputation (TMA) with a local tissue flap. Second, a 41-year-old female presented for vascular evaluation with extensive pedal gangrene three months after hospitalization for COVID-19. After arteriotomy improved pedal blood flow, she underwent a Lisfranc amputation followed by superficial circumflex iliac artery perforator (SCIP) flap reconstruction. Sufficient evidence suggests that COVID-19 impairs microcirculatory function and can be especially detrimental in diabetic patients. Reconstructive techniques in patients with severe gangrene with COVID toes help patients regain functionality.

Lepromatous Leprosy and Charcot Neuroarthropathy of Insensate Feet: A Case Report.

Leprosy is a chronic infection of the skin, eyes, and peripheral nerves due to the slow-growing, acid-fast bacillus Mycobacterium leprae. Devastating complications include Charcot neuroarthropathy and insensate hands and feet. We present the case of an 81-year-old female with rheumatoid arthritis and 50 years of polar lepromatous leprosy who suffered from bilateral collapsed arches, flat feet, and bone deformities of Charcot feet.

Evaluating the impact of an interdisciplinary integrated limb preservation service operating concurrently with a single-specialty service.

BACKGROUND: This study examined the efficacy of an interdisciplinary limb preservation service (LPS) in improving surgical outcomes for diabetic foot ulcer (DFU) patients compared to traditional care. METHODS: Data from January 1, 2017 to September 30, 2020 were retrospectively reviewed. An interdisciplinary LPS clinic began on August 1, 2018, coexisting with a preexisting single specialty service. Primary outcomes were major/minor amputation rates and ratios and hospital length of stay. Surgical endpoints pre- and post-LPS launch were compared. RESULTS: Among 976 procedures for 731 unique DFU patients, most were male (80.4%) and Hispanic (89.3%). Patient demographics were consistent before and after LPS initiation. Major amputation rates decreased by 45.5% (15.4%-8.4%, p = 0.001), with outpatient procedures increasing over 5-fold (3.3% pre-LPS to 18.7% post-LPS, p < 0.001). Hospital stay reduced from 10.1 to 8.5 days post-LPS (p < 0.001). The major to minor amputation ratio declined from 22.4% to 12.7%. CONCLUSIONS: The interdisciplinary LPS improved patient outcomes, marked by fewer major amputations and reduced hospital stays, suggesting the model's potential for broader application.

Tackling diabetic foot: limb salvage during the COVID-19 pandemic.

Purpose: Lower extremity amputation resulting from diabetic foot ulcer, with neuropathic and/or ischemic etiologies, remains a devastating and costly complication of diabetes mellitus. This study evaluated changes in care delivery of diabetic foot ulcer patients during the COVID-19 pandemic. A longitudinal assessment evaluating the ratio of major lower extremity amputation to minor lower extremity amputations after implementation of novel strategies to combat access restrictions was compared to the pre-COVID-19 era. Methods: The ratio of major to minor lower extremity amputation (i.e. the high-to-low ratio) was assessed at two academic institutions, the University of Michigan, and University of Southern California, in a population of patients with diabetes who had direct access to multidisciplinary foot care clinics in the 2 years prior to the pandemic and the first 2 years of the COVID-19 pandemic. Results: Patient characteristics and volumes including patients with diabetes and those with a diabetic foot ulcer were similar between eras. In addition, inpatient diabetic foot-related admissions were similar, but were suppressed by government shelter in placed mandates and subsequent COVID-19 variants surges (e.g. delta, omicron). In the control group, the Hi-Lo ratio increased every 6 months by an average of 11.8%. Meanwhile, following STRIDE implementation during the pandemic, the Hi-Lo ratio reduced by (-)11% (p < 0.001) and doubled limb salvage efforts as compared to the baseline era. The reduction of the Hi-Lo ratio was not influenced significant by patient volumes or inpatient admissions for foot infections. Conclusion: These findings signify the importance of podiatric care in the at-risk diabetic foot population. Through strategic planning and rapid implementation of at-risk diabetic foot ulcer triage, multidisciplinary teams were able to maintain accessible care during the pandemic which resulted in a reduction of amputations. Furthermore, this manuscript highlights the value of the Hi-Lo ratio as an indicator of institutional limb salvage efforts.

Remission Strategies with Fat Grafting to Prevent Recurrence of Pedal Ulcerations and Pain: A Case Series.

Background: Foot deformities and gait abnormalities can result in locally elevated peak pedal pressures or atypical pedal biomechanics. Combined with underlying comorbidities such as neuropathy, stroke, atrophic fat padding and history of ulcerations, this can lead to recurrent ulcerations and pain. Pedal fat grafting (PFG) is a treatment modality that has been shown to reduce peak pressures and accelerate wound healing. This study aimed to investigate the utility of PFG to treat and prevent ulcerations. Methods: We retrospectively analyzed medical history, demographics, wound volume at time of procedure, volume of fat injected, surgical outcomes, and presence of new wounds in 15 patients who underwent PFG at Keck Hospital between 2018 and 2023. Results: Seventeen feet from 15 patients (63 ±â€…12 years old, body mass index 30.9 ±â€…3.1) received PFG with an average volume of fat injected of 10.7 mL and procedure time of 84.6 minutes. At the time of PFG, nine wounds were present on nine feet with an average wound volume of 1.6 ±â€…2.7 cm3. Average follow-up was 6.9 months (range 1-36 months), with no complications or recurrent ulcerations since the procedure. Conclusions: PFG is a promising treatment option for reducing peak pedal pressure and preventing ulcer recurrence in patients with various conditions. Further study is warranted for long-term follow-up.

Initial Clinical Experience with a Simple, Home System for Early Detection and Monitoring of Diabetic Foot Ulcers: The Foot Selfie.

BACKGROUND: Diabetic foot ulcers (DFUs) are a leading cause of disability and morbidity. There is an unmet need for a simple, practical, home method to detect DFUs early and remotely monitor their healing. METHOD: We developed a simple, inexpensive, smartphone-based, "Foot Selfie" system that enables patients to photograph the plantar surface of their feet without assistance and transmit images to a remote server. In a pilot study, patients from a limb-salvage clinic were asked to image their feet daily for six months and to evaluate the system by questionnaire at five time points. Transmitted results were reviewed weekly. RESULTS: Fifteen patients (10 male) used the system after approximately 5 minutes of instruction. Participants uploaded images on a median of 76% of eligible study days. The system captured and transmitted diagnostic quality images of the entire plantar surface of both feet, permitting clinical-management decisions on a remote basis. We monitored 12 active wounds and 39 pre-ulcerative lesions (five wounds and 13 pre-ulcerative lesions at study outset); we observed healing of seven wounds and reversal of 20 pre-ulcerative lesions. Participants rated the system as useful, empowering, and preferable to their previous methods of foot screening. CONCLUSIONS: With minimal training, patients transmitted diagnostic-quality images from home on most days, allowing clinicians to review serial images. This system permits inexpensive home foot screening and monitoring of DFUs. Further studies are needed to determine whether it can reduce morbidity of DFUs and/or the associated cost of care. Artificial intelligence integration could improve scalability.

Prescribing Home Digital Thermometry Coupled with Activity Dosing and Optimized Offloading to Prolong Diabetic Foot Remission: A Case Report.

People with a history of diabetic foot ulcers (DFUs) experience diminished health-related quality of life and are at a 40% annual risk of DFU recurrence. Due to a fear of DFU recurrence, people in DFU remission participate less in physical activity and moderate-intensity exercise when compared to people with diabetes who have not had wounds. There is novel evidence to suggest that too little activity during DFU remission contributes to only low magnitudes of repetitive tissue loading creating a higher susceptibility to skin trauma during inadvertent high-activity bouts. Conversely, a hasty return to too much activity could lead to rapid recurrence. There is now high-level evidence from multiple meta-analyses to indicate that home-based foot temperature monitoring, coupled with activity modification and daily inspection of the feet for impending signs of ulceration, could reduce the risk of ulcer recurrence by 50%. There is little evidence, however, to guide the decision-making regarding the appropriate quantity and frequency of physical activity during DFU remission and the acceptability from the patient perspective. This has resulted in limited uptake of this novel intervention in clinical practice. Earlier, we proposed that activity can be dosed for people in foot ulcer remission, just like insulin or medication is dosed. Here, we describe a patient-centered approach to implementing home foot temperature monitoring coupled with daily foot checks and dosage-based return to physical activity in a patient in DFU remission, including his perspective. We believe using such an approach could maximize ulcer-free days in remission, thereby improving quality of life.

Evolution of WIfI: Expansion of WIfI Notation After Intervention.

Nearly a decade ago, the Society for Vascular Surgery (SVS)'s wound, ischemia, and foot Infection (WIfI) classification was first developed to help assess overall limb threat. However, managing conditions such as diabetic foot ulcer and chronic limb-threatening ischemia can be complex. For instance, certain investigative findings might initially be pending such as the level of ischemia or extent of infection before the final classification is established. In addition, wounds evolve rapidly, and the current classification does not allow for tracking their progression over time during treatment. Therefore, we propose a supplemental consistent notation for scoring WifI re-assessment during treatment of a threatened limb inspired by the cancer staging before and after neoadjuvant treatment classification system. Thus, we describe the re-scoring system and how to use it. Our suggestion supports a coherent method to longitudinally communicate characteristics of a threatened limb. This has potential to support high quality interdisciplinary, patient-centered care and enhance the use of this classification in research. Further work is required to validate this modification of a common language of risk.

Dosing Activity and Return to Preulcer Function in Diabetes-Related Foot Ulcer Remission.

Diabetes-related foot ulcers are a leading cause of global morbidity, mortality, and health-care costs. People with a history of foot ulcers have a diminished quality of life attributed to limited walking and mobility. One of the largest concerns is ulceration recurrence. Approximately 40% of patients with ulcerations will have a recurrent ulcer in the year after healing, and most occur in the first 3 months after wound healing. Hence, this period after ulceration is called "remission" due to this risk of reulceration. Promoting and fostering mobility is an integral part of everyday life and is important for maintaining good physical health and health-related quality of life for all people living with diabetes. In this short perspective, we provide recommendations on how to safely increase walking activity and facilitate appropriate off-loading and monitoring in people with a recently healed foot ulcer, foot reconstruction, or partial foot amputation. Interventions include monitored activity training, dosed out in steadily increasing increments and coupled with daily skin temperature monitoring, which can identify dangerous "hotspots" prone to recurrence. By understanding areas at risk, patients are empowered to maximize ulcer-free days and to enable an improved quality of life. This perspective outlines a unified strategy to treat patients in the remission period after ulceration and aims to provide clinicians with appropriate patient recommendations based on best available evidence and expert opinion to educate their patients to ensure a safe transition to footwear and return to activity.

Saving the Diabetic Foot During the COVID-19 Pandemic: A Tale of Two Cities.

Of all the late complications of diabetes, those involving the foot have traditionally required more face-to-face patient visits to clinics to treat wounds by debridement, offloading, and many other treatment modalities. The advent of the coronavirus disease 2019 (COVID-19) pandemic has resulted not only in the closing of most outpatient clinics for face-to-face consultations but also in the inability to perform most laboratory and imaging investigations. This has resulted in a paradigm shift in the delivery of care for those with diabetic foot ulcers. The approaches to this challenge in two centers with an interest in diabetic foot disease, including virtual consultations using physician-to-patient and physician-to-home nurse telemedicine as well as home podiatry visits, are described in this review and are illustrated by several case vignettes. The outcomes from these two centers suggest that we may be witnessing new possibilities in models of care for the diabetic foot.

Midterm Fate of the Contralateral Foot in Charcot Arthropathy.

BACKGROUND: The contralateral foot in Charcot arthropathy or neuroarthropathy (CN) is subject to increased plantar pressure. To date, the clinical consequences of this pressure elevation are yet to be determined. The aim of this study was to evaluate ulcer and amputation rates of the contralateral foot in CN. METHODS: We abstracted the medical records of 130 consecutive subjects with unilateral CN. Rates of contralateral CN development and recurrence, contralateral ulcer development, and contralateral amputations were recorded. Statistical analysis was performed to identify possible risk factors for contralateral CN and ulcer development, and contralateral amputation. Mean follow-up was 6.2 (SD 4) years. RESULTS: After a mean of 2.5 years, 19.2% patients developed contralateral CN. Female gender was associated with contralateral CN development (odds ratio 3.13, 95% confidence interval 1.27, 7.7). Overall, 46.2% patients developed a contralateral ulcer. Among the patients who developed contralateral CN, 60% developed an ulcer. Sanders type 2 at the index foot (midfoot CN) was significantly associated with contralateral ulcer development. Ulcer-free survival (UFS) differed significantly between patients with diabetes type 1 (median UFS 5131 days) and patients with diabetes type 2 (median UFS 2158 days). A total of 25 amputations had to be performed in 22 (16.9%) patients. Three of those 22 patients (2.3%) needed major amputation. CONCLUSION: Almost 20% of patients developed contralateral CN. Nearly half of people with CN developed a contralateral foot ulceration. Patients with type 2 diabetes had significantly shorter UFS than patients with diabetes type 1. Every sixth patient needed an amputation, with the majority being minor amputations. The contralateral foot should be monitored closely and included in the treatment in patients with CN. LEVEL OF EVIDENCE: Level IV, retrospective study.

Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance.

The lymphatic system plays crucial roles in tissue homeostasis, lipid absorption, and immune cell trafficking. Although lymphatic valves ensure unidirectional lymph flows, the flow itself controls lymphatic valve formation. Here, we demonstrate that a mechanically activated ion channel Piezo1 senses oscillating shear stress (OSS) and incorporates the signal into the genetic program controlling lymphatic valve development and maintenance. Time-controlled deletion of Piezo1 using a pan-endothelial Cre driver (Cdh5[PAC]-CreERT2) or lymphatic-specific Cre driver (Prox1-CreERT2) equally inhibited lymphatic valve formation in newborn mice. Furthermore, Piezo1 deletion in adult lymphatics caused substantial lymphatic valve degeneration. Piezo1 knockdown in cultured lymphatic endothelial cells (LECs) largely abrogated the OSS-induced upregulation of the lymphatic valve signature genes. Conversely, ectopic Piezo1 overexpression upregulated the lymphatic valve genes in the absence of OSS. Remarkably, activation of Piezo1 using chemical agonist Yoda1 not only accelerated lymphatic valve formation in animals, but also triggered upregulation of some lymphatic valve genes in cultured LECs without exposure to OSS. In summary, our studies together demonstrate that Piezo1 is the force sensor in the mechanotransduction pathway controlling lymphatic valve development and maintenance, and Piezo1 activation is a potentially novel therapeutic strategy for congenital and surgery-associated lymphedema.

Building a scalable diabetic limb preservation program: four steps to success.

Over the past generation, limb preservation programs and diabetic foot services have begun to proliferate within academic health science centers as well as within health-care systems in general. We describe four key components for a successful program that, developed sequentially with temporal overlap, can allow the program to scale. The first component includes establishment of a 'hot foot line' for urgent emergency department/inpatient referral. The second includes development of a wound-healing clinic to address outpatient care through to remission. The third component focuses on the diabetic foot in remission to maximize ulcer-free days following healing. The fourth and final component focuses on implementation of local and widespread screening clinics to identify and triage patients into appropriate therapeutic and surveillance programs for healing, remission, and primary prevention. Along with developing each of these components, we describe discrete methods to quantify success.

Human mesenchymal stem cell grafts enhance normal and impaired wound healing by recruiting existing endogenous tissue stem/progenitor cells.

Mesenchymal stem cells (MSCs) have been investigated as a clinical therapy to promote tissue repair. However, the disappearance of grafted cells soon after engraftment suggests a possible role as initiators of repair rather than effectors. We evaluated the relative contribution of grafted human MSCs and host stem/progenitor cells in promoting wound healing by using a novel asymmetric wound model in normal and impaired healing diabetic (db/db) mice to discriminate between the effect of direct engraftment and the subsequent systemic response. Experimental animals received paired wounds, with one wound receiving human mesenchymal stem cells (hMSCs) and the other wound receiving vehicle to assess local and systemic effects, respectively. Control animals received vehicle in both wounds. Grafted hMSCs significantly improved healing in both normal and impaired healing animals; produced significant elevation of signals such as Wnt3a, vascular endothelial growth factor, and platelet-derived growth factor receptor-α; and increased the number of pre-existing host MSCs recruited to the wound bed. Improvement was also seen in both the grafted and nongrafted sides, suggesting a systemic response to hMSC engraftment. Healing was enhanced despite the rapid loss of hMSCs, suggesting that mobilizing the host response is the major outcome of grafting MSCs to tissue repair. We validate that hMSCs evoke a host response that is clinically relevant, and we suggest that therapeutic efforts should focus on maximizing the mobilization of host MSCs.

Impaired therapeutic capacity of autologous stem cells in a model of type 2 diabetes.

Endogenous stem cells in the bone marrow respond to environmental cues and contribute to tissue maintenance and repair. In type 2 diabetes, a multifaceted metabolic disease characterized by insulin resistance and hyperglycemia, major complications are seen in multiple organ systems. To evaluate the effects of this disease on the endogenous stem cell population, we used a type 2 diabetic mouse model (db/db), which recapitulates these diabetic phenotypes. Bone marrow-derived mesenchymal stem cells (MSCs) from db/db mice were characterized in vitro using flow cytometric cell population analysis, differentiation, gene expression, and proliferation assays. Diabetic MSCs were evaluated for their therapeutic potential in vivo using an excisional splint wound model in both nondiabetic wild-type and diabetic mice. Diabetic animals possessed fewer MSCs, which were proliferation and survival impaired in vitro. Examination of the recruitment response of stem and progenitor cells after wounding revealed that significantly fewer endogenous MSCs homed to the site of injury in diabetic subjects. Although direct engraftment of healthy MSCs accelerated wound closure in both healthy and diabetic subjects, diabetic MSC engraftment produced limited improvement in the diabetic subjects and could not produce the same therapeutic outcomes as in their nondiabetic counterparts in vivo. Our data reveal stem cell impairment as a major complication of type 2 diabetes in mice and suggest that the disease may stably alter endogenous MSCs. These results have implications for the efficiency of autologous therapies in diabetic patients and identify endogenous MSCs as a potential therapeutic target.

Doublecortin is necessary for the migration of adult subventricular zone cells from neurospheres.

Mutations in human doublecortin (DCX) and knockdown of Dcx in rodents cause radial migration defects in the embryonic cerebral cortex. However, the brain phenotype of Dcx knockout mice is largely normal suggesting that Dcx is not necessary for most migration events. Adult subventricular zone (SVZ) cells migrate tangentially in the rostral migratory stream to the olfactory bulbs. Dcx is expressed in the SVZ but it is unknown if it is necessary for migration. We show that Dcx RNAi reduced SVZ cell migration in vitro, both cell autonomously and non-cell autonomously. Overexpression of Dcx rescued migration after knockdown, but did not increase migration by itself. Thus, Dcx is necessary not only for embryonic radial migration but also migration of adult SVZ cells.