Search Results (101)

Objectives: Guidelines widely recommend endovascular therapy (ET) for infrainguinal peripheral artery diseases (PAD) despite the lack of adequately powered data. This meta-analysis aimed to directly compare the clinical safety and efficacy of ET versus vein bypass (VBP) in patients with infrainguinal PAD from available randomized controlled trials (RCTs). Methods: We conducted a systematic literature search of MEDLINE, Embase, and the Cochrane databases from inception until 21 July 2023 for RCTs comparing ET and VBP. Treatment effects were expressed as odds ratios (OR) with 95% confidence intervals (CIs), pooled using the Mantel–Haenszel method. Study quality was assessed via the Cochrane Risk of Bias tool. Results: From 2210 identified studies, four low-risk-of-bias RCTs were included. Pooled analysis demonstrated that ET was associated with significantly higher risks of reintervention (OR = 4.69, 3.69–6.04), major reintervention (OR = 2.80, 1.96–4.00), and any reintervention (OR = 1.92, 1.44–2.56) compared to VBP. ET also showed a lower rate of index procedure technical success (OR = 0.13, 0.07–0.25) and site infection (OR = 0.05, 0.01–0.25). However, no significant differences were observed between the two strategies regarding 30-day mortality (OR = 0.66, 0.34–1.29), all-cause mortality (HR = 1.05, 0.90–1.22), index limb amputation (OR = 1.29, 0.90–1.86), MACE (OR = 1.20, 0.94–1.54), or bleeding events (OR = 0.86, 0.30–2.50). Conclusions: This analysis of RCT data still supports VBP, which retained certain advantages over ET for patients with infrainguinal peripheral artery disease in terms of both efficacy and safety. In cases where a suitable vein is available, vein bypass should be considered as the primary treatment option. Full article

Background/Objectives: Endovascular therapy (EVT) is the treatment of choice for femoropopliteal artery (FPA) disease manifesting as critical limb-threatening ischemia (CLTI) or intermittent claudication (IC). This study aimed to compare the clinical outcomes of patients with CLTI with those of patients with IC after EVT in a real-world setting. Methods: In total, 1924 patients with FPA disease (CLTI: n = 812, IC: n = 1112) from the K-VIS ELLA (Korean Vascular Intervention Society Endovascular Therapy in Lower Limb Artery Diseases) registry who underwent EVT between 2006 and 2021 were analyzed. The primary endpoint was defined as target limb amputation or clinically driven (CD) target extremity revascularization (TER) 2 years after the procedure. Results: The incidence of the primary endpoint after inverse probability of treatment weighting (IPTW) was significantly higher in the CLTI group (hazard ratio [HR], 1.314; 95% confidence interval [CI], 1.105–1.561; p = 0.002). The incidences of loss of clinical patency, major adverse limb events (MALEs), and all-cause mortality were also higher in the CLTI group (hazard ratio [HR], 1.312; 95% confidence interval [CI], 1.157–1.488; p < 0.001). However, the risk of repeat percutaneous transluminal angioplasty (PTA) was similar between the groups (HR, 1.014; 95% CI, 0.833–1.234; p = 0.920). The use of drug-coated balloons (DCBs) was associated with favorable primary outcomes in both groups, particularly in patients with IC (HR: 0.429, 95% CI: 0.25–0.734; p = 0.002). Conclusions: Patients with CLTI undergoing EVT for FPA disease experienced worse clinical outcomes than those with IC, although the repeat PTA rates were similar. The use of DCBs showed promising results in both groups. Full article

Chronic wounds, particularly those associated with diabetes, persist as a significant clinical challenge due to prolonged or incomplete healing, elevated infection rates, and the ensuing risk of lower-limb amputation. This review summarises recent advances in biomaterials for wound healing, focusing on chitosan-based systems modified with metal nanoparticles and polyphenols. The text emphasises the pivotal function of nanotechnology in facilitating targeted delivery and synergistic bioactivity. The present study places particular emphasis on the synergistic use of chitosan and polyphenols in drug delivery systems and next-generation wound dressings. This combination successfully overcomes the key limitations of their individual use, such as the poor solubility of polyphenols and the limited stability of chitosan. The encapsulation of polyphenols within the nanostructures of chitosan is a process enabled by nanotechnology. This process has been shown to enhance the bioavailability of the polyphenols, to allow for controlled release, and to improve their biological performance. This review methodically synthesises the extant experimental evidence demonstrating that these multifunctional systems exhibit regenerative, antioxidant, and antimicrobial properties that may support selected biological processes relevant to wound repair. The promotion of angiogenesis, fibroblast growth, and epithelial regeneration is accompanied by a reduction in infection-related complications. Whilst the majority of the studies under review are of a preclinical nature, the body of evidence suggests that further enhancement and quantitative evaluation of these systems has the potential to pave the way for clinically relevant therapies for chronic and diabetic wounds. Full article

Background/Objectives: To evaluate the long-term impact of a structured diabetic foot education program on major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) in individuals with type 1 diabetes. Methods: Retrospective cohort study including 327 adults with type 1 diabetes who participated in a structured diabetic foot education program between 1990 and 2014. The program included 10 h of education focused on diabetes self-management and foot care. Participants were encouraged to attend annual refresher sessions. The primary outcomes were the first occurrence of MALE (major amputation or lower-limb revascularization) and MACE (non-fatal stroke, non-fatal myocardial infarction, or all-cause death). Cox proportional hazards models were used to assess associations between the number of educational programs (EPs) attended (1, 2–3, >3) and outcomes. Results: Participants attended a median of two EPs during a median follow-up of 26.3 years. Of the total number of events, 21 were MALEs (crude incidence of 1.9 per 1000 person-years) and 108 were MACEs (incidence of 12.9 per 1000 person-years). Risk of MALE was not associated with the number of EPs attended (p = 0.384). In contrast, participants who attended >3 EPs had a significantly lower risk of MACE compared with those attending only one program (HR 0.48, 95% CI 0.24–0.99, p = 0.044), although this association was attenuated after adjusting for smoking status. Conclusions: Frequent participation in a structured diabetic foot education program was associated with fewer cardiovascular events, but this benefit was diminished by smoking. Integrating tobacco cessation into education programs may enhance their long-term impact. Full article

Diabetic foot ulcers drive non-traumatic lower-limb amputation; limb salvage surgery is often pursued to preserve function and survival. Predictors of adverse outcomes remain incompletely defined, and evidence for multidisciplinary team (MDT) care is heterogeneous. We aimed to clarify risk factors for major amputation and death after diabetic limb salvage and evaluate MDT impact. We systematically reviewed 49 studies (2020–2025) reporting major amputation or mortality after limb salvage in diabetes (PROSPERO CRD420251044859). Risk factors spanned demographic, clinical, and surgical domains (e.g., older age, male sex, renal/cardiovascular disease, ischemia, osteomyelitis, advanced ulcer classification). MDT models generally showed lower amputation rates and improved wound healing, with occasional survival benefits; heterogeneity precluded meta-analysis. As a real-world comparator, the Mid Essex Diabetes Amputation Reduction Plan (MEDARP) treated 72 high-risk patients using a “toe and flow” MDT. Major amputation occurred in 6.9% and mortality in 12.5%, both at or below published ranges, with gains in patient-reported outcomes. Findings support MDT-based strategies, but conclusions should be interpreted cautiously given the predominantly observational evidence, and highlight the need for standardized outcome definitions and reporting. Full article

Background: Diabetes-related foot diseases represent a global health problem because of the associated complications, the risk of amputation, and the economic burden on health systems. Negative pressure wound therapy (NPWT) is a technique that uses sub-atmospheric pressure to help promote wound healing by reducing the inflammatory exudate while keeping the wound moist, inhibiting bacterial growth, and promoting the formation of granulation tissue. Objective: This study aimed to assess the effectiveness of NPWT in preventing major amputation in diabetic patients with complicated foot or lower limb infections and to contextualize the results through a review of the existing literature. Materials and methods: We conducted a retrospective study at the First Surgical Department of “Dr. I. Cantacuzino” Clinical Hospital in Bucharest, Romania, over a 15-year period, including 30 consecutive adult patients with diabetes and soft tissue foot or lower limb infections treated with NPWT. Patients with non-diabetic ulcers, incomplete medical data, or aged under 18 were excluded. All patients underwent initial surgical debridement, minor amputation, or drainage procedures, followed by the application of NPWT using a standard protocol. Dressings were changed every 2–4 days for a total of 7–10 days. Antibiotic therapy was adapted according to the culture results. The primary outcome was limb preservation, defined as avoidance of major amputation. Secondary outcomes included in-hospital mortality and wound status at discharge. Results: NPWT was associated with a favorable outcome in 24 patients (80%), defined by wound granulation or healing without the need for major amputation. Five patients (16.6%) underwent major amputation because of failure of the primary lesion treatment, and one patient died. No statistically significant association was observed between the outcomes and standard classification scores (WIFI, IWGDF, and TPI). A comprehensive literature review helped to integrate these findings into the existing pool of knowledge. Conclusions: NPWT may support limb preservation in selected diabetic foot cases. While the retrospective design and the small sample size of the study limit generalizability, these results reinforce the need for further controlled studies to evaluate NPWT in real-life clinical settings. The correct use of NPWT combined with etiological treatment may offer a maximum chance to avoid major amputation in patients with diabetes-related foot diseases. Full article

Background and Objectives: Diabetic foot gangrene remains a major cause of lower limb amputation, driven by vascular, neuropathic, and infectious mechanisms. Identifying predictors for amputation type is essential to optimizing outcomes and reducing disability. We aimed to analyze the burden of diabetic foot gangrene and the patients’ characteristics according to the type of surgery, minor or major amputations. Methods: We conducted a retrospective observational study including 295 diabetic patients who underwent surgery for foot lesions at a Romanian tertiary center (January 2023–December 2024). Patients were classified according to surgical outcome as minor (toe/foot-level) or major (below/above-knee) amputations. Clinical, demographic, and pathological variables were compared between groups. Statistical analysis was performed with IBM SPSS Statistics 20.0. Categorical variables were expressed as frequencies and percentages, and continuous variables as mean ± SD or median (min–max). Group comparisons used Student’s t-test, Mann–Whitney U, Chi-square, or Fisher’s exact test, and binary logistic regression was applied to calculate odds ratios (OR) with 95% confidence intervals (CI). Results: Among the patients included (mean age 64.8 ± 10.8 years; 69.2% male), 191 (64.7%) underwent minor amputations/debridement and 104 (35.3%) required major amputations. Patients with major amputations were older (66.8 ± 11.3 vs. 63.7 ± 10.4 years, p = 0.012) and less frequently male (56.7% vs. 75.9%, p = 0.001). Lesion extension to the foot or beyond strongly predicted major amputation (p < 0.001). Peripheral arterial disease was more prevalent in the major group (85.6% vs. 65.4%, OR = 3.13, 95% CI = 1.68–5.84), while neuropathy was associated with minor procedures (12.6% vs. 3.8%, p = 0.015). Anemia (70.2% vs. 56.5%, p = 0.021) and leukocytosis (68.3% vs. 49.2%, p = 0.002) were also independent predictors of major amputation. Conclusions: The study highlights the need for early detection, coordinated multidisciplinary care, and personalized assessment of diabetes burden and its complications to minimize the risk of major limb amputation. Full article

Background: Post-traumatic osteomyelitis (PTO) of the lower extremity is among the most demanding problems in orthoplastic reconstructive surgery. It typically follows open fractures, failed osteosynthesis, or implant infection. Effective management requires coordinated infection control, stable skeletal fixation, and timely vascularized soft-tissue coverage. Methods: We conducted a retrospective case series of 20 consecutive patients with PTO of the lower limb treated between 2021 and 2024 at a tertiary orthoplastic center. All patients underwent radical debridement, culture-directed intravenous antibiotic administration, and soft-tissue reconstruction using local muscle, fasciocutaneous, or free flaps; vascularized bone flaps were used to select nonunion cases. The primary outcomes were flap survival, complications, infection resolution, and limb salvage. Exploratory analyses included descriptive subgroup summaries by flap category. Results: Among 20 patients (15 men, 5 women; mean age 53.6 years), reconstructions included reverse/pedicled sural flaps (n = 9), hemisoleus muscle flaps (n = 7), medial gastrocnemius muscle flaps (n = 2), peroneus brevis muscle flaps (n = 2), and free flaps (n = 6), which comprised anterolateral thigh (ALT), medial femoral condyle (MFC) osteoperiosteal, deep circumflex iliac artery (DCIA) osteocutaneous, and radial forearm free flaps (RFFFs). Single-flap reconstructions were performed in 13 cases, whereas multistage/multiflap strategies were used in 7. Overall flap survival was 90%. Major flap complications comprised partial necrosis in two reverse sural flaps and one complete loss of a reverse sural flap; two patients had minor wound dehiscence. Infection resolved in 18/20 patients (90%; 95% CI ≈ 0.70–0.97). One patient requested below-knee amputation due to persistent nonunion associated with a pathological fracture. At a mean 10-month follow-up, all limb-salvaged patients were ambulatory. Conclusions: Effective reconstruction of PTO is improved by using a patient-specific algorithm that considers the defect location, vascular status, and host comorbidities. Local muscle and fasciocutaneous flaps remain dependable for most defects, with free or vascularized bone flaps reserved for composite or recalcitrant cases. Early referral to high-volume centers, radical debridement, and orthoplastic collaboration are critical for optimizing limb salvage. Our findings should be interpreted in light of the study’s retrospective design and small sample size. Full article

Background and Objectives: The impact of peripheral below-the-knee (BTK) fractional flow reserve (FFR) on long-term clinical outcomes remains unknown. Materials and Methods: We enrolled 40 patients with severe BTK lesions (Rutherford 4–6). FFR (using 40 mg papaverin) and skin perfusion toe pressure (SPTP) by laser Doppler were measured during the index procedure. The primary outcomes were major adverse limb events (MALEs) (defined as reintervention on the index arterial segment or amputation of the index limb) and death during follow-up. Results: The median follow-up was 7 [IQR 4–8] years. After the index procedure, FFR increased significantly (p < 0.001) and post-revascularization SPTP was significantly higher in the FFR ≥ 0.80 group (p = 0.022). Multivariable regressions showed no association between change in FFR (absolute or percentage) and the risk of death (p = 0.39, p = 0.28) or MALEs (p = 0.83, p = 0.29), but both pre- and post-revascularization FFR values could predict MALEs at follow-up (p = 0.018, p = 0.012). Lower SPTP was also associated with the risk of MALEs (p = 0.027). SPTP > 97.8 mmHg was 100% specific for FFR ≥ 0.80. Conclusions: While there is no association between change in FFR and the risk of death or MALEs, lower FFR values either before or after revascularization were associated with higher long-term risk of MALEs. Moreover, a lower SPTP was associated with a higher risk of MALEs. Aiming for approximately 100 mmHg in SPTP represents a non-invasive surrogate of FFR ≥ 0.80. Larger studies are needed to validate the impact of post-revascularization FFR-SPTP-adjacent values on clinical outcomes. Full article

Background: Limb amputation is a life-altering event with substantial physical, psychological, and social consequences. Despite advances in healthcare, amputation remains a major global health concern, particularly in regions with high burdens of diabetes and vascular disease. This study aims to analyze demographic characteristics, etiologies, and trends in amputations over a ten-year period at a tertiary-care center. Methods: We retrospectively reviewed medical records of patients who underwent amputation at our tertiary-care hospital. Collected variables included patients’ demographics, etiology, level of amputation, type of admission, and surgical specialty involved. Descriptive statistics were used to summarize the data. Associations between categorical variables were analyzed using chi-square tests, with post hoc pairwise comparisons adjusted using the Bonferroni method where applicable. Continuous variables were compared using the Mann–Whitney U test. A p-value of <0.05 was considered statistically significant. All analyses were conducted using IBM SPSS version 26.0. Results: A total of 647 patients underwent amputation, with a mean age of 56 years and a male predominance (65%). Diabetic complications were the leading cause (67.7%), followed by trauma (11.7%) and vascular diseases (11.6%). Lower limb amputations were more prevalent, with toe amputations being the most frequent (39%). Emergency procedures accounted for 72% of cases, and vascular surgery was the most involved specialty, followed by orthopedic surgery. Conclusions: Our study highlights a substantial burden of amputations, predominantly involving the lower limb, as well as a significant association with diabetic complications. These findings emphasize the urgent need for integrated diabetic care, early interventions, and public health strategies to reduce the burden of amputations in Saudi Arabia. Full article

Background: Medial arterial calcification (MAC) is a vascular disorder that affects the arterial media layer. It represents a predictor of major adverse limb events in patients affected by diabetes mellitus (DM). This single-center retrospective observational study investigates whether ultrasound (US) detection of MAC in below-the-knee (BTK) vessels represents a negative predictor of major adverse cardiovascular events (MACE) in asymptomatic patients. Methods: In 2019, 584 patients, referred to the Vascular Surgery Unit for lower limb US, were examined by the same operator, who assessed the presence of BTK MAC. The primary outcome was the rate of MACE during a 5-year follow-up period. The secondary outcomes included the development of peripheral arterial disease (PAD), the overall survival rates, lower limb revascularizations, and major amputations. Results: MAC in BTK vessels was highlighted in 239 patients (MAC+) who exhibited a younger age (p < 0.001), DM (p < 0.001), and chronic kidney disease (CKD) (p = 0.048). The 345 subjects without MAC (MAC−) showed prior myocardial infarction (p < 0.001), stroke (p = 0.034), and smoking habits (p < 0.001). After propensity score matching, the MAC+ group presented a higher risk of MACE (HR: 1.84; CI: 1.01–3.38; p = 0.047) during a median follow-up of 57 months. Age (HR: 1.06; CI: 1.01–1.12) and MAC (HR: 1.22; CI: 1.06–1.57) were independently associated with MACE. New diagnoses of PAD mainly occurred in the MAC− group (p < 0.001). No differences were observed in major amputations, revascularization procedures, or overall survival rates. Conclusions: Ultrasound detection of BTK MAC was associated with the presence of DM and CKD and with a 1.8-fold increased risk of developing a MACE within 5 years in asymptomatic patients. Full article

Background/objectives: Falls are the most common adverse events in hospitals. This study aimed to estimate excess hospitalisation costs attributable to inpatient falls, using Diagnosis-Related Group (DRG) relative weights as a proxy for resource consumption. Methods: Case–control study. Cases included patients who had sustained a fall during hospitalisation between 2020 and 2022 in 19 inpatient units. Controls were selected with matching technique based on age and admission period. Diagnosis-Related Groups and their resource consumption and cost estimators (relative weights) were provided by the Hospital’s Coding Unit. Results: A total of 613 falls were analysed against 623 controls. The Diagnosis-Related Group ‘Lower limb amputation except toes’ was associated with a fourfold higher risk of falling compared to others. Five more were identified in which the case group incurred significantly higher costs than the control group. These included three surgical Diagnosis-Related Group, ‘Urethral and transurethral procedures’, ‘Heart valve procedures without acute myocardial infarction or complex diagnosis’, and ‘Arterial procedures on the lower limb’, and two medical, ‘Heart failure’ and ‘Major pulmonary infections and inflammations’. Conclusions/Implications for practice: Identifying Diagnosis-Related Groups in which falls are associated with increased hospitalisation costs allows for a comprehensive assessment of the process, taking into account resource consumption and the clinical characteristics of hospitalised patients. These findings will enable nurses to develop targeted strategies to enhance the safety of hospitalised patients that contribute to the sustainability of the healthcare system. Full article

Chronic skin wounds are difficult to heal or nonhealing. These wounds may become infected and progress to tissue necrosis, potentially leading to limb amputation, sepsis, reduced quality of life, depression, economic burden on the healthcare system, and social isolation. Several clinical strategies, including negative pressure wound therapy, antibiotic-based infection control, and wound debridement, have been developed to treat skin wounds. However, these approaches primarily target local wound conditions and offer only short-term relief, not achieving sustained functional regeneration. Stem cell-based therapy has emerged as an alternative therapeutic method for skin wound treatment owing to its ability to suppress inflammation, stimulate angiogenesis, and promote cellular proliferation. However, the low post-transplantation survival rate of stem cells remains a major limitation. Exosomes, nanosized extracellular vesicles, transport proteins, lipids, mRNAs, and miRNAs and mediate regenerative functions, including anti-inflammatory effects, angiogenesis promotion, and extracellular matrix remodeling. Stem cell-derived exosomes (SC-Exos) offer several advantages over their parent cells, including greater stability, lower immunogenicity, absence of tumorigenic risks, and ease of storage and distribution. These attributes render SC-Exos particularly attractive for cell-free regenerative therapies. In this review, we introduce exosomes derived from various types of stem cells and explore their therapeutic applications in skin wound regeneration. Full article

(1) Background: Comparison of clinical outcomes between patients with moderate-severe aortic valve stenosis and those with mild or no aortic valve stenosis undergoing surgical revascularization for critical limb threating ischemia (CLTI). (2) Methods: Single center retrospective analysis of consecutive patients undergoing surgical lower limb revascularization with femoro-distal bypass for critical ischemia between 2016 and 2022. All patients were evaluated preoperatively by echocardiographic examination and divided into two cohorts: group A with moderate-severe aortic valve stenosis (AVA-cm² < or =1.5 cm²) and group B with mild or absent stenosis (AVA-cm² > 1.5 cm²). Primary outcomes were major limb amputation and mortality between the two groups. The rate of major cardiovascular events (stroke, myocardial infarction, sudden cardiac death) and change in “preoperative functional status” were the secondary outcomes. Descriptive statistics for continuous variables were performed by calculating means, standard deviation (SD) medians, and interquartile range (IQR) while, for categorical variables, frequencies and percentages were performed. Intergroup comparison tests, for continuous variables, were performed by t-test or corresponding nonparametric tests (Mann-Whitney test) while, for categorical variables, Chi-square test was used. Evaluation of cut-offs for the variable AVA-fx-cm², in terms of predictive of outcome outcomes, was calculated by ROC curves. Comparison between clinical and outcome variables was performed using logistic regression models. A total of 316 patients were analyzed and divided in two groups: 50 (16%) patients with moderate or severe aortic valve stenosis (group A) and 266 (84%) with no or mild aortic valve stenosis (AVA > 1.5 cm²). Patients in group A were significantly older than those in group B (78 years vs. 74 years, p value = 0.005); no other significant comorbidity differences were found between the two groups. The mean follow-up was 1178 days (SD 991 days; 2–3869 days). There were no statistically significant differences between group A and group B in terms of major amputation rate (20% vs. 16.5%; p = 0.895) and overall mortality (48.0% vs. 40.6%; p = 0.640). In the total cohort, the statistically significant variables associated with the major amputation were systemic perioperative complication (OR 5.83, 95% CI: 2.36, 14.57, p < 0.001), bypass-related complication within 30 days of surgery (OR 2.74, 95% CI: 1.17, 6.45, p = 0.020), surgical revascularization below the knee (OR 7.72, 95% CI: 1.53, 140.68, p = 0.049), and the presence of a previous cardiovascular event (OR 2.65, 95% CI: 1.14, 6.26, p = 0.024). In patients undergoing surgical revascularization for CLTI, no significant difference in major amputation rate and overall mortality was found between subjects with mild or no aortic valve stenosis and those with moderate/severe stenosis. As expected, overall mortality was higher in older patients with worse functional status. A significantly higher rate of limb amputation was found in those subjects undergoing subgenicular revascularization, early bypass failure, or previous cardiovascular event. Full article

Background/Objectives: Peripheral artery disease (PAD) impacts more than 200 million individuals globally and leads to mortality and morbidity secondary to progressive limb dysfunction and amputation. However, clinical management of PAD remains suboptimal, in part because of the lack of standardized biomarkers to predict patient outcomes. Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has been studied extensively in cardiovascular disease, but its investigation in PAD remains limited. This study aimed to use explainable statistical and machine learning methods to assess the prognostic value of GDF15 for limb outcomes in patients with PAD. Methods: This prognostic investigation was carried out using a prospectively enrolled cohort comprising 454 patients diagnosed with PAD. At baseline, plasma GDF15 levels were measured using a validated multiplex immunoassay. Participants were monitored over a two-year period to assess the occurrence of major adverse limb events (MALE), a composite outcome encompassing major lower extremity amputation, need for open/endovascular revascularization, or acute limb ischemia. An Extreme Gradient Boosting (XGBoost) model was trained to predict 2-year MALE using 10-fold cross-validation, incorporating GDF15 levels along with baseline variables. Model performance was primarily evaluated using the area under the receiver operating characteristic curve (AUROC). Secondary model evaluation metrics were accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Prediction histogram plots were generated to assess the ability of the model to discriminate between patients who develop vs. do not develop 2-year MALE. For model interpretability, SHapley Additive exPlanations (SHAP) analysis was performed to evaluate the relative contribution of each predictor to model outputs. Results: The mean age of the cohort was 71 (SD 10) years, with 31% (n = 139) being female. Over the two-year follow-up period, 157 patients (34.6%) experienced MALE. The XGBoost model incorporating plasma GDF15 levels and demographic/clinical features achieved excellent performance for predicting 2-year MALE in PAD patients: AUROC 0.84, accuracy 83.5%, sensitivity 83.6%, specificity 83.7%, PPV 87.3%, and NPV 86.2%. The prediction probability histogram for the XGBoost model demonstrated clear separation for patients who developed vs. did not develop 2-year MALE, indicating strong discrimination ability. SHAP analysis showed that GDF15 was the strongest predictive feature for 2-year MALE, followed by age, smoking status, and other cardiovascular comorbidities, highlighting its clinical relevance. Conclusions: Using explainable statistical and machine learning methods, we demonstrated that plasma GDF15 levels have important prognostic value for 2-year MALE in patients with PAD. By integrating clinical variables with GDF15 levels, our machine learning model can support early identification of PAD patients at elevated risk for adverse limb events, facilitating timely referral to vascular specialists and aiding in decisions regarding the aggressiveness of medical/surgical treatment. This precision medicine approach based on a biomarker-guided prognostication algorithm offers a promising strategy for improving limb outcomes in individuals with PAD. Full article