The correlation between serum vitamin D status and the occurrence of diabetic foot ulcers: a comprehensive systematic review and meta-analysis.

The association between vitamin D concentrations and the occurrence of diabetic foot ulcers (DFUs) remains a topic of ongoing debate. In order to provide a comprehensive and updated review, we conducted this meta-analysis to further investigate the relationship between vitamin D concentrations and DFUs occurrence. The following databases, including Cochrane Library, EMBASE, Web of Science, PubMed, CBM, CNKI, WANFANG DATA and VIP Database, were systematically searched for studies published up to Dec. 20th, 2023. The combined estimation was calculated using both fixed-effects and random-effects models. The overall effect size was reported as a weighted mean difference (WMD) with a corresponding 95% confidence interval (95%CI). Data analysis was performed utilizing Review Manager 5.4 and Stata 14. The Protocol has been registered in PROSPERO CRD42024503468. This updated meta-analysis, incorporating thirty-six studies encompassing 11,298 individuals with or without DFUs, demonstrated a significant association between vitamin D deficiency/insufficiency and an elevated risk of DFUs occurrence (< 25 nmol/L, OR 3.28, P < 0.00001; < 50 nmol/L, OR 2.25, P < 0.00001; < 75 nmol/L, OR 1.67, P = 0.0003). Vitamin D concentrations were significantly lower in individuals with DFUs compared to those without DFUs (P < 0.00001). Subgroup analyses consistently demonstrated this trend among the older population (> 50 years, P < 0.00001), individuals with long duration of diabetes (> 10 years, P < 0.00001), and those with poor glycemic control (mean HbA1c 8%-9% and > 9%, P < 0.00001).

[Establishment and evaluation of a nomogram model for predicting the risk of sepsis in diabetic foot patients].

OBJECTIVE: To establish a nomogram model for predicting the risk of sepsis in diabetic foot patients, and to provide reference for clinical prevention and treatment. METHODS: The clinical data of 430 patients with diabetic foot who were hospitalized in Chu Hsien-I Memorial Hospital of Tianjin Medical University from January 2022 to March 2023 were reviewed and collected, including age, gender, past medical history, smoking and drinking history, family history, diabetes course, Texas grade of diabetic foot and laboratory indicators within 24 hours after admission. Patients were divided into sepsis group and non-sepsis group according to the presence or absence of sepsis during hospitalization. The differences in clinical data between the two groups were compared. Multivariate Logistic regression analysis was used to screen the influencing factors of sepsis in patients with diabetic foot during hospitalization, and a nomogram predictive model was established. The performance of the prediction model was evaluated by receiver operator characteristic curve (ROC curve), calibration curve and decision curve analysis (DCA). Internal validation was performed by using Bootstrap method. RESULTS: A total of 430 patients were enrolled, among which 90 patients developed sepsis during hospitalization and 340 patients did not. There were statistically significant differences in diabetes course, Texas grade of diabetic foot, white blood cell count (WBC), neutrophil count (NEU), lymphocyte count (LYM), neutrophil to lymphocyte ratio (NLR), hemoglobin (Hb), albumin (Alb), glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), and blood urea nitrogen (BUN) between the two groups. Multivariate Logistic regression analysis showed that diabetes course [odds ratio (OR) = 2.774, 95% confidence interval (95%CI) was 1.053-7.308, P = 0.039], Texas grade of diabetic foot (OR = 2.312, 95%CI was 1.014-5.273, P = 0.046), WBC (OR = 1.160, 95%CI was 1.042-1.291, P = 0.007), HbA1c (OR = 1.510, 95%CI was 1.278-1.784, P < 0.001), CRP (OR = 1.007, 95%CI was 1.000-1.014, P = 0.036) were independent risk factors for sepsis in patients with diabetic foot during hospitalization, while Alb was a protective factor (OR = 0.885, 95%CI was 0.805-0.972, P = 0.011). A nomogram predictive model was constructed based on the above 6 indicators. The ROC curve showed that the area under ROC curve (AUC) of the nomogram predictive model for identifying the sepsis patients was 0.919 (95%CI was 0.889-0.948). The AUC of the nomogram predictive model after internal verification was 0.918 (95%CI was 0.887-0.946). Hosmer-Lemeshow test showed χ 2 = 2.978, P = 0.936, indicating that the calibration degree of the predictive model was good. Calibration curve showed that the predicted probability of sepsis was in good agreement with the actual probability. DCA curve showed that the nomogram predictive model had good clinical usefulness. CONCLUSIONS: The nomogram predictive model based on the risk factors of diabetes course, Texas grade of diabetic foot, WBC, HbA1c, CRP and Alb has good predictive value for the occurrence of sepsis in patients with diabetic foot during hospitalization, which is helpful for clinical screening of the possibility of diabetic foot patients progressing to sepsis, and timely personalized intervention for different patients.

Association between anemia and diabetic lower extremity ulcers among US outpatients in the National Health and Nutrition Examination Survey: a retrospective cross-sectional study.

Purpose: The aim of this study was to explore the relationship between hemoglobin levels, anemia and diabetic lower extremity ulcers in adult outpatient clinics in the United States. Methods: A retrospective cross-sectional study was conducted on 1673 participants in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. Three logistic regression models were developed to evaluate the relationship between anemia and diabetic lower extremity ulcers. Model 1 adjusted for demographic and socioeconomic variables (age, sex, race and ethnicity, educational level, family income, and marital status). Model 2 included additional health-related factors (BMI, cardiovascular disease, stroke, family history of diabetes, hyperlipidemia, alcohol and smoking status). Model 3 further included clinical and laboratory variables (HbA1c, CRP, total cholesterol, and serum ferritin levels). Stratified analyses were also conducted based on age, sex, HbA1c level, body mass index (BMI), and serum ferritin level. Results: The study included 1673 adults aged 40 years and older, with a mean age of 64.7 ± 11.8 years, of whom 52.6% were male. The prevalence of diabetic lower extremity ulcers (DLEU) was 8.0% (136 participants). Anemia was found in 239 participants, accounting for 14% of the study group. Model 1 showed an OR of 2.02 (95% CI=1.28~3.19) for anemia, while Model 2 showed an OR of 1.8 (95% CI=1.13~2.87). In Model 3, the OR for DFU in patients with anemia was 1.79 (95% CI=1.11~2.87). Furthermore, when serum ferritin was converted to a categorical variable, there was evidence of an interaction between DLEU status and serum ferritin in increasing the prevalence of DLEU. Conclusion: After adjusting for confounding variables, higher levels of anemia were proportionally associated with an increased risk of incident DLEU. These results suggest that monitoring T2DM patients during follow-up to prevent the development of DLEU may be important. However, further prospective studies are needed to provide additional evidence.

Effects of continuous negative pressure suction combined with autologous platelet-rich gel on the levels of CRP, IL-6, wound healing and length of stay in clients with diabetic foot.

OBJECTIVE: Continuous passive pressure suction and APG gel therapy effect diabetic foot IL-6, CRP, wound healing, and hospitalization. METHODS: Clinicopathological data from 102 diabetic foot ulcer patients treated at our institution between March 2018 and May 2022 was examined. Tables generated 51 joint and controlling teams randomly. The observation team received passive pressure suction and APG gel whereas the controlled team received conventional treatment. Teams monitored therapy outcomes, adverse responses, wound healing, hospital stay, and costs. Both teams compared blood uric acid, cystatin C, homocysteine, and serum IL-6, IL-10, and CRP before and after medication. RESULTS: The joint team had higher hospitalization costs, shorter stays, and faster wound healing than the controlled team. Diaparity was significant (P < 0.05). The united team worked 100 %, unlike the controlling team. This difference was significant (P < 0.05). Both teams showed significant decreases in CRP, IL-6, and IL-10 levels after therapy (P < 0.05). After therapy, both the combined and controlled teams had substantial differences in blood CRP, IL-6, and IL-10 levels (P < 0.05). Both teams had significantly decreased uric acid, cystatin C, and homocysteine after treatment. The combined team showed significantly decreased uric acid, cystatin C, homocysteine levels following therapy compared to the control team (P < 0.05). CONCLUSION: The joint team experienced considerably fewer adverse events (3.92 % vs. 17.65 %) than the controls team (P < 0.05). Permanent passive pressure suction and APG gel therapy lower inflammatory response, blood uric acid, cystatin C, and homocysteine, speeding wound healing, reducing side effects.

Association of vitamin D status and vitamin D receptor polymorphism in diabetic foot ulcer patients: A prospective observational study in a South-Indian tertiary healthcare facility.

Objective of the study was to find the association of vitamin D receptor (VDR) polymorphisms (Fokl, Taql and Apal) with vitamin D levels in diabetic foot ulcer (DFU) patients in South India. In this case-control study, plasma vitamin D levels and VDR genotype frequencies of 70 cases (DFU patients) were compared with 70 diabetic (diabetes mellitus [DM] [non-DFU]) patients and 70 apparently healthy controls (HC) from South India. Plasma vitamin D levels were measured using the ELISA technique, and genotyping of VDR polymorphisms was carried out using real-time polymerase chain reaction. Logistic regression was used to find the association between DFU versus HC and DFU versus DM traits. Association analysis was performed based on additive, dominant and recessive models with age and gender as covariates. A 45.7% of DFU patients have sufficient vitamin D levels than 48.6% and 40% of DM patients and HC, respectively. Linkage disequilibrium analysis for DFU versus HC and DFU versus DM traits shows that single nucleotide polymorphisms (SNPs) Taq1 (rs731236) and Apal (rs7975232) are in strong linkage disequilibrium in DFU patients. The alleles and genotype frequencies were similar in all three groups. Although the additive model does not show statistical significance, age and sex correlate with the three SNPs (Fokl, Taql and Apal). No association was found between VDR gene polymorphisms and vitamin D levels in DFU patients in Southern India. On the other hand, age and sex correlate with the three SNPs.

Associations of phosphorus concentrations with medial arterial calcification in lower-extremity arteries and diabetic foot in people with diabetes: a retrospective cross-sectional study.

BACKGROUND: The aim of this study was to investigate the associations of blood phosphorus levels with the risk of developing medial arterial calcification (MAC) in lower-limb arteries and diabetic foot (DF) in diabetes patients. We sought to enhance the understanding of the pathophysiology of diabetic complications and develop strategies to mitigate diabetes-related risks. METHODS: We conducted a retrospective analysis of 701 diabetic patients from the Department of Endocrinology at Sun Yat-Sen Memorial Hospital (2019-2023). We utilized multimodel-adjusted logistic regression to investigate the associations of serum phosphorus levels and the risk of developing MAC and DF. Restricted cubic spline plots were employed to model the relationships, and threshold analysis was used to identify inflection points. Subgroup analyses were performed to explore variations across different demographics. The diagnostic utility of phosphorus concentrations was assessed via the C index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Of the 701 patients (mean age 63.9 years; 401 (57.20%) were male), 333 (47.50%) had MAC, and 329 (46.93%) had DF. After controlling for numerous confounding variables, each one-unit increase in phosphorus concentrations was associated with an increased risk of developing MAC (OR 2.65, 95% CI 1.97-3.57, p < 0.001) and DF (OR 1.54, 95% CI 1.09-2.18, p = 0.014). Phosphorus levels demonstrated a linear risk association, with risk not being uniform on either side of the inflection point, which was approximately 3.28 mg/dL for MAC and varied for DF (3.26 to 3.81 mg/dL). Adding the phosphorus as an independent component to the diagnostic model for MAC and DF increased the C index, NRI, and IDI to varying degrees. CONCLUSIONS: Elevated serum phosphorus levels are significantly associated with an increased risk of developing MAC and DF among diabetic people. These findings suggest that phosphorus management could be integrated into routine diagnostic processes to improve the identification and management of lower-extremity diabetic complications.

Analysis of Circulating miRNA Expression Profiles in Type 2 Diabetes Patients with Diabetic Foot Complications.

Type 2 diabetes mellitus (T2DM) is associated with various complications, including diabetic foot, which can lead to significant morbidity and mortality. Non-healing foot ulcers in diabetic patients are a major risk factor for infections and amputations. Despite conventional treatments, which have limited efficacy, there is a need for more effective therapies. MicroRNAs (miRs) are small non-coding RNAs that play a role in gene expression and have been implicated in diabetic wound healing. miR expression was analyzed through RT-qPCR in 41 diabetic foot Mexican patients and 50 controls. Diabetic foot patients showed significant increases in plasma levels of miR-17-5p (p = 0.001), miR-191-5p (p = 0.001), let-7e-5p (p = 0.001), and miR-33a-5p (p = 0.005) when compared to controls. Elevated levels of miR-17, miR-191, and miR-121 correlated with higher glucose levels in patients with diabetic foot ulcers (r = 0.30, p = 0.004; r = 0.25, p = 0.01; and r = 0.21, p = 0.05, respectively). Levels of miR-17 showed the highest diagnostic potential (AUC 0.903, p = 0.0001). These findings underscore the possible role of these miRs in developing diabetes complications. Our study suggests that high miR-17, miR-191, and miR-121 expression is strongly associated with higher glucose levels and the development of diabetic foot ulcers.

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

AIM: To 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. METHODS: Retrospective 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. RESULTS: A 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. CONCLUSIONS: Only 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.

Correlation between initial serum 25-hydroxyvitamin D and granulation growth in diabetic foot ulcers.

OBJECTIVE: To determine the correlation between initial serum 25-hydroxyvitamin D (25(OH)D) levels with granulation growth in diabetic foot ulcers (DFUs) after 21 days of treatment. METHOD: This cohort study involved patients with type 2 diabetes who had a DFU treated at hospital. Blood samples were taken from patients on admission. The chemiluminescent immunoassay technique was used to measure 25(OH)D levels. Granulation tissue growth was analysed by comparing the photographs from the initial treatment to day 21 of treatment. RESULTS: The median value of 25(OH)D levels at initial treatment was 8 ng/ml. The result showed no correlation between 25(OH)D levels and the granulation growth in DFUs (p=0.86). CONCLUSION: The initial serum 25(OH)D level was not correlated with the growth of granulation tissue in DFUs.

Association between monocyte to lymphocyte ratio and diabetic foot ulcer in the population of the US with diabetes based on the 1999-2004 National Health and Nutrition Examination Survey data: a retrospective cross-sectional study.

Background: Diabetic foot ulcer (DFU) is a severe complication that occurs in patients with diabetes and is a primary factor that necessitates amputation. Therefore, the occurrence and progression of DFU must be predicted at an early stage to improve patient prognosis and outcomes. In this regard, emerging evidence suggests that inflammation-related markers play a significant role in DFU. One such potential marker, the monocyte-lymphocyte ratio (MLR), has not been extensively studied in relation to DFU. This study aimed to define a connection between MLR and DFU. Methods: A cross-sectional study was conducted using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004. DFU was defined based on survey questionnaires assessing the presence of nonhealing ulcers in the lower extremities for more than 4 weeks in diabetes patients. The MLR was calculated as the ratio of the monocyte count to the lymphocyte count, which was directly obtained from laboratory data files. Logistic regression analysis was performed to assess the relationship between the MLR and DFU. Stratified analysis according to age, sex, body mass index, blood glucose, hemoglobin, and glycated hemoglobin categories was conducted, and multiple imputations were applied to missing data. Results: In total, 1246 participants were included; the prevalence of DFU was 9.4% (117/1246). A multivariable regression model revealed a significant association between DFU and a 0.1 unit increase in MLR after adjusting for all covariates (adjusted odds ratio=1.16, 95% confidence interval: 1.02-1.33). Subgroup analyses revealed consistent findings regarding the impact of MLR on the presence of DFU (p > 0.05). Conclusion: MLR is significantly associated with DFU in diabetes patients, and can be used as one of the indicators for predicting the occurrence of DFU. MLR assessment may be a valuable component in the follow-up of patients with diabetes.

Factors Influencing Wound Healing in Diabetic Foot Patients.

Background and objectives: Diabetic foot stands out as one of the most consequential and devastating complications of diabetes. Many factors, including VIPS (Vascular management, Infection management, Pressure relief, and Source of healing), influence the prognosis and treatment of diabetic foot patients. There are many studies on VIPS, but relatively few studies on "sources of healing". Nutrients that affect wound healing are known, but objective data in diabetic foot patients are insufficient. We hypothesized that "sources of healing" would have many effects on wound healing. The purpose of this study is to know the affecting factors related to the source of healing for diabetic foot patients. Materials and Methods: A retrospective review identified 46 consecutive patients who were admitted for diabetic foot management from July 2019 to April 2021 at our department. Several laboratory tests were performed for influencing factor evaluation. We checked serum levels of total protein, albumin, vitamin B, iron, zinc, magnesium, copper, Hb, HbA1c, HDL cholesterol, and LDL cholesterol. These values of diabetic foot patients were compared with normal values. Patients were divided into two groups based on wound healing rate, age, length of hospital stay, and sex, and the test values between the groups were compared. Results: Levels of albumin (37%) and Hb (89%) were low in the diabetic foot patients. As for trace elements, levels of iron (97%) and zinc (95%) were low in the patients, but levels of magnesium and copper were usually normal or high. There were no differences in demographic characteristics based on wound healing rate. However, when compared to normal adult values, diabetic foot patients in our data exhibited significantly lower levels of hemoglobin, total protein, albumin, iron, zinc, copper, and HDL cholesterol. When compared based on age and length of hospital stay, hemoglobin levels were significantly lower in both the older age group and the group with longer hospital stays. Conclusions: Serum levels of albumin, Hb, iron, and zinc were very low in most diabetic foot patients. These low values may have a negative relationship with wound healing. Nutrient replacements are necessary for wound healing in diabetic foot patients.

Update of biomarkers to diagnose diabetic foot osteomyelitis: A meta-analysis and systematic review.

The aim of this study was to evaluate the diagnostic characteristics of biomarker for diabetic foot osteomyelitis (DFO). We searched PubMed, Scopus, Embase and Medline for studies who report serological markers and DFO before December 2022. Studies must include at least one of the following diagnostic parameters for biomarkers: area under the curve, sensitivities, specificities, positive predictive value, negative predictive value. Two authors evaluated quality using the Quality Assessment of Diagnostic Accuracy Studies tool. We included 19 papers. In this systematic review, there were 2854 subjects with 2134 (74.8%) of those patients being included in the meta-analysis. The most common biomarkers were erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and procalcitonin (PCT). A meta-analysis was then performed where data were evaluated with Forrest plots and receiver operating characteristic curves. The pooled sensitivity and specificity were 0.72 and 0.75 for PCT, 0.72 and 0.76 for CRP and 0.70 and 0.77 for ESR. Pooled area under the curves for ESR, CRP and PCT were 0.83, 0.77 and 0.71, respectfully. Average diagnostic odds ratios were 16.1 (range 3.6-55.4), 14.3 (range 2.7-48.7) and 6.7 (range 3.6-10.4) for ESR, CRP and PCT, respectfully. None of the biomarkers we evaluated could be rated as 'outstanding' to diagnose osteomyelitis. Based on the areas under the curve, ESR is an 'excellent' biomarker to detect osteomyelitis, and CRP and PCT are 'acceptable' biomarkers to diagnose osteomyelitis. Diagnostic odds ratios indicate that ESR, CRP and PCT are 'good' or 'very good' tools to identify osteomyelitis.

Association between hemoglobin levels and diabetic foot ulcer in patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: Anemia is prevalent among patients with T2DM with DFU. However, there is limited research on the relationship between Hb level and DFU. OBJECTIVE: To investigate the characteristics and relationship between Hb level and prognosis in patients with DFU. MATERIALS AND METHODS: A total of 212 patients with T2DM were included and grouped according to the presence (n = 105) or absence (n = 107) of DFU. The independent t test and multiple logistic regression analysis were used to analyze the effect of different factors on the occurrence of anemia in patients with DFU and whether Hb level could be used to predict prognosis. RESULTS: There were significant differences in clinical indicators that directly or indirectly contributed to anemia in patients with DFU (P < .05). Hb level was independently associated with DFU (OR, 0.899; P < .05). Hb levels were significantly decreased in patients aged 65 years or older (P < .05). Mild anemia was prevalent among most patients with DFU (59.62%). Hb level decreased with the severity of foot ulcer (P < .05) and was correlated with the duration of diabetes (R2 = 0.653; P < .05). The AUC value was 0.82, with a cutoff value of 122.5 g/L to identify patients with DFU at high risk of adverse outcomes. CONCLUSION: Anemia is common in patients with DFU. Anemia is a marker of DFU severity, and Hb level can predict poor prognosis in patients with DFU.

The potential impact and diagnostic value of inflammatory markers on diabetic foot progression in type II diabetes mellitus: A case-control study.

BACKGROUND: The wound-healing process in diabetic foot is affected by pro and anti-inflammatory markers, and any disruption in the inflammatory reaction interferes with tissue homeostasis, leading to chronic non-wound healing. AIM: This study aimed to determine the diagnostic value and effect of CRP, IL-6, TNF, and HbA1c on initiation the and progression of diabetic foot ulcers. METHOD: ELISA was used to quantify IL-6, TNF, CRP, and HbA1c in 205 patients with diabetes, and 105 were diabetic foot free. The prevalence and progression of diabetic foot were also evaluated. The area under the curve (AUC) was calculated using the receiver operating characteristic (ROC) curve to analyze the predictive values. Forward stepwise logistic regression analysis was used to compute the odds ratio (OR) and the corresponding 95% confidence intervals (CIs). RESULTS: CRP, IL-6, and FBS were found to be significant predictors of diabetic foot (OR=1.717, 95% CI=1.250-2.358, P=0.001; OR=1.434, 95% CI=1.142-1.802, P=0.002; and OR=1.040, 95% CI=1.002-1.080, P=0.037), respectively. The AUCs for CRP, IL-6, and HbA1c in predicting diabetic foot were 0.839, 0.728, and 0.834, respectively, demonstrating a good predictive value for each diagnostic marker. CONCLUSION: The current study demonstrated that IL-6, CRP, and HbA1c may be useful biomarkers to indicate diabetic foot progression. Furthermore, our findings showed a substantial relationship between CRP and HbA1c in individuals with diabetic foot conditions.

Short-term glucose variability as a determinant of the healing rate of diabetic foot ulcer: A retrospective study.

BACKGROUND: The aim of this study was to describe the clinical characteristics of people with diabetic foot ulcer (DFU) according to glucose variability (GV) and to investigate the relationship between GV and DFU outcome in a population with type 2 diabetes (T2D) and DFU. METHODS: This is a retrospective study of 300 individuals aged 64.3 years (181 males) treated for DFU in a tertiary-care center with a regular follow-up for 6 months. Laboratory measurements and clinical assessments were collected at baseline. According to the coefficient of variation (CV) cut-off (≥36%), people were divided into two groups (low and high GV). RESULTS: Compared with low GV group (n = 245), high GV group (n = 55) had significant longer duration of diabetes [low vs high GV, mean ± Standard Deviation (SD), 17.8 ± 11.8 vs 22.4 ± 10.8, P = 0.012], higher levels of glycated haemoglobin [median (IQR), 7.4 (6.6, 8.8) vs 8.2 (7.0, 9.6), P = 0.010] and urinary albumin excretion [25.2 (11.9, 77.0) vs 48.0 (23.2, 106.0), P = 0.031]. Moreover, 10 days self-monitoring of blood glucose-derived glycemic metrics were significantly different between groups. No differences among clinical features were found. The multiple logistic regression analysis identified CV and SD as negative predictors of healing. CONCLUSIONS: In a population of people with T2D and DFU treated in a tertiary-care center, individuals with high GV had a 3-fold higher risk of healing failure, as compared with those with low GV. CV and SD were related to poor healing within 6 months follow-up.

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

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

Comparison of vitamin D levels in diabetes mellitus patients with and without diabetic foot ulcers: An analytical observational study in Jakarta, Indonesia.

Diabetic foot ulcer (DFU) is a form of chronic wound which becomes a serious complication in diabetes mellitus (DM). Recently, the role of vitamin D on T cell-mediated immunity, pancreatic insulin secretion, and its mechanism on cell growth and healing processes have been reported. This study aims to compare the vitamin D level of DM patients with DFU and without DFU to assess the duration and severity of DFU and its correlation with vitamin D levels. The sociodemographic characteristics and DFU duration were documented. The severity was examined in accordance with PEDIS classification. 25-hydroxyvitamin D (25[OH]D) was analysed using in-vitro chemiluminescent immunoassay (CLIA). Statistical analysis was performed and the P-value <.05 was considered as statistically significant. The vitamin D levels in DM patients with and without DFU were 8.90 ng/mL (6.52-10.90) and 16.25 ng/mL (13-19.59), respectively, with P < .001. There was no correlation between the duration of DFU and DFU severity by PEDIS score with vitamin D levels. Vitamin D levels in DM patients with DFU are lower than those in patients without DFU. However, there was insufficient evidence to conclude that there is no correlation between the DFU duration and DFU severity by PEDIS score with vitamin D levels.

Evaluación de la seguridad, la validez diagnóstica y la efectividad clínica de la medición transcutánea de la presión parcial de oxígeno en el manejo del pie diabético / Evaluation of the security, validity diagnosis and the clinical effectiveness of transcutaneous measurement of the partial pressure of oxygen in handling diabetic foot

ANTECEDENTES/INTRODUCCIÓN La causa más común de complicaciones y hospitalizaciones entre los pacientes con diabetes mellitus (DM) es el pie diabético, que se define como un síndrome que causa ulceración, infección o gangrena del pie asociada a neuropatía diabética y a diferentes grados de enfermedad arterial periférica (EAP). El 25% de los pacientes con DM se encuentra en riesgo de desarrollar una úlcera en el pie, pudiendo implicar la amputación del miembro inferior y una pérdida de la calidad de vida de los pacientes, así como unos costes sanitarios elevados. La EAP se observa en el 50% de los casos con DM y se asocia con aparición de úlceras, amputación del miembro inferior, complicaciones cardiovasculares y aumento del riesgo de muerte. Por lo tanto, la identificación y evaluación de la EAP tiene un papel importante en el manejo de pacientes con DM y pie diabético. Teniendo en cuenta las necesidades en el manejo del pie diabético, son necesarias tecnologías que permitan: a) identificar la EAP en pacientes con DM, b) pronosticar la evolución del pie diabético y c) seleccionar y monitorizar el tratamiento vascular del pie diabético. Actualmente, se dispone de diferentes pruebas no invasivas que se utilizan en el diagnóstico y seguimiento de la EAP, así como en la clasificación del riesgo de la úlcera. Una de las más utilizadas es el índice tobillo-brazo (ITB). Sin embargo, se ha sugerido que este método presentaría algunas limitaciones, especialmente en pacientes que presentan calcificación de las arterias. Por este motivo, se ha propuesto el uso de la medición transcutánea de la presión parcial de oxígeno (TcPO2 ). Los dispositivos de TcPO2 son tecnologías que estiman la presión parcial de oxígeno en la superficie de la piel mediante un electrodo no invasivo e informan sobre el aporte de oxígeno proveniente de la circulación microvascular subyacente. El objetivo general del presente informe es evaluar el uso de la medición de TcPO2 en el manejo del pie diabético y comparar su seguridad, validez diagnóstica, utilidad pronóstica en la evolución del pie diabético, y utilidad predictiva en el tratamiento vascular del pie diabético respecto a otras pruebas utilizadas en la evaluación del estado vascular del paciente, principalmente el ITB. METODOLOGÍA Se ha realizado una revisión sistemática con el fin de identificar estudios que dieran respuestaal objetivo del presente informe. Se incluyeron estudios que hubieran evaluado la medición de TcPO2 en pacientes con DM sin complicaciones o con pie diabético y hubieran comparado sus resultados con el ITB, el índice dedo-brazo, la palpación de pulsos, la arteriografía, la angioRMN o la angioTAC. Como diseños de estudio, se consideraron revisiones sistemáticas con metanálisis (RSMA), ensayos clínicos, estudios cuasiexperimentales, estudios comparativos, estudios de prueba diagnóstica, estudios de cohortes y estudios de casos y controles. La fecha de la búsqueda fue 10 de noviembre de 2021, sin restricciones en cuanto al periodo temporal. RESULTADOS Se identificaron un total de 573 referencias. Tras la revisión por título y resumen, se seleccionaron 123 referencias, de las cuales 111 no cumplieron con los criterios de inclusión. Finalmente, doce estudios fueron considerados para la síntesis de la evidencia: una RSMA de estudios observacionales y once estudios observacionales no incluidos en dicha revisión. Globalmente, la calidad de los estudios identificados fue considerada incierta o baja. Dos estudios observacionales aportaron resultados en relación con los resultados de seguridad y validez diagnóstica de EAP de la medida de TcPO2 . Uno de ellos se realizó en el ámbito de la atención primaria en pacientes con DM sin complicaciones. Se observaron diferencias significativas en la tasa de diagnosticados con EAP entre diferentes pruebas no invasivas, que fue mayor con el ITB (70%) seguido del IDB (57%), la medida de TcPO2 (30%) y la palpación de pulsos (23%). En pacientes con úlcera, un estudio observacional comunicó los valores predictivos (VPP y VPN) en la identificación de la EAP para el ITB (0,45 y 0,79), para el IDB (0,45, 0,73) y para la TcPO2 (0,28, 0,66). La sensibilidad y especificidad fueron del 68% y 59% para el ITB, del 89% y 45% para el IDB y del 28% y 66% para la medida de TcPO2 . La mayoría de los estudios presentaron resultados de utilidad pronóstica de la TcPO2 en el manejo del pie diabético. La RSMA incluida mostró una sensibilidad y especificidad para la curación de la úlcera del 72% y 86% con la medida de TcPO2 (30 mmHg) y del 48% y 52% con el ITB (0,8). Sus resultados de sensibilidad y especificidad para la amputación fueron de 52% y de 73% con el ITB y de 75% y 58% con la TcPO2 , respectivamente. Algunos de los estudios individuales aportaron resultados de curación de úlcera y amputación con diferentes puntos de corte que obtuvieron resultados heterogéneos de sensibilidad y especificidad de la TcPO2 . Un único estudio mostró la utilidad pronóstica de la TcPO2 sobre la mortalidad, asociando una TcPO2 < 25 mmHg a una mayor tasa de mortalidad a un año. Los resultados sobre la utilidad predictiva de la TcPO2 relacionada con el tratamiento del pie diabético se encontraron en dos estudios observacionales que evaluaron su uso en el procedimiento de revascularización. Tanto los valores de TcPO2 como el resultado del ITB mostraron cambios significativos después de la intervención. No obstante, el ITB no pudo realizarse en el 42% y el 15% de los pacientes incluidos en los respectivos estudios debido a las siguientes causas: por no obtener ninguna señal, no poder comprimirse la arteria o por la existencia de calcificaciones en la capa media arterial. CONCLUSIONES Globalmente, la evidencia identificada sobre el uso de la TcPO2 en el manejo del pie diabético es de calidad incierta o baja. Los resultados de seguridad y la validez diagnóstica de la TcPO2 en pacientes con DM sin complicaciones o pie diabético no son concluyentes. La mayor evidencia se encuentra en el uso de la TcPO2 en el pronóstico de curación de úlceras y amputación en pacientes con pie diabético, y es sugestiva de que la medida de TcPO2 es superior al ITB. La mejor precisión de la TcPO2 indicativa de curación de la úlcera se encuentra en el punto de corte 22,5-28,5 mmHg. Sin embargo, hay incertidumbre acerca del punto de corte de la TcPO2 asociado a un mayor riesgo de amputación. Algunos estudios sugieren que el aumento observado en la TcPO2 después de un procedimiento de revascularización presentaría una mayor sensibilidad y especificidad respecto del ITB.

BACKGROUND/INTRODUCTION The leading cause of complications and hospitalization in patients with diabetes mellitus (DM) is the diabetic foot, defined as a syndrome causing ulceration, infection or gangrene of the foot associated with diabetic neuropathy and varying degrees of peripheral arterial disease (PAD). About 25% of people with DM are at risk of developing a foot ulcer, which can lead to lower limb amputation and a loss of quality of life for patients, and high healthcare costs. PAD occurs in 50% of cases of DM and is associated with ulceration, lower limb amputation, cardiovascular events and increased risk of death. Therefore, the identification and assessment of PAD plays a major role in the management of patients with DM and diabetic foot. Considering the needs of the diabetic foot management, we need technologies to: a) identify PAD in patients with DM, b) predict the evolution of the diabetic foot, and c) select and monitor the vascular treatment of the diabetic foot. Currently, several non-invasive tests are used to diagnose and monitor PAD and to classify the risk of ulceration. One of the most widely used is the ankle-brachial index (ABI). However, it has been suggested that this method has some limitations, especially in patients with calcified arteries. For this reason, the use of transcutaneous partial pressure of oxygen (TcPO2 ) measurement has been proposed. TcPO2 devices are technologies that use a non-invasive electrode to estimate the partial pressure of oxygen at the skin surface and report the oxygen supply from the underlying microvascular circulation. The overall aim of this report is to evaluate the use of TcPO2 measurement in diabetic foot management and to compare its safety, diagnostic validity, prognostic utility in diabetic foot outcomes, and predictive utility in diabetic foot vascular management with other tests used to assess the patient's vascular status, primarily ABI. METHODOLOGY A systematic review was conducted to identify studies that addressed the objective of this report. We included studies that had evaluated TcPO2 measurement in patients with uncomplicated DM or diabetic foot and compared their results with ABI, finger-arm index, pulse palpation, arteriography, MR angiography or CT angiography. Study designs included 26 INFORMES, ESTUDIOS E INVESTIGACIÓN systematic reviews with meta-analyses (SRMAs), clinical trials, cohort studies and case-control studies. The search date was 10 November 2021, with no time restrictions. RESULTS We identified 573 references. After title and abstract screening, we selected 123 references, of which 111 did not meet the inclusion criteria. Finally, 12 studies were included in the evidence synthesis: one SRMA of observational studies and 11 observational studies not included in this review. The quality of the identified studies was considered uncertain or low. Two observational studies provided results on the safety and diagnostic validity of TcPO2 measurement for PAD. One of these was conducted in a primary care setting in patients with uncomplicated DM. Significant differences were observed in the rate of diagnosis of PAD between different non-invasive tests, which was higher for ABI (70%), followed by digit-brachial index (57%), TcPO2 (30%), and pulse palpation (23%). In patients with ulceration, an observational study reported the predictive values (PPV and NPV) of ABI (0.45 y 0.79), digit-brachial index (0.45, 0.73), and TcPO2 (0.28, 0.66) to detect PAD. Sensitivity and specificity were 68% and 59% for ABI, 89% and 45% for digit-brachial index, and 28% and 66% for TcPO2 . Most studies presented results on the prognostic utility of TcPO2 for diabetic foot management. The included SRMA showed sensitivity and specificity results for ulcer healing of 72% and 86% with TcPO2 (30 mmHg), and 48% and 52% with ABI (0.8). The sensitivity and specificity results for amputation were 52% and 73% with ABI, and 75% and 58% with TcPO2 . Some individual studies reported ulcer healing and amputation results with different cut-off points, resulting in heterogeneous sensitivity and specificity results for TcPO2 . A single study showed the prognostic utility of TcPO2 for mortality, with a TcPO2 < 25 mmHg associated with a higher one-year mortality rate. Two observational studies assessing the use of TcPO2 in revascularization procedures provided results on the predictive utility of TcPO2 in diabetic foot management. Both TcPO2 values and ABI score showed significant changes after the procedure. However, ABI could not be not used in some patients (42% and 15%, respectively). CONCLUSIONS Overall, the evidence identified for the use of TcPO2 in the management of the diabetic foot is of uncertain or low quality. The safety results and diagnostic validity of TcPO2 in patients with uncomplicated DM or diabetic foot are inconclusive. The strongest evidence is found for the use of TcPO2 in the prognosis of ulcer healing and amputation in patients with diabetic foot, suggesting that the TcPO2 measurement may be superior to ABI. The best accuracy of TcPO2 as an indicator of ulcer healing is at the cut-off point of 22.5-28.5 mmHg. However, there is uncertainty about the TcPO2 cut-off point associated with an increased risk of amputation. Some studies suggest that the increase in TcPO2 observed after revascularization may have a higher sensitivity and specificity than ABI.

Tandem mass tag-based serum proteomic profiling revealed diabetic foot ulcer pathogenesis and potential therapeutic targets.

Diabetic foot ulcer (DFU), one of the most serious complications of diabetes mellitus, is associated with a high amputation rate and decreased life quality. The impact of blood serum proteins on the occurrence and development of DFU has attracted a lot of interest. In this study, we aimed to define and compare the serum proteome of patients with DFU and healthy control (HC) to provide new insights into DFU pathogenesis. DFU patients and age- and sex-matched HCs were enrolled in this study (n = 54). We screened alterations in blood serum proteins from DFU patients and HC using a tandem mass tag (TMT) method based on liquid chromatography-mass spectrometry (LC-MS/MS) quantitative proteomics, and the differentially expressed proteins (DEPs) were further validated by parallel reaction monitoring (PRM) and enzyme-linked immunosorbent assay (ELISA). A total of 173 DEPs (100 up-regulated and 73 down-regulated) were identified between the DFU and HC groups (P < 0.05). Proteomic and bioinformatics analyses indicated that the proteins in the DFU group were mainly related to extracellular matrix (ECM)-receptor interaction and complement and coagulation cascades. The up-regulated DEPs were further verified by PRM and ELISA. LRG1, CD5L, CRP, IGHA1, and LBP were proved upregulated in DFU and these proteins are mainly related to immune response and complement activation. Our findings help to provide a more comprehensive understanding of the pathogenesis of DFU and new insight into potential therapeutic targets.

Clinical evidence for elevated levels of caveolin-1 in circulation of patients with diabetic foot ulcers.

Caveolin-1 directly interacts vascular endothelial growth factor receptor-2 (VEGFR2) and therefore prevents VEGF-induced angiogenesis. In addition, the production of nitric oxide (NO), which is effective in reducing ischemia in diabetic foot ulcers (DFU), is suppressed by caveolin-1 in endothelial cells. The present study was designed to investigate the change of caveolin-1 concentrations in DFU patients. A total of 150 participants were consecutively enrolled, including 40 DFU patients (DFU group), 40 diabetes patients without DFU (type 2 diabetes mellitus [T2DM] group), and 70 participants without diabetes (control group). Significant increased levels of plasma caveolin-1, accompanied with decreased concentration of plasma VEGF-A (vascular endothelial growth factor-A) and NO, were detected in DFU patients. Moreover, Pearson's correlation analysis revealed a negative correlation between plasma caveolin-1 and VEGF-A as well as NO levels in DFU patients. Furthermore, DFU patients had higher expression of caveolin-1 in the popliteal artery, compared to those in control and T2DM groups. Simultaneously, the amounts of eNOS (an enzyme responsible for the production of NO) and VEGFR2 were attenuated in the popliteal artery of DFU patients. Taken together, our study provided clinical evidence for the possible association of elevated caveolin-1 levels and the development of DFU. This may be induced by the suppressed VEGF-A/VEGFR2 and eNOS/NO signalling axis.