RESUMO
Despite the known higher risk of cardiovascular disease in individuals with type 2 diabetes, the pathophysiology and optimal management of diabetic foot ulcers (DFUs), a leading complication associated with diabetes, is complex and continues to evolve. Complications of type 2 diabetes, such as DFUs, are a major cause of morbidity and mortality and the leading cause of major lower extremity amputation in the United States. There has recently been a strong focus on the prevention and early treatment of DFUs, leading to the development of multidisciplinary diabetic wound and amputation prevention clinics across the country. Mounting evidence has shown that, despite these efforts, amputations associated with DFUs continue to increase. Furthermore, due to increasing patient complexity of management secondary to comorbid conditions, such as cardiovascular disease, the management of peripheral artery disease associated with DFUs has become increasingly difficult, and care delivery is often episodic and fragmented. Although structured, process-specific approaches exist at individual institutions for the management of DFUs in the cardiovascular patient population, there is insufficient awareness of these principles in the general medicine communities. Furthermore, there is growing interest in better understanding the mechanistic underpinnings of DFUs to better define personalized medicine to improve outcomes. The goals of this scientific statement are to provide salient background information on the complex pathogenesis and current management of DFUs in cardiovascular patients, to guide therapeutic and preventive strategies and future research directions, and to inform public policy makers on health disparities and other barriers to improving and advancing care in this expanding patient population.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Pé Diabético , Humanos , Estados Unidos/epidemiologia , Pé Diabético/diagnóstico , Pé Diabético/epidemiologia , Pé Diabético/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , American Heart AssociationRESUMO
BACKGROUND: Diabetic foot ulcers (DFU) is the most serious complication of diabetes mellitus, which has become a global health problem due to its high morbidity and disability rates and the poor efficacy of conventional treatments. Thus, it is urgent to identify novel molecular targets to improve the prognosis and reduce disability rate in DFU patients. RESULTS: In the present study, bulk RNA-seq and scRNA-seq associated with DFU were downloaded from the GEO database. We identified 1393 DFU-related DEGs by differential analysis and WGCNA analysis together, and GO/KEGG analysis showed that these genes were associated with lysosomal and immune/inflammatory responses. Immediately thereafter, we identified CLU, RABGEF1 and ENPEP as DLGs for DFU using three machine learning algorithms (Randomforest, SVM-RFE and LASSO) and validated their diagnostic performance in a validation cohort independent of this study. Subsequently, we constructed a novel artificial neural network model for molecular diagnosis of DFU based on DLGs, and the diagnostic performance in the training and validation cohorts was sound. In single-cell sequencing, the heterogeneous expression of DLGs also provided favorable evidence for them to be potential diagnostic targets. In addition, the results of immune infiltration analysis showed that the abundance of mainstream immune cells, including B/T cells, was down-regulated in DFUs and significantly correlated with the expression of DLGs. Finally, we found latamoxef, parthenolide, meclofenoxate, and lomustine to be promising anti-DFU drugs by targeting DLGs. CONCLUSIONS: CLU, RABGEF1 and ENPEP can be used as novel lysosomal molecular signatures of DFU, and by targeting them, latamoxef, parthenolide, meclofenoxate and lomustine were identified as promising anti-DFU drugs. The present study provides new perspectives for the diagnosis and treatment of DFU and for improving the prognosis of DFU patients.
Assuntos
Pé Diabético , Lisossomos , Humanos , Lisossomos/genética , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Pé Diabético/genética , Pé Diabético/tratamento farmacológico , Pé Diabético/patologia , RNA-Seq , Análise de Célula Única/métodos , Perfilação da Expressão Gênica , Prognóstico , Masculino , Feminino , Aprendizado de Máquina , Análise da Expressão Gênica de Célula ÚnicaRESUMO
Diabetic foot ulcer (DFU) is one of the most costly and serious complications of diabetes. Treatment of DFU is usually challenging and new approaches are required to improve the therapeutic efficiencies. This review aims to update new and upcoming adjunctive therapies with noninvasive characterization for DFU, focusing on bioactive dressings, bioengineered tissues, mesenchymal stem cell (MSC) based therapy, platelet and cytokine-based therapy, topical oxygen therapy, and some repurposed drugs such as hypoglycemic agents, blood pressure medications, phenytoin, vitamins, and magnesium. Although the mentioned therapies may contribute to the improvement of DFU to a certain extent, most of the evidence come from clinical trials with small sample size and inconsistent selections of DFU patients. Further studies with high design quality and adequate sample sizes are necessitated. In addition, no single approach would completely correct the complex pathogenesis of DFU. Reasonable selection and combination of these techniques should be considered.
Assuntos
Pé Diabético , Humanos , Pé Diabético/terapia , Pé Diabético/tratamento farmacológico , Bandagens , AnimaisRESUMO
AIMS/HYPOTHESIS: The risk of dying within 2 years of presentation with diabetic foot ulceration is over six times the risk of amputation, with CVD the major contributor. Using an observational evaluation of a real-world implementation pilot, we aimed to assess whether for those presenting with diabetic foot ulceration in England, introducing a 12-lead ECG into routine care followed by appropriate clinical action was associated with reduced mortality. METHODS: Between July 2014 and December 2017, ten multidisciplinary diabetic foot services in England participated in a pilot project introducing 12-lead ECGs for new attendees with foot ulceration. Inception coincided with launch of the National Diabetes Footcare Audit (NDFA), whereby all diabetic footcare services in England were invited to enter data on new attendees with foot ulceration. Poisson regression models assessed the mortality RR at 2 and 5 years following first assessment of those receiving care in a participating pilot unit vs those receiving care in any other unit in England, adjusting for age, sex, ethnicity, deprivation, type and duration of diabetes, ulcer severity, and morbidity in the year prior to first assessment. RESULTS: Of the 3110 people recorded in the NDFA at a participating unit during the pilot, 33% (1015) were recorded as having received an ECG. A further 25,195 people recorded in the NDFA had attended another English footcare service. Unadjusted mortality in the pilot units was 16.3% (165) at 2 years and 37.4% (380) at 5 years for those who received an ECG, and 20.5% (430) and 45.2% (950), respectively, for those who did not receive an ECG. For people included in the NDFA at other units, unadjusted mortality was 20.1% (5075) and 42.6% (10,745), respectively. In the fully adjusted model, mortality was not significantly lower for those attending participating units at 2 (RR 0.93 [95% CI 0.85, 1.01]) or 5 years (RR 0.95 [95% CI 0.90, 1.01]). At participating units, mortality in those who received an ECG vs those who did not was lower at 5 years (RR 0.86 [95% CI 0.76, 0.97]), but not at 2 years (RR 0.87 [95% CI 0.72, 1.04]). Comparing just those that received an ECG with attendees at all other centres in England, mortality was lower at 5 years (RR 0.87 [95% CI 0.78, 0.96]), but not at 2 years (RR 0.86 [95% CI 0.74, 1.01]). CONCLUSIONS/INTERPRETATION: The evaluation confirms the high mortality seen in those presenting with diabetic foot ulceration. Overall mortality at the participating units was not significantly reduced at 2 or 5 years, with confidence intervals just crossing parity. Implementation of the 12-lead ECG into the routine care pathway proved challenging for clinical teams-overall a third of attendees had one, although some units delivered the intervention to over 60% of attendees-and the evaluation was therefore underpowered. Nonetheless, the signals of potential mortality benefit among those who had an ECG suggest that units in a position to operationalise implementation may wish to consider this. DATA AVAILABILITY: Data from the National Diabetes Audit can be requested through the National Health Service Digital Data Access Request Service process at: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/national-diabetes-audit-nda.
Assuntos
Pé Diabético , Eletrocardiografia , Humanos , Pé Diabético/mortalidade , Feminino , Masculino , Inglaterra/epidemiologia , Idoso , Projetos Piloto , Pessoa de Meia-Idade , Amputação Cirúrgica/estatística & dados numéricosRESUMO
This research aimed to find important genes and pathways related to cellular senescence (CS) in diabetic foot ulcers (DFU) and to estimate the possible pathways through which CS affects diabetic foot healing. The GSE80178 dataset was acquired from the Gene Expression Omnibus (GEO) database, containing six DFU and three diabetic foot skin (DFS) samples. The limma package was used to identify differentially expressed genes (DEGs). At the same time, DEGs associated with CS (CS-DEGs) were found using the CellAge database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the CS-DEGs. A protein-protein interaction (PPI) network was built using the String database, and the cytoHubba plug-in within Cytoscape helped identify hub genes. Lastly, the miRNA-TF-mRNA regulatory network for these hub genes was established. In total, 66 CS-DEGs were obtained. These genes mainly focus on CS, Kaposi sarcoma-associated herpesvirus infection and Toll-like receptor signalling pathway. Eight hub genes were identified to regulate cell senescence in DFU, including TP53, SRC, SIRT1, CCND1, EZH2, CXCL8, AR and CDK4. According to miRNA-TF-mRNA regulatory network, hsa-mir-132-3p/SIRT1/EZH2 axis is involved in senescence cell accumulation in DFU.
Assuntos
Diabetes Mellitus , Pé Diabético , MicroRNAs , Humanos , Sirtuína 1/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Perfilação da Expressão Gênica , RNA Mensageiro/genética , Biologia ComputacionalRESUMO
BACKGROUND: Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis. METHODS: We downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset. RESULTS: In both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929). CONCLUSION: This study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.
Assuntos
Diabetes Mellitus , Pé Diabético , Humanos , Pé Diabético/genética , Glutamina , Biologia Computacional , Bases de Dados Factuais , BiomarcadoresRESUMO
OBJECTIVE: The objective of this study was to examine the potential of USP7 as a target for senolytic therapy and to investigate the molecular mechanism by which its inhibitor selectively induced apoptosis in senescent HDF and enhanced DFU wound healing. METHODS: Clinical samples of DFU were collected to detect the expression of USP7 and aging-related proteins using immunohistochemistry and Western blot. In addition, ß-galactosidase staining, qPCR, flow cytometry, ROS and MMP kits, and Western blot were used to analyze the biological functions of P5091 on senescence, cycle, and apoptosis. RNAseq was employed to further analyze the molecular mechanism of P5091. Finally, the DFU rat model was established to evaluate the effect of P5091 on wound healing. RESULTS: The expression of USP7 and p21 were increased in DFU clinical samples. After treatment with d-glucose (30 mM, 7 days), ß-galactosidase staining was deepened, proliferation rate decreased. USP7 inhibitors (P5091) could reduce the release of SASP factors, activate the production of ROS, and reduce MMP. In addition, it induced apoptosis and selectively clears senescent cells through the p53 signaling pathway. Finally, P5091 can improve diabetic wound healing in rats. CONCLUSION: This study clarified the molecular mechanism of USP7 inhibitor (P5091) selectively inducing apoptosis of high glucose senescent HDF cells. This provides a new senolytics target and experimental basis for promoting DFU wound healing.
Assuntos
Senescência Celular , Transdução de Sinais , Proteína Supressora de Tumor p53 , Peptidase 7 Específica de Ubiquitina , Cicatrização , Peptidase 7 Específica de Ubiquitina/metabolismo , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Animais , Cicatrização/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Humanos , Senescência Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ratos , Masculino , Pé Diabético/tratamento farmacológico , Pé Diabético/metabolismo , Pé Diabético/patologia , Apoptose/efeitos dos fármacos , Ratos Sprague-Dawley , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas , TiofenosRESUMO
OBJECTIVE: Diabetic foot ulcer (DFU) is a severe complication with high mortality. High plantar pressure and poor microcirculation are considered main causes of DFU. The specific aims were to provide a novel technique for real-time measurement of plantar skin blood flow (SBF) under walking-like pressure stimulus and delineate the first plantar metatarsal head dynamic microcirculation characteristics because of life-like loading conditions in healthy individuals. METHODS: Twenty young healthy participants (14 male and 6 female) were recruited. The baseline (i.e., unloaded) SBF of soft tissue under the first metatarsal head were measured using laser Doppler flowmetry (LDF). A custom-made machine was utilized to replicate daily walking pressure exertion for 5 min. The exerted plantar force was adjusted from 10 N (127.3 kPa) to 40 N (509.3 kPa) at an increase of 5 N (63.7 kPa). Real-time SBF was acquired using the LDF. After each pressure exertion, postload SBF was measured for comparative purposes. Statistical analysis was performed using the R software. RESULTS: All levels of immediate-load and postload SBF increased significantly compared with baseline values. As the exerted load increased, the postload and immediate-load SBF tended to increase until the exerted load reached 35 N (445.6 kPa). However, in immediate-load data, the increasing trend tended to level off as the exerted pressure increased from 15 N (191.0 kPa) to 25 N (318.3 kPa). For postload and immediate-load SBF, they both peaked at 35 N (445.6 kPa). However, when the exerted force exceeds 35 N (445.6 kPa), both the immediate-load and postload SBF values started to decrease. CONCLUSIONS: Our study offered a novel real-time plantar soft tissue microcirculation measurement technique under dynamic conditions. For the first metatarsal head of healthy people, 20 N (254.6 kPa)-plantar pressure has a fair microcirculation stimulus compared with higher pressure. There might be a pressure threshold at 35 N (445.6 kPa) for the first metatarsal head, and soft tissue microcirculation may decrease when local pressure exceeds it.
Assuntos
Pé , Microcirculação , Pele , Humanos , Masculino , Feminino , Microcirculação/fisiologia , Adulto , Pele/irrigação sanguínea , Pele/fisiopatologia , Pé/irrigação sanguínea , Pressão , Ossos do Metatarso/irrigação sanguínea , Ossos do Metatarso/fisiopatologia , Fluxometria por Laser-Doppler/métodos , Adulto Jovem , Caminhada/fisiologia , Pé Diabético/fisiopatologiaRESUMO
BACKGROUND: Diabetic foot ulcer (DFU) is the most devastating complication of diabetes mellitus (DM) and plays a major role in disability and death in DM patients. NADH: ubiquinone oxidoreductase subunit B5 (NDUFB5) plays an important role in maintaining mitochondrial respiration, but whether it is involved in regulating the progression of advanced glycation end products (AGEs)-mediated DFU is still unclear. METHODS: Firstly, the role of AGEs on cell viability, migration, and mitochondrial respiration in human umbilical vein endothelial cells (HUVECs) was explored in vitro. Next, NDUFB5 expression was detected in human samples and AGEs-treated HUVECs, and NDUFB5's effect on AGEs-induced HUVECs injury and skin wound in diabetic mice was further clarified. In addition, the role of m6A modification mediated by methyltransferase-like 3 (METTL3) in regulating NDUFB5 expression and AGEs-induced HUVECs injury was investigated. RESULTS: NDUFB5 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs, whereas mitochondrial fusion promoter M1 facilitated cell viability, migration, and mitochondrial oxiadative respiration in NDUFB5 knockdown HUVECs. Meanwhile, NDUFB5 promotes skin wound healing in diabetic mice. Besides, METTL3-mediated m6A modification and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) enhanced NDUFB5 expression in HUVECs. Furthermore, METTL3 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs by increasing NDUFB5. CONCLUSION: METTL3-mediated NDUFB5 m6A modification inhibits AGEs-induced cell injury in HUVECs. METTL3 and NDUFB5 might serve as potential targets for DFU therapy in the future.
Assuntos
Movimento Celular , Pé Diabético , Células Endoteliais da Veia Umbilical Humana , Metiltransferases , Mitocôndrias , Cicatrização , Animais , Humanos , Masculino , Camundongos , Respiração Celular , Sobrevivência Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Pé Diabético/patologia , Pé Diabético/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Metiltransferases/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismoRESUMO
Diabetic foot ulcers (DFU) are a type of chronic wound that constitute one of the most serious and debilitating complications associated with diabetes. The lack of clinically efficacious treatments to treat these recalcitrant wounds can lead to amputations for those worst affected. Biomaterial-based approaches offer great hope in this regard, as they provide a template for cell infiltration and tissue repair. However, there is an additional need to treat the underlying pathophysiology of DFUs, in particular insufficient vascularization of the wound which significantly hampers healing. Thus, the addition of pro-angiogenic moieties to biomaterials is a promising strategy to promote the healing of DFUs and other chronic wounds. In this review, we discuss the potential of biomaterials as treatments for DFU and the approaches that can be taken to functionalise these biomaterials such that they promote vascularisation and wound healing in pre-clinical models.
Assuntos
Diabetes Mellitus , Pé Diabético , Humanos , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Cicatrização , Pé Diabético/tratamento farmacológico , Matriz ExtracelularRESUMO
BACKGROUND: Staphylococcus aureus isolates are the leading cause of diabetic foot infections (DFIs). Identification of specific virulence factors of S. aureus involved in the pathogenesis of DFIs may help control the infection more effectively. Since the most prevalent virulence factor genes are probably related to the DFI pathogenesis, the aim of this study is to evaluate the proportion of virulence factor genes of S. aureus isolates from DFIs. MATERIALS AND METHODS: We conducted a systematic search of PubMed, Embase, Web of Science, and Scopus to identify all articles reporting the proportion of different types of virulence factors of S. aureus isolates from DFI samples. RESULTS: Seventeen studies were eligible, in which 1062 S. aureus isolates were obtained from 1948 patients and 2131 DFI samples. Among the toxin virulence factors, hld 100.0% (95% CI: 97.0, 100.0%), hlg 88.0% (95% CI: 58.0, 100.0%), hla 80.0% (95% CI: 31.0, 100.0%), hlgv 79.0% (95% CI: 35.0, 100.0%) and luk-ED 72.0% (95% CI: 42.0, 95.0%) had the highest proportion respectively. Among the genes associated with biofilm formation, both icaA and icaD had the highest proportion 100.0% (95% CI: 95.6, 100.0%). CONCLUSION: The results of the present study showed that among the toxin virulence factors, hemolysins (hld, hlg, hla, hlgv) and luk-ED and among the non-toxin virulence factors, icaA and icaD have the greatest proportion in S. aureus isolates from DFIs. These prevalent genes may have the potential to evaluate as virulence factors involved in DFI pathogenesis. Finding these probable virulence factor genes can help control diabetic foot infection more effectively via anti-virulence therapy or preparation of multi-epitope vaccines.
Assuntos
Diabetes Mellitus , Pé Diabético , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Fatores de Virulência/genética , Virulência/genéticaRESUMO
BACKGROUND: Patients with diabetic feet are prone to be infected due to the impaired immune system. However, the prognostic outcome of different microbial infections remains controversial. Identification and rapid screening of the pathogenic microorganisms that pose the greatest threat to the prognosis of patients with diabetic foot infections (DFIs) is critical. METHODS: Clinical data were statistically analyzed, which were obtained from 522 patients with DFIs, including pathogenic bacterial culture results and treatment outcomes at the last return visit. In addition, a loop-mediated isothermal amplification (LAMP) detection method was developed to identify the prevalent subtype of methicillin-resistant Staphylococcus aureus (MRSA) in DFIs patients. This study was approved by the Ethics Committee of Nanfang Hospital (NFEC-202012-K6) and registered on ClinicalTrials.gov (NCT04916457) on June 1, 2021. RESULTS: We found that the proportion of patients with infections of Staphylococcus aureus (S. aureus) and MRSA was 27.7% (145/522) and 33.7% (49/145), respectively. Additionally, the incidence of osteomyelitis was 46.9% (23/49) and amputation/disability was 40.8% (20/49) in patients with MRSA infection, which were significantly higher compared to patients with other types of bacterial infections such as methicillin-susceptible Staphylococcus aureus (MSSA). Notably, we demonstrated that the main prevalent subtype of MRSA in DFIs patients in our hospital was Staphylococcal chromosomal cassettes mec (SCCmec) type II. In addition, it only takes 1.5 h to complete the entire experimental procedure in this LAMP assay, providing high sensitivity (100%) and specificity (77.8%) in hospitalized patients with DFIs. CONCLUSIONS: We demonstrated there is a very high rate of MRSA isolation in patients with DFIs and revealed that patients infected with MRSA are at a higher risk of developing osteomyelitis, and amputation or disability. Importantly, we have developed a method for quickly screening newly admitted patients for MRSA.
Assuntos
Diabetes Mellitus , Pé Diabético , Staphylococcus aureus Resistente à Meticilina , Osteomielite , Infecções Estafilocócicas , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus/genética , Antibacterianos/uso terapêutico , Prevalência , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Diabetes Mellitus/tratamento farmacológicoRESUMO
BACKGROUND: Foot ulcers and/or infections are common long-term complications of diabetes and are associated with increased mortality, especially from cardiovascular disease, though only a few studies have investigated the independent contribution of these events to risk of death. This study aimed at assessing the association of history of diabetic foot with all-cause mortality in individuals with type 2 diabetes, independent of cardiovascular risk factors, other complications, and comorbidities. METHODS: This prospective cohort study enrolled 15,773 Caucasian patients in 19 Italian centers in the years 2006-2008. Prior lower extremity, coronary, and cerebrovascular events and major comorbidities were ascertained by medical records, diabetic retinopathy by fundoscopy, diabetic kidney disease by albuminuria and estimated glomerular filtration rate, cardiovascular risk factors by standard methods. All-cause mortality was retrieved for 15,656 patients on 31 October 2015. RESULTS: At baseline, 892 patients (5.7%) had a history of diabetic foot, including ulcer/gangrene and/or amputation (n = 565; 3.58%), with (n = 126; 0.80%) or without (n = 439; 2.78%) lower limb revascularization, and revascularization alone (n = 330; 2.09%). History of diabetic foot was associated with all-cause death over a 7.42-year follow-up (adjusted hazard ratio, 1.502 [95% confidence interval, 1.346-1.676], p < 0.0001), independent of confounders, among which age, male sex, smoking, hemoglobin A1c, current treatments, other complications, comorbidities and, inversely, physical activity level and total and HDL cholesterol were correlated independently with mortality. Both ulcer/gangrene and amputation alone were independently associated with death, with a higher strength of association for amputation than for ulcer/gangrene (1.874 [1.144-3.070], p = 0.013 vs. 1.567 [1.353-1.814], p < 0.0001). Both ulcer/gangrene/amputation and lower limb revascularization alone were independently associated with death; mortality risk was much higher for ulcer/gangrene/amputation than for revascularization (1.641 [1.420-1.895], p < 0.0001 vs. 1.229 [1.024-1.475], p = 0.018) and further increased only slightly for combined ulcer/gangrene/amputation and revascularization (1.733 [1.368-2.196], p < 0.0001). CONCLUSIONS: In patients with type 2 diabetes, an history of diabetic foot event, including ulcer/gangrene, amputation, and lower limb revascularization, was associated with a ~ 50% increased risk of subsequent death, independent of cardiovascular risk factors, other complications and severe comorbidities, which were also significantly associated with mortality. The association with mortality was greatest for amputation, whereas that for revascularization alone was relatively modest. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Pé Diabético , Insuficiência Renal , Humanos , Masculino , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/complicações , Pé Diabético/diagnóstico , Pé Diabético/epidemiologia , Pé Diabético/terapia , Gangrena/complicações , Itália/epidemiologia , Estudos Prospectivos , Fatores de Risco , Úlcera/complicações , FemininoRESUMO
BACKGROUND: To evaluate the association between diabetic foot disease (DFD) and the incidence of fatal and non-fatal events in individuals with type 2 diabetes (T2DM) from primary-care settings. METHODS: We built a cohort of people with a first DFD episode during 2010-2015, followed up until 2018. These subjects were 1 to 1 propensity score matched to subjects with T2DM without DFD. The incidence of all-cause mortality, the occurrence of new DFD, amputations, cardiovascular diseases, or composite outcome, including all-cause mortality and/or cardiovascular events during the follow-up period, were calculated. A Cox proportional hazard analysis was conducted to evaluate the hazard ratios (HR) for different events. RESULTS: Overall, 11,117 subjects with T2DM with a first episode of DFD were compared with subjects without DFD. We observed higher incidence rates (IRs) for composite outcome (33.9 vs. 14.5 IR per 100 person-years) and a new DFD episode event (22.2 vs. 1.1 IR per 100 person-years) in the DFD group. Compared to those without DFD, those with a first episode of DFD had a higher HR for all events, with excess rates particularly for amputation and new DFD occurrence (HR: 19.4, 95% CI: 16.7-22.6, HR: 15.1, 95% CI: 13.8-16.5, respectively) was found. CONCLUSIONS: Although DFD often coexists with other risk factors, it carries an intrinsic high risk of morbidity and mortality in individuals with T2DM. DFD should be regarded as a severe complication already at its onset, as it carries a poor clinical prognosis.
Assuntos
Amputação Cirúrgica , Diabetes Mellitus Tipo 2 , Pé Diabético , Pontuação de Propensão , Humanos , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Pé Diabético/mortalidade , Pé Diabético/diagnóstico , Pé Diabético/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Amputação Cirúrgica/mortalidade , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Incidência , Medição de Risco , Fatores de Tempo , Prognóstico , Causas de Morte , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Índice de Gravidade de DoençaRESUMO
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.
Assuntos
Biomarcadores , Pé Diabético , Doença Arterial Periférica , Fósforo , Calcificação Vascular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Feminino , Estudos Transversais , Fósforo/sangue , Calcificação Vascular/sangue , Calcificação Vascular/epidemiologia , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/diagnóstico , Idoso , Fatores de Risco , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/sangue , Doença Arterial Periférica/epidemiologia , Pé Diabético/diagnóstico , Pé Diabético/sangue , Pé Diabético/epidemiologia , Medição de Risco , Biomarcadores/sangue , Prognóstico , Extremidade Inferior/irrigação sanguíneaRESUMO
OBJECTIVE: Annual trends of lower extremity amputation due to end-stage chronic disease are on the rise in the United States. These amputations are leading to massive expenses for patients and the medical system. In Oklahoma, we have a high-risk population because access to care is low, the number of uninsured is high, cardiovascular health is poor, and our overall health care performance is ranked 50th in the country. But we know little about Oklahomans and their risk of limb loss. It is, therefore, imperative to look closely at this population to discover contemporary rates, trends, and state-specific risk factors for amputation due to diabetes and/or peripheral arterial disease (PAD). We hypothesize that state-specific groups will be identified as having the highest risk for limb loss and that contemporary trends in amputations are rising. To create implementable solutions to limb preservation, a baseline must be set. METHODS: We conducted a 12-consecutive-year observational study using Oklahoma's hospital discharge data. Discharges among patients 20 years or older with a primary or secondary diagnosis of diabetes and/or PAD were included. Diagnoses and amputation procedures were identified using International Classification of Disease-9 and -10 codes. Amputation rates were calculated per 1000 discharges. Trends in amputation rates were measured by annual percentage changes (APC). Prevalence ratios evaluated the differences in amputation rates across demographic groups. RESULTS: Over 5,000,000 discharges were identified from 2008 to 2019. Twenty-four percent had a diagnosis of diabetes and/or PAD. The overall amputation rate was 12 per 1000 discharges for those with diabetes and/or PAD. Diabetes and/or PAD-related amputation rates increased from 8.1 to 16.2 (APC, 6.0; 95% confidence interval [CI], 4.7-7.3). Most amputations were minor (59.5%), and although minor, increased at a faster rate compared with major amputations (minor amputation APC, 8.1; 95% CI, 6.7-9.6 vs major amputation APC, 3.1; 95% CI, 1.5-4.7); major amputations were notable in that they were significantly increasing. Amputation rates were the highest among males (16.7), American Indians (19.2), uninsured (21.2), non-married patients (12.7), and patients between 45 and 49 years of age (18.8), and calculated prevalence ratios for each were significant (P = .001) when compared within their respective category. CONCLUSIONS: Amputation rates in Oklahoma have nearly doubled in 12 years, with both major and minor amputations significantly increasing. This study describes a worsening trend, underscoring that amputations due to chronic disease is an urgent statewide health care problem. We also present imperative examples of amputation health care disparities. By defining these state-specific areas and populations at risk, we have identified areas to pursue and improve care. These distinctive risk factors will help to frame a statewide limb preservation intervention.
Assuntos
Amputação Cirúrgica , Doença Arterial Periférica , Humanos , Oklahoma/epidemiologia , Amputação Cirúrgica/tendências , Amputação Cirúrgica/estatística & dados numéricos , Fatores de Risco , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Doença Arterial Periférica/cirurgia , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/diagnóstico , Fatores de Tempo , Medição de Risco , Estudos Retrospectivos , Resultado do Tratamento , Salvamento de Membro/tendências , Adulto , Idoso de 80 Anos ou mais , Adulto Jovem , Pé Diabético/cirurgia , Pé Diabético/epidemiologia , Pé Diabético/diagnóstico , Bases de Dados FactuaisRESUMO
This systematic review and meta-analysis pooled evidence from randomised controlled trials (RCTs) on the effectiveness of educational programs for people with or at risk of diabetes-related foot disease (DFD). A systematic search identified RCTs evaluating the effectiveness of educational programs in preventing or managing DFD. The primary outcome was risk of developing a foot ulcer. Secondary outcomes included any amputation, mortality, changes in cardiovascular risk factors, foot-care knowledge and self-care behaviours. Meta-analyses were performed using random effects models. Risk of bias was assessed using Cochrane's ROB-2 tool. Education programs were tested in 29 RCTs (n = 3891) and reduced risk of a foot ulcer by approximately half although the upper 95% confidence interval (CI) reached 1.00 (odds ratio [OR], OR 0.54; 95% CI 0.29, 1.00, I2 = 65%). Education programs reduced risk of any amputation (OR 0.34; 95% CI 0.13, 0.88, I2 = 38%) and HbA1c levels (standardized mean difference -0.73; 95% CI -1.26, -0.20, I2 = 93%) without affecting all-cause mortality (OR 1.09; 95% CI 0.57, 2.07, I2 = 0%). Education programs mostly significantly improved DFD knowledge (13 of 16 trials) and self-care behaviour scores (19 of 20 trials). Only one trial was deemed at low risk of bias. Previously tested education programs have mostly effectively improved participants' knowledge and self-care behaviours and reduced risk of foot ulceration and amputation. Larger high quality trials with longer follow-up are needed.
Assuntos
Diabetes Mellitus , Pé Diabético , Doenças do Pé , Humanos , Pé Diabético/etiologia , Pé Diabético/prevenção & controle , Amputação CirúrgicaRESUMO
Multiple disciplines are involved in the management of diabetes-related foot disease and a common vocabulary is essential for clear communication. Based on the systematic reviews of the literature that form the basis of the International Working Group on the Diabetic Foot (IWGDF) Guidelines, the IWGDF has developed a set of definitions and criteria for diabetes-related foot disease. This document describes the 2023 update of these definitions and criteria. We suggest these definitions be used consistently in both clinical practice and research, to facilitate clear communication with people with diabetes-related foot disease and between professionals around the world.
Assuntos
Diabetes Mellitus , Pé Diabético , Doenças do Pé , Humanos , Pé Diabético/diagnóstico , Pé Diabético/etiologiaRESUMO
AIMS: Diabetes-related foot disease is a major source of patient burden and societal costs. Investing in evidence-based international guidelines on diabetes-related foot disease is important to reduce this burden and costs, provided the guidelines are focused on outcomes important to key stakeholders and are evidence-based and properly implemented. MATERIALS AND METHODS: The International Working Group on the Diabetic Foot (IWGDF) has published and updated international guidelines since 1999. The 2023 updates were made using the Grading of Recommendations Assessment Development and Evaluation evidence-to-decision framework. This concerns formulating relevant clinical questions and important outcomes, conducting systematic reviews of the literature and meta-analyses where appropriate, completing summary of judgement tables, and writing recommendations that are specific, unambiguous and actionable, along with their transparent rationale. RESULTS: We herein describe the development of the 2023 IWGDF Guidelines on the prevention and management of diabetes-related foot disease, which consists of seven chapters, each prepared by a separate working group of international experts. These chapters provide guidelines related to diabetes-related foot disease on prevention; classification of diabetes-related foot ulcer, offloading, peripheral artery disease, infection, wound healing interventions, and active Charcot neuro-osteoarthropathy. Based on these seven guidelines, the IWGDF Editorial Board also produced a set of practical guidelines. Each guideline underwent extensive review by the members of the IWGDF Editorial Board as well as independent international experts in each field. CONCLUSIONS: We believe that the adoption and implementation of the 2023 IWGDF guidelines by healthcare providers, public health agencies, and policymakers will improve the prevention and management of diabetes-related foot disease, and subsequently reduce the worldwide patient and societal burden caused by this disease.
Assuntos
Pé Diabético , Doenças do Pé , Doença Arterial Periférica , Humanos , Pé Diabético/etiologia , Pé Diabético/prevenção & controle , Cicatrização , Agências InternacionaisRESUMO
BACKGROUND: Offloading treatment is crucial to heal diabetes-related foot ulcers (DFU). This systematic review aimed to assess the effectiveness of offloading interventions for people with DFU. METHODS: We searched PubMed, EMBASE, Cochrane databases, and trials registries for all studies relating to offloading interventions in people with DFU to address 14 clinical question comparisons. Outcomes included ulcers healed, plantar pressure, weight-bearing activity, adherence, new lesions, falls, infections, amputations, quality of life, costs, cost-effectiveness, balance, and sustained healing. Included controlled studies were independently assessed for risk of bias and had key data extracted. Meta-analyses were performed when outcome data from studies could be pooled. Evidence statements were developed using the GRADE approach when outcome data existed. RESULTS: From 19,923 studies screened, 194 eligible studies were identified (47 controlled, 147 non-controlled), 35 meta-analyses performed, and 128 evidence statements developed. We found non-removable offloading devices likely increase ulcers healed compared to removable offloading devices (risk ratio [RR] 1.24, 95% CI 1.09-1.41; N = 14, n = 1083), and may increase adherence, cost-effectiveness and decrease infections, but may increase new lesions. Removable knee-high offloading devices may make little difference to ulcers healed compared to removable ankle-high offloading devices (RR 1.00, 0.86-1.16; N = 6, n = 439), but may decrease plantar pressure and adherence. Any offloading device may increase ulcers healed (RR 1.39, 0.89-2.18; N = 5, n = 235) and cost-effectiveness compared to therapeutic footwear and may decrease plantar pressure and infections. Digital flexor tenotomies with offloading devices likely increase ulcers healed (RR 2.43, 1.05-5.59; N = 1, n = 16) and sustained healing compared to devices alone, and may decrease plantar pressure and infections, but may increase new transfer lesions. Achilles tendon lengthening with offloading devices likely increase ulcers healed (RR 1.10, 0.97-1.27; N = 1, n = 64) and sustained healing compared to devices alone, but likely increase new heel ulcers. CONCLUSIONS: Non-removable offloading devices are likely superior to all other offloading interventions to heal most plantar DFU. Digital flexor tenotomies and Achilles tendon lengthening in combination with offloading devices are likely superior for some specific plantar DFU locations. Otherwise, any offloading device is probably superior to therapeutic footwear and other non-surgical offloading interventions to heal most plantar DFU. However, all these interventions have low-to-moderate certainty of evidence supporting their outcomes and more high-quality trials are needed to improve our certainty for the effectiveness of most offloading interventions.