High Risk Of Amputation Research Articles

Passive Movement Exercise of the Lower Limbs May Facilitate Wound Healing in Patients With Diabetic Foot Ulcers.

Diabetic foot ulcers are a frequent and serious complication of diabetes with a high risk of amputation. Exercise has been shown to promote wound healing; however, patients with non-healing foot ulcers have limited ability to exercise due to the foot ulcer. Other strategies are therefore warranted. We evaluated the effect of eight weeks of two-leg passive movement exercise on wound healing in patients with non-healing diabetic foot ulcers. Twenty-one patients were included in the study and randomized into either a control or a passive movement exercise intervention group. The primary outcome measure was the wound area. Sixteen participants completed the trial. Wound sizes for the passive movement intervention group were 274 mm2 and 58 mm2 at baseline and week 8, compared to 148 mm2 (p=0.31) and 136 mm2 (p=0.51) in the control group (week 16; 7 mm2 vs. 23 mm2, p=0.55). The mean wound area percentual reduction between baseline and week 8 was higher in the intervention group (76% vs. 36%, difference 40%, p=0.062). The two-leg passive movement intervention showed a non-significant difference in wound healing and was well tolerated by patients with diabetic foot ulcers. Although the study shows potential, the results should be interpreted with its limitations of being underpowered and potentially confounded. We encourage larger randomized controlled trials to be conducted, to elucidate whether the two-leg passive movement intervention can be used to accelerate wound healing in non-healing ulcers.

Prognostic Performance of the Maximal Systolic Acceleration at the Hallux in Healing of Foot Ulcers: A Retrospective Cohort Study

The accurate prediction of foot ulcer healing remains a major challenge in clinical practice. To date, no reliable bedside tests are available. The primary aim of this study was to determine the prognostic performance of the maximal systolic acceleration (ACCmax) to predict ulcer healing. Secondary objectives comprised the investigation of the prognostic accuracy in patients prone to medial arterial calcification and to assess the potential risk of amputation. A single-center retrospective cohort study was conducted. Patients aged ≥18 years who presented with a new-onset ulcer (i.e. Fontaine IV and neuropathic ulcers) on the foot and underwent an ACCmax measurement at the hallux were included. Ulcer healing was defined as an intact skin with epithelialization after 3 or 12months of follow-up. Prognostic performance was calculated by using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). In total, 136 patients with 143 wounds were included. Almost half of the patients were diagnosed with diabetes mellitus (47%), and wound infection was present in 42% of cases. After 3months of follow-up, an NPV of 97.9%, PLR of 3.25, and NLR of 0.19 were found when applying an ACCmax threshold of 0.5m/s2. When looking at 12months, these numbers were 85.6%, 2.72, and 0.50, respectively. Subgroup analysis for patients with diabetes mellitus and chronic kidney disease showed comparable results. The risk of amputation increased significantly when a measurement below 1.0m/s2 was present (odd ratio 5.3, P=0.010). ACCmax measurements at the hallux can have additional prognostic value in patients with foot ulcers. An ACCmax below 1.0m/s2 is associated with nonhealing of an ulcer and a higher risk of amputation, while higher ACCmax values are associated with limb salvage. Therefore, ACCmax could be used for grading ischemia in a wound classification system.

Atherogenic markers and 1-year amputation risk in adults with diabetic foot in a tertiary level hospital: A retrospective cohort study

AimTo determine the association between atherogenic markers, such as total cholesterol/high density lipoprotein cholesterol ratio (TC/HDL-C), triglycerides/HDL-C ratio (TG/HDL-C), and triglycerides-glucose index (TyG), and the risk of 1-year amputation in adults with diabetic foot in a tertiary level hospital. MethodsRetrospective cohort study conducted in 162 adult patients with diabetic foot. The outcome was amputation, defined as “primary amputation in patients' clinical history after their first hospitalization due to foot ulcer.”. The cutoff point was determined using Youden's J statistic. The relative risk (RR) was presented as an association measure. ResultsA TyG index of >9.4 [RR: 1.64 (1.10–2.45)] was associated with a high risk of amputation after 1-year in adults with diabetic foot. However, while a TC/HDL ratio of >4.69 [RR: 1.38 (0.94–2.03)] and a TG/HDL-C ratio > 3.57 [RR: 1.35 (0.89–2.06)] did not show associations with risk of amputation after 1-year. ConclusionsOnly a TyG index of >9.4 was associated with an increased risk of 1-year amputation in adults with diabetic foot. Future studies with larger samples and a longitudinal design may provide more robust evidence and a better understanding of clinical implications.

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia

BackgroundCritical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the variability seen in several factors such as cell combinations or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties.Herein, we have evaluated, for the first time, the regenerative and vasculogenic potential of a combination of endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) isolated from adipose-tissue (AT), compared with ECFCs from umbilical cord blood (CB-ECFCs) and AT-MSCs, in a murine model of CLTI.MethodsBalb-c nude mice (n:32) were distributed in four different groups (n:8/group): control shams, and ischemic mice (after femoral ligation) that received 50 µl of physiological serum alone or a cellular combination of AT-MSCs with either CB-ECFCs or AT-ECFCs. Follow-up of blood flow reperfusion and ischemic symptoms was carried out for 21 days, when mice were sacrificed to evaluate vascular density formation. Moreover, the long-term molecular changes in response to CLTI and both cell combinations were analyzed in a proteomic quantitative approach.ResultsAT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia. Besides, they modulated the inflammatory and necrotic related processes, although the CB group presented the slowest ischemic progression along the assay. Moreover, many proteins involved in the repairing mechanisms promoted by cell treatments were identified.ConclusionsThe combination of AT-MSCs with AT-ECFCs or with CB-ECFCs promoted similar revascularization in CLTI mice, by restoring blood flow levels, together with the modulation of the inflammatory and necrotic processes, and reduction of muscle damage. The protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs-induced revascularization (immune response, vascular repair, muscle regeneration, etc.).

Contemporary National Incidence and Outcomes of Acute Limb Ischemia

Acute limb ischemia (ALI) is a morbid and deadly diagnosis. However, existing epidemiologic studies describing ALI predate the introduction of the Affordable Care Act in 2010 and direct oral anticoagulants in 2011. Thus, we synergized the National Inpatient Sample (NIS) and United States Census to define contemporary trends in the incidence, treatment, and outcomes of ALI in the US. We included emergent admissions of adults with primary diagnosis of lower extremity ALI in survey-weighted NIS data (2005-2020). Mann-Kendal trend test evaluated ALI incidence (primary outcome), anticoagulation usage, insurance coverage, revascularization type, and in-hospital amputation/death. Multivariable logistic regression quantified covariate associations with in-hospital amputation/death. Of the 582,322,862 estimated hospitalizations in the NIS, 227,440 met the inclusion criteria (mean age 68.80years, 49.94% women, 76.66% White). ALI incidence peaked in 2006 (7.16/100,000 person-years) but has declined since 2015 to 4.16/100,000 person-years in 2020 (ptrend=0.008). Endovascular revascularization, anticoagulation, and Medicaid coverage increased, while self-pay insurance decreased (ptrend < 0.05). Amputation rates significantly decreased from 8.04 to 6.54% (ptrend=0.01) while death rate remained at 5.59% (ptrend=0.16) over the study period. Prehospitalization anticoagulation was associated with decreased amputation (adjusted odds ratio [aOR]=0.74 (95% confidence interval [CI] 0.65-0.84)) and death (aOR=0.50 (95% CI 0.43-0.57)). When controlling for covariates, women had a higher risk of death (aOR=1.17 (95% CI 1.07-1.27), P<0.0001), while Black patients had a higher risk of amputation (aOR=1.24 (95% CI 1.10-1.41), P<0.0001). Our US population based epidemiological study demonstrates that ALI incidence and in-hospital amputation rates are decreasing, while mortality remains unchanged. We further highlight the ongoing need for ALI investigation specifically as it relates to access to care, antithrombotic therapy use, treatment strategy, and strategies to combat gender and racial disparities.

NEUROMUSCULAR TAPING IMPROVES MICROVASCULAR CIRCULATION IN TYPE 2 DIABETES MELLITUS PATIENTS

Background: The most common complications in Diabetes Mellitus patients are foot problems and high risk for amputation. Factors that trigger problems in diabetic feet in the form of neuropathy factors, namely loss of sensory nerve function and circulatory disorders. One of the non-pharmacological therapies to prevent these problems is safe Neuromuscular Taping (NMT) which is applied to the skin with elastic plaster through a decompression method to prevent a decrease in peripheral blood circulation and improve blood circulation. Objectives: The purpose of this study was to determine the comparison of the effectiveness of Neuromuscular Taping (NMT) intervention on microvascular circulation which was assessed by Ankle Brachial Pressure Index (ABPI) measurement in type 2 Diabetes Mellitus patients. Methods: This study used a quasi-experimental research design with a pretest-posttest control group approach. The number of respondents to this study was 60 type 2 DM patients divided into treatment group respondents and control group respondents. The intervention group was given NMT intervention for 2 weeks with daily plaster changes while the control group was given standard foot care education. The data collected is an ABPI score that describes microvascular circulation using a sphygmomanometer. Analysis was carried out using paired sample t-tests which were used to determine the effectiveness of the intervention. Results: Based on the results of the study, significant changes were obtained in the microvascular circulation of the treatment group (p = 0.000) α 0.05 which is the category of normal microvascular circulation or no disturbance. Increased microvascular circulation is caused by the application of NMT for 2 weeks. Conclusion: There was an increase in microvascular circulation seen through changes in Ankle Brachial Pressure Index (ABPI) values before and after Neuromuscular Taping (NMT) intervention. There were significant differences between the intervention and control groups in changes in ABPI scores.

Development of an Education Material Targeting Patients Undergoing Lower Extremity Amputation due to Severe Limb Ischemia–A Qualitative Study

IntroductionCritical limb-threatening ischemia (CLTI) is associated with a high risk of amputation, yet patients undergoing amputation due to CLTI have little knowledge of the amputation process and the rehabilitation that awaits. The aim of the present study was to develop and validate information material for patients undergoing amputation. MethodsNine participants were included in the study. Two focus group interviews were performed with seven patients who had undergone lower extremity amputation due to CLTI within the past 2 y. Additionally, two individual interviews were carried out. A semistructured interview guide was used, and the interviews were transcribed verbatim and analysed using qualitative content analysis with a deductive approach. ResultsThree themes were identified as essential for the design of the written information: Perspectives on design and formatting, Providing information to enhance participation in care, and Accessibility to information and support. The prototyped information leaflet was perceived as acceptable, useable, relevant, and comprehensible by the participants. ConclusionsFor patients to actively engage in their care, it is vital that their information needs are met and that they are provided with psychosocial support when needed. Written and oral information should be provided by a trusted healthcare professional.

Accelerating Diabetic Wound Healing by Modulating the Inflammatory Environment Using Quercetin–Rosemary Oil Lipid Nanoemulsions with Artificial Intelligence‐Based Wound Closure Analysis

AbstractDiabetic wounds are a significant complication of diabetes that is characterized by delayed wound healing and a high risk of amputation. The overexpression of pro‐inflammatory macrophages (M1) and matrix metallo protease‐9 (MMP‐9) plays a crucial role in the extended inflammatory phase, which is characteristic of these wounds. This study develops multifunctional lipid nanoemulsions known as Quercetin and Rosemary Oil Lipid Nanoemulsions (Q‐RLNEs) that can effectively convert M1 to M2 macrophages, inhibit MMP‐9 and prevent microbial infections, thereby expediting the healing of diabetic wounds. Q‐RLNEs exhibit excellent biocompatibility, cellular uptake, ROS scavenging, macrophage polarization, MMP‐9 inhibition, and potent antimicrobial properties against Staphylococcus aureus in vitro. In vivo experiments further reveal Q‐RLNE's ability to accelerate complete wound healing in diabetic‐induced rats by reducing inflammation, promoting angiogenesis, and facilitating proper collagen deposition and dermal projection regeneration. This study introduces the application of the Segment Anything Model (SAM). SAM combines attention‐fusion and hybrid fusion strategies for accurate segmentation, enabling comprehensive analysis of wound attributes over time and guiding treatment decisions. The SAM analysis results also align with Q‐RLNE in vitro and in vivo. The findings of this study suggest that Q‐RLNE is a promising new therapeutic agent for accelerating diabetic wound healing.

Lower Extremity Amputation and Peripheral Revascularisation Rates in Romania and Their Relationship with Comorbidities and Vascular Care.

(1) Background: This retrospective Romanian study aimed to calculate the rate of, and comparison between, amputation and revascularisation for patients with either cardiovascular or diabetic comorbidities. (2) Materials: In our hospital-based database, we analysed patient-level data from a series of 61 hospitals for 2019, which covers 44.9% of the amputation patients for that year. The national database is compiled by the national houses of insurance and was used to follow amputations and revascularisations between 2016 and 2021. (3) Results: During the six-year period, the mean number of amputations and revascularisations was 72.4 per 100,000 inhabitants per year for both groups. In this period, a decline in open-surgical revascularisation was observed from 58.3% to 47.5% in all interventions but was not statistically significant (r = -0.20, p = 0.70). The mean age of patients with amputation (hospital-based database) was 67 years. Of these patients, only 5.1% underwent revascularisation in the same hospital prior to amputation. The most common comorbidities in those undergoing amputations were peripheral arterial disease (76.8%), diabetes (60.8%), and arterial hypertension (53.5%). Most amputations were undertaken by general surgeons (73.0%) and only a small number of patients were treated by vascular surgeons (17.4%). (4) Conclusions: The signal from our data indicates that Romanian patients probably have a high risk of amputation > 5 years earlier than Western European countries, such as Denmark, Finland, and Germany. The prevalence of revascularisations in Romania is 64% lower than in the Western European countries.

Primary aldosteronism and lower-extremity arterial disease: a two-sample Mendelian randomization study

Background and AimsPrimary aldosteronism (PA) is an adrenal disorder of autonomous aldosterone secretion which promotes arterial injury. We aimed to explore whether PA is causally associated with lower-extremity arterial disease (LEAD).MethodsWe included 39,713 patients with diabetes and 419,312 participants without diabetes from UK Biobank. We derived a polygenic risk score (PRS) for PA based on previous genome-wide association studies (GWAS). Outcomes included LEAD and LEAD related gangrene or amputation. We conducted a two-sample Mendelian randomization analysis for PA and outcomes to explore their potential causal relationship.ResultsIn whole population, individuals with a higher PA PRS had an increased risk of LEAD. Among patients with diabetes, compared to the subjects in the first tertile of PA PRS, subjects in the third tertile showed a 1.24-fold higher risk of LEAD (OR 1.24, 95% CI 1.03–1.49) and a 2.09-fold higher risk of gangrene (OR 2.09, 95% CI 1.27–3.44), and 1.72-fold higher risk of amputation (OR 1.72, 95% CI 1.10–2.67). Among subjects without diabetes, there was no significant association between PA PRS and LEAD, gangrene or amputation. Two-sample Mendelian randomization analysis indicated that genetically predictors of PA was significantly associated with higher risks of LEAD and gangrene (inverse variance weighted OR 1.20 [95% CI 1.08–1.34]) for LEAD, 1.48 [95% CI 1.28–1.70] for gangrene), with no evidence of significant heterogeneity or directional pleiotropy.ConclusionsPrimary aldosteronism is genetically and causally associated with higher risks of LEAD and gangrene, especially among patients with diabetes. Targeting on the autonomous aldosterone secretion may prevent LEAD progression.

Clinical profile, management and risk factors for seizure-related burn injuries among patients with epilepsy in southwest China

ObjectiveThe epidemiological information associated with seizure-related burn injuries is lacking in China. Therefore, this study aims to analyze the clinical profile, management, outcome, and risk factors of burns that are directly caused by seizures among epileptic patients, and identify the epidemiological characteristics to develop effective preventive strategies. MethodsThis study was conducted between January 2002 and December 2022 in a large Chinese burn center. Data including clinical profile, wound treatment, and outcome were analyzed. A multiple linear regression was used to screen the risk factors for the length of hospital stay (LOS), and a multiple logistic regression was used to screen the contributory factors for the amputation. ResultsA total of 184 burn patients (55.98 % females) were enrolled, with a 0.78 % incidence rate during the study period. The mean age of the patients was 36.16 years (SD: 17.93). Patients aged 20–29 were the most affected age groups (23.37 %). Most burns were caused by flame, accounting for 60.33 % (111/184) of all cases. In total, 76.09 % of the 184 patients underwent at least one operation, and 35 patients (19.02 %) still required amputation during the study period. Burn sites (hands) had the greatest impact on amputation (OR = 3.799), followed by flame burns (OR = 3.723). The mean LOS/TBSA was 6.90 ± 8.53 d, and a larger TBSA, full-thickness burns, and a higher number of operations were identified as the risk factors for a longer LOS. There was one death among the 184 patients, with a mortality rate of 0.54 %. ConclusionThis study demonstrates that burn injuries are extremely harmful to individuals with epilepsy in China because they are at high risk of amputation and disability. Effective healthcare education and preventive programs that focus on lifestyle modifications and seizure control should be implemented to reduce the burn incidence in these populations.

Validity of Mangled Extremity Score System to Predict Limb Salvage on Cases of Traumatic Popliteal Artery Injuries: A Case Series and Review of the Literature

Background: Popliteal artery injuries carry a risk of amputation rate ranging from 9.7% to 28%. The mangled extremity score system (MESS) was originally authenticated in only 26 patients and it was concluded that an MESS ≥ 7 equated to a 100% rate of amputation. In this study we add the effects of combined arterial venous injuries and combined arterial venous and nerve injuries to the risk of amputation and correlate them with the MESS.Methods: This is a retrospective single arm cohort study conducted using 25 patients included between 1 January 2020 and 1 January 2023 at two hospitals, Ain Shams University Hospital and Shebin Elkoom Teaching Hospital. The study defined two groups: the amputation and non-amputation groups. It assessed the validity of the MESS to predict limb salvage in cases of traumatic popliteal artery injuries.Results: The overall rate of amputation was 64%. Patients presenting with MESS ≥ 8 had an amputation rate of 25%, while patients with MESS ≥ 9 had an amputation rate of 75%. Patients presenting with combined popliteal artery and vein or combined artery, vein and nerve injury had a 100% rate of amputation (MESS ≥ 8). There was no 30-day mortality.Conclusions: MESS ≥ 9 carries a high risk of amputation (75%). Combined arterial and venous injuries or arterial, venous and nerve injuries, which already have a high MESS, also carry a high risk of amputation. All of them could be predictors of limb salvage in popliteal artery injury.

Abstract 11450: The Association of Care Fragmentation on Limb Outcomes After Endovascular PAD Procedures Requiring Reintervention

Introduction: Several policies exist that incentivize improved care coordination. Reintervention care fragmentation (when a patient requires a reintervention at another facility that is different than the index facility) for peripheral artery disease (PAD) has not been well-characterized. The intent of this work is to explore the frequency, characteristics, and differences in outcomes for patients when a vascular reintervention occurs at a non-index facility. Methods: National cohort of adults over age 65 who underwent an endovascular procedure for PAD within the Vascular Quality Initiative between January 1, 2010 to December 31, 2018 and had subsequent vascular reintervention. Data was linked to Medicare claims and American Hospital Association. We excluded emergency procedures, those performed for aneurysm, and those performed in an office-based setting. The primary outcomes were 90-day and 180-day amputation. Covariates of interest included sociodemographic, anatomic, procedural, and facility-level characteristics. Mixed effect logistic regression models (clustered at the facility-level) were used to determine the association between reintervention at an index versus non-index facility and the outcomes of interest. Results: Among 4,470 patients who underwent a vascular reintervention after an index endovascular procedure for PAD, 18.1% had their reintervention performed at a non-index facility. There were no differences noted by sex or level of community distress among those who went to the index facility versus a non-index facility for their vascular reintervention. Compared to those who had their reintervention at an index facility, vascular reintervention at a non-index facility was associated with significantly higher likelihood of major amputation (90-d amputation: Odds Ratio (OR) 1.61 [95% Confidence Interval (CI) 1.08-2.39]; 180-day amputation: OR 1.75 [95% CI 1.14-2.70]). Conclusions: Care fragmentation for patients who require vascular reintervention after an index endovascular PAD procedure is associated with higher risk of amputation. Additional work is needed to better understand which patients are at greatest risk for care fragmentation and how to better coordinate care in the post-procedural setting.

Perceptions, Experiences, Barriers and Facilitators Regarding Nutritional Intake of Patients with Chronic Limb Threatening Ischemia: A Qualitative Study

Patients with chronic limb threatening ischemia (CLTI) are at high risk for amputation and other cardiovascular adverse events. Nutrition-related symptoms and malnutrition are common in the CLTI population, and lead to worse clinical outcomes. Understanding of the factors influencing nutritional intake is required to determine whether optimization of nutritional intake in this population requires interventions. Therefore, this study aimed to describe perceptions and experiences on nutrition of patients with CLTI, and to identify perceived barriers and facilitators influencing their nutritional intake. In this phenomenological qualitative study, individual semi-structured, face-to-face interviews were conducted with patients with CLTI who lived independently. Interviews were transcribed verbatim, and reflexive thematic analysis was performed. Twelve participants were interviewed. Five themes were generated: (1) lack of nutritional risk perception, (2) role of nutrition for health, functioning, and surviving, (3) multiple factors influencing nutritional intake, (4) limited nutritional advice, and (5) no intention to change current nutritional intake. Patients with CLTI perceive nutritional intake as a necessity to survive and function. Patients express limited risk perception regarding adequate nutritional intake and undernutrition. Nutritional intake is mainly based on non-health-related factors, as habits and taste, and multiple barriers hinder nutritional intake. Patients received no or only limited nutritional advice. Together this leads to an expressed lack of intention to change nutritional intake. Findings of this study stress the urgency for patient-centered nutritional support, to increase nutrition-related knowledge and motivation, to prevent or treat undernutrition, and may improve clinical outcomes in patients with CLTI.

Retrospective Data Analysis of the Use of an Autologous Multilayered Leukocyte, Platelet, and Fibrin Patch for Diabetic Foot Ulcers Treatment in Daily Clinical Practice.

To describe the healing outcome of chronic, hard-to-heal diabetic foot ulcers (DFUs) treated with an autologous multilayered leukocyte, platelet, and fibrin (MLPF) patch in addition to the best standard of care, in a real-world clinical setting of two US amputation preventive centers. In this retrospective study of patients treated between September 2021 and October 2022, the authors analyzed DFU healing outcomes based on Wound, Ischemia, and foot Infection-derived amputation risk. All 36 patients had a diagnosis of type 2 diabetes and 29 (81%) were male. Their average age was 61.4 years, body mass index was 29.2 kg/m2, and glycated hemoglobin was 7.9. Twenty-seven patients (78%) were diagnosed with peripheral vascular disease, 20 (56%) underwent a peripheral vascular procedure, 15 (42%) had a prior amputation, and 6 (17%) were on hemodialysis. Average wound size was 4.9 cm2, and wound age was 9.5 months. Twelve patients (32%) were classified as low risk, 15 (39%) as moderate risk, and 11 (29%) as high risk for amputation. Within 12 weeks of the first MLPF patch application, nine wounds (24%) healed. After 20 weeks, 23 wounds (61%) were closed, and by follow-up, 30 wounds (79%) healed. No amputations were noted. Compared with published data, 40% fewer patients underwent readmission within 30 days, with 72% shorter admission duration. Real-world clinical experiences using the MLPF patch to treat hard-to-heal DFUs resulted in the majority of wounds healing. Few patients experienced a readmission within 30 days, and the average admission duration was short.

Outcomes of lower extremity arterial bypass using the Human Acellular Vessel in patients with chronic limb-threatening ischemia

ObjectivePatients with chronic limb-threatening ischemia (CLTI) and no great saphenous vein to use as a conduit for arterial bypass have a high risk for amputation despite advances in medical and endovascular therapies. This report presents findings from a U.S. Food and Drug Administration (FDA) supported study of the Human Acellular Vessel (HAV) (Humacyte Inc.) used as a conduit for arterial bypass in patients with CLTI and inadequate or absent autologous conduit. MethodsThe HAV is a 6-mm, 40-cm vessel created from human vascular smooth muscle cells seeded onto a polyglycolic acid scaffold pulsed in a bioreactor for 8 weeks as cells proliferate and the scaffold dissolves. The resultant vessel is decellularized, creating a nonimmunogenic conduit composed of collagen, elastin, and extracellular matrix. The FDA issued an Investigational New Drug for an intermediate-sized, single-center study of the HAV under the agency's Expanded Access Program in patients with advanced CLTI and inadequate or absent autologous conduit. Technical results and clinical outcomes were analyzed and reported. ResultsBetween March 2021 and July 2023, 29 patients (20 males; mean age, 71 ± 11 years) underwent limb salvage operation using the HAV as a bypass conduit. Most patients had advanced CLTI (Rutherford class 5/6 in 72%; wound, ischemia, and foot infection stage 3/4 in 83%), and 97% had previously failed revascularization(s) of the extremity. Two HAVs were sewn together to attain the needed bypass length in 24 patients (83%). Bypasses were to tibial arteries in 23 patients (79%) and to the popliteal artery in 6 (21%). Technical success was 100%, and the 30-day mortality rate was 7% (2 patients). With 100% follow-up (median, 9.3 months), the limb salvage rate was 86% (25/29 patients). There were 16 reinterventions to restore secondary patency, of which 15 (94%) were successful. Primary and secondary patency of the HAV at 9 months were 59% and 71%, respectively. ConclusionsThe HAV has demonstrated short- to intermediate-term safety and efficacy as an arterial bypass conduit in a complex cohort of patients with limb-threatening ischemia and no autologous options. This experience using the FDA’s Expanded Access Program provides real-world data to inform regulatory deliberations and future trials of the HAV, including the study of the vessel as a first-line bypass conduit in less severe cases of chronic limb ischemia.

Role of LCN2 in a murine model of hindlimb ischemia and in peripheral artery disease patients, and its potential regulation by miR-138-5P

Background and aimsPeripheral arterial disease (PAD) is a leading cause of morbimortality worldwide. Lipocalin-2 (LCN2) has been associated with higher risk of amputation or mortality in PAD and might be involved in muscle regeneration. Our aim is to unravel the role of LCN2 in skeletal muscle repair and PAD. Methods and resultsWT and Lcn2−/− mice underwent hindlimb ischemia. Blood and crural muscles were analyzed at the inflammatory and regenerative phases. At day 2, Lcn2−/− male mice, but not females, showed increased blood and soleus muscle neutrophils, and elevated circulating pro-inflammatory monocytes (p < 0.05), while locally, total infiltrating macrophages were reduced (p < 0.05). Moreover, Lcn2−/− soleus displayed an elevation of Cxcl1 (p < 0.001), and Cxcr2 (p < 0.01 in males), and a decrease in Ccl5 (p < 0.05). At day 15, Lcn2 deficiency delayed muscle recovery, with higher density of regenerating myocytes (p < 0.04) and arterioles (αSMA+, p < 0.025). Reverse target prediction analysis identified miR-138-5p as a potential regulator of LCN2, showing an inverse correlation with Lcn2 mRNA in skeletal muscles (rho = -0.58, p < 0.01). In vitro, miR-138-5p mimic reduced Lcn2 expression and luciferase activity in murine macrophages (p < 0.05). Finally, in human serum miR-138-5p was inversely correlated with LCN2 (p ≤ 0.001 adjusted, n = 318), and associated with PAD (Odds ratio 0.634, p = 0.02, adjusted, PAD n = 264, control n = 54). ConclusionsThis study suggests a possible dual role of LCN2 in acute and chronic conditions, with a probable role in restraining inflammation early after skeletal muscle ischemia, while being associated with vascular damage in PAD, and identifies miR-138-5p as one potential post-transcriptional regulator of LCN2.

Guard against internal and external: An antibacterial, anti-inflammation and healing-promoting spray gel based on lyotropic liquid crystals for the treatment of diabetic wound

The diabetic wound is a prevalent and serious complication of diabetes, which easily deteriorates due to susceptibility to infection and difficulty in healing, causing a high risk of amputation and economic burden to patients. Bacterial infection, persistent excessive inflammation, and cellular and angiogenesis disorders are the main reasons for the difficulty of diabetic wound healing. In this study, glycerol monooleate (GMO) was used to prepare lyotropic liquid crystal hydrogel (LLC) containing the natural antimicrobial peptide LL37 and carbenoxolone (CBX) to achieve antibacterial, anti-inflammation, and healing promotion for the treatment of diabetic wounds. The shear-thinning properties of the LLC precursor solution allowed it to be administered in the form of a spray, which perfectly fitted the shape of the wound and transformed into a gel after absorbing wound exudate to act as a wound protective barrier. The faster release of LL37 realized rapid sterilization of wounds, controlled the source of inflammation, and accelerated wound healing. The inflammatory signaling pathway was blocked by the subsequently released CBX, and the spread of the inflammatory response was inhibited and then further weakened. In addition, CBX down-regulated connexin (Cx43) to assist LL37 to promote cell migration and proliferation better. Combined with the pro-angiogenic effect of LL37, the healing of diabetic wounds was significantly accelerated. All these advantages made LL37-CBX-LLC a promising approach for the treatment of chronic diabetic wounds.

The Role Played by Novel Inflammatory Markers in Assessment of Peripheral Artery Disease.

Background and Objectives: Atherosclerosis is a multifactorial process in which inflammatory markers have both therapeutic and prognostic roles. Recent studies bring into question the importance of assessing new inflammatory markers in relation to the severity of peripheral artery disease (PAD), such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-C-reactive protein ratio (LCR). Materials and Methods: We conducted a retrospective and descriptive study including 652 patients with PAD, who were divided into two groups according to the severity of the ankle-brachial index value: mild and moderate obstruction (257 patients) and severe obstruction (395 patients). We evaluated demographics, anthropometric data and clinical and paraclinical parameters in relation to the novel inflammatory biomarkers mentioned above. Results: Weight (p = 0.048), smoking (p = 0.033), the number of cardiovascular risk factors (p = 0.041), NLR (p = 0.037), LCR (p = 0.041) and PLR (p = 0.019), the presence of gangrene (p = 0.001) and the number of lesions detected via peripheral angiography (p < 0.001) were statistically significant parameters in our study. For the group of patients with severe obstruction, all three inflammatory biomarkers were statistically significantly correlated with a serum low-density lipoprotein-cholesterol level, the number of cardiovascular risk factors, rest pain, gangrene and a risk of amputation. In addition, directly proportional relationships were found between NLR, PLR and the number of stenotic lesions (p = 0.018, p = 0.016). Also, NLR (area under the curve <AUC> = 0.682, p = 0.010) and PLR (AUC = 0.692, p = 0.006) were predictors associated with a high risk of amputation in patients with an ABI < 0.5. Conclusions: in our study, we demonstrated the importance of assessing inflammatory markers in relation to the presence of cardiovascular risk factors through the therapeutic and prognostic value demonstrated in PAD.

Clinical and laboratory characteristics of patients with type 2 diabetes and diabetic foot syndrome

Background: Diabetes mellitus (DM) is one of the most common chronic diseases, leading to the development of many complications includingdiabetic foot syndrome (DFS). The problem of a progressive increase in the number of patients with DFS and the high risk of amputation in the population of patients with DM requires research to identify risk factors and specify ways to correct them.Aim: To study the clinical and laboratory characteristics of patients of the limb rescue center suffering from type 2 diabetes (DM2).Materials and Methods: A retrospective analysis of 729 medical histories of patients with T2D hospitalized in the foot rescue department of the limb rescue center of the State Clinical Hospital named after V.P. Demikhov in the period between 2019 and 2020 was carried out. An analysis of anamnestic data, clinical and laboratory parameters, drug therapy, the nature of surgical intervention and the outcome of hospitalization was performed. The statistical analysis was carried out using STATISTICA 8.0.Results: The study included 729 patients with T2D. Men dominated among patients (58%). The median of age was 66 [59.0; 73.0] years. 50.89% had experience of diabetes for more than 10 years. 53% of these patients had DFS, 79.2% had diabetic polyneuropathy, 45% had previously undergone amputation of the lower extremity, 24.8% had revascularization. A significant proportion of patients at admission had uncontrolled high level of glycemia. The median of glucose level was 9.9 mmol/l [7.2; 13.8]. Median meaning of HbA1c was 7.8% [6.7; 9.1]. BMI and lipid profile were not evaluated in all patients. In the department 224 patients were diagnosed with DFS for the first time. Gangrene prevailed among the ulcerative-necrotic complications of DFS. Arterial hypertension (AH) prevailed among the concomitant pathologies. GFR ˂ 60 ml/min/1.73m2 was observed in 45.36% of patients. According to X-ray data, 27.16% of patients (107 out of 394) showed signs of impaired bone density. In the department, 113 patients underwent revascularization, 372 — amputation of the lower limb, while 37 patients (9.95%) underwent amputation at the level above the knee, and 335 (90.05%) — at the level below the knee. Only 244 patients received local treatment among patients with DFS. A total of 718 patients were discharged; 11 patients died. The median duration of hospitalization of discharged patients was 13.0 [9.0; 18.0] bed days, the average duration of hospitalization of deceased patients was 11.31±2.21 (95% CI 6.49–16.13) bed days.Conclusion: Most of the patients with DM2 and DFS had prolonged decompensation of carbohydrate metabolism, dyslipidemia, increased BMI, hypertension. The study concluded that it is important to monitor and correct risk factors to improve the prognosis of the disease.