Non-traumatic Lower Limb Amputation Research Articles

Neutrophil Extracellular Traps (NETs) Are Associated with Type 2 Diabetes and Diabetic Foot Ulcer Related Amputation: A Prospective Cohort Study.

The prevalence of diabetes mellitus and its sequelae has been on the rise, and diabetic foot ulcer (DFU) is the leading cause of non-traumatic lower limb amputation globally. The rising occurrence and financial burden associated with DFU necessitate improved clinical assessment and treatment. Diabetes has been found to enhance the formation of neutrophil extracellular traps (NETs) by neutrophils, and excessive NETs have been implicated in tissue damage and impaired wound healing. However, there is as yet insufficient evidence to clarify the value of NETs in assessing and predicting outcomes of DFU. We designed this prospective study with three cohorts formed from type 2 diabetes mellitus (T2DM) patients with DFU (n = 200), newly diagnosed T2DM patients (n = 42), and healthy donors (n = 38). Serum levels of NETs were detected for all groups, and the prognostic value for DFU-related amputation was analyzed. The results showed that serum NET levels of the DFU group were significantly higher than in the T2DM group (P < 0.05), which also had significantly elevated serum NET levels compared to healthy donors (P < 0.05). Multivariate Cox regression showed that serum NET levels, diabetic foot surgical history, and Wagner grade were the risk factors for amputation (P < 0.05), and these three variables also exhibited the highest coefficient values in additional Lasso Cox regression. For patients with DFU, Kaplan-Meier curves showed that high serum NET levels associated with higher amputation probability (HR = 0.19, P < 0.01) and ROC curve based on NET value showed good validity for amputation (AUC: 0.727, CI 0.651-0.803). Elevated serum NET levels serve as an easily accessible serological prognostic marker for assessing the risk of DFU-related amputation, thereby offering evaluation metrics for healthcare providers. Further investigations are necessary to understand the mechanisms driving this relationship.

Can Early Post-Operative Scoring of Non-Traumatic Amputees Decrease Rates of Revision Surgery?

Background and Objectives: Medical registries evolved from a basic epidemiological data set to further applications allowing deriving decision making. Revision rates after non-traumatic amputation are high and dramatically impact the following rehabilitation of the amputee. Risk scores for revision surgery after non-traumatic lower limb amputation are still missing. The main objective was to create an amputation registry allowing us to determine risk factors for revision surgery after non-traumatic lower-limb amputation and to develop a score for an early detection and decision-making tool for the therapeutic course of patients at risk for non-traumatic lower limb amputation and/or revision surgery. Materials and Methods: Retrospective data analysis was of patients with major amputations lower limbs in a four-year interval at a University Hospital of maximum care. Medical records of 164 patients analysed demographics, comorbidities, and amputation-related factors. Descriptive statistics analysed demographics, prevalence of amputation level and comorbidities of non-traumatic lower limb amputees with and without revision surgery. Correlation analysis identified parameters determining revision surgery. Results: In 4 years, 199 major amputations were performed; 88% were amputated for non-traumatic reasons. A total of 27% of the non-traumatic cohort needed revision surgery. Peripheral vascular disease (PVD) (72%), atherosclerosis (69%), diabetes (42%), arterial hypertension (38%), overweight (BMI > 25), initial gangrene (47%), sepsis (19%), age > 68.2 years and nicotine abuse (17%) were set as relevant within this study and given a non-traumatic amputation score. Correlation analysis revealed delayed wound healing (confidence interval: 64.1% (47.18%; 78.8%)), a hospital length of stay before amputation of longer than 32 days (confidence interval: 32.3 (23.2; 41.3)), and a BKA amputation level (confidence interval: 74.4% (58%; 87%)) as risk factors for revision surgery after non-traumatic amputation. A combined score including all parameters was drafted to identify non-traumatic amputees at risk for revision surgery. Conclusions: Our results describe novel scoring systems for risk assessment for non-traumatic amputations and for revision surgery at non-traumatic amputations. It may be used after further prospective evaluation as an early-warning system for amputated limbs at risk of revision.

Epidemiology of Non-Traumatic Lower Extremities Amputations in West Africa: Nationwide Data from Togo

Non-traumatic lower limb amputation (NT-LLA) has consequences at individual and public health levels. Population based studies in sub-Saharan Africa are scarce and often related to single centre series. This study aimed to estimate the incidence of NT-LLA (minor and major) and to describe epidemiological, clinical, and prognostic aspects in Togo. This was a population based observational study conducted among all patients who underwent NT-LLA. Traumatic amputations were excluded. Sociodemographic, clinical, and work up data were collected from clinical files in any Togolese health centre from 1 January 2016 to 31 December 2021. Incidence rates were adjusted for age. Over the six year period, 352 patients (59% males) underwent NT-LLA (mean ± standard deviation age 60 ± 15.7 years). The average age adjusted incidence rate of NT-LLA was 8.5 per million/year (95% confidence interval [CI] 7.6 - 9.4). Men were 1.7 times more likely to undergo a NT-LLA than women. The relative risk of NT-LLA was 48 times higher in patients with diabetes than in patients without diabetes. Around 61.0% of the NT-LLAs occurred within the 50 - 74 age group and 54.3% had diabetes mellitus. Among amputees, 54.5% had a diagnosis of peripheral artery disease (PAD) and 52.8% had diabetic ulcers, with co-existence of several factors. Less than 5% of participants had a history of smoking tobacco. Average length of hospital stay was 12 days. The in hospital mortality rate was 8.8% (9.0% for major, 6.7% for minor amputations). Only 18.2% had duplex ultrasound performed and 1.7% angiography prior to amputation. No patient underwent vascular intervention prior to amputation. This is the first study to report nationwide and contemporary epidemiological data on NT-LLAs in West Africa, highlighting several specificities. Large scale interventions are needed to ameliorate the care of diabetes and PAD and improve facilities for optimal management of patients at risk of amputation in Africa.

Ambulatory Status before Diabetic Foot Ulcer Development as a Predictor of Amputation and 1-Year Outcomes: A Retrospective Analysis.

Up to 25% of people with diabetes develop a diabetic foot ulcer (DFU) during their lifetime, which precedes approximately 85% of nontraumatic lower limb amputations. Diabetic limb salvage has been at the forefront of recent research, as major amputation is associated with 5-year mortality rates of 52%-80%. We sought to determine if ambulatory status before DFU diagnosis is predictive of amputations and outcomes within 1 year, as no studies have directly examined this relationship. A retrospective review of patients diagnosed with DFUs from January 2011 to December 2021 was performed. Patients aged 18 years or more with type II diabetes were included. Ambulatory status was defined as the primary form of mobility reported by the patient before development of DFU, and was categorized as independent ambulation, ambulatory with assisting device (AWAD), or nonambulatory (NA). Statistical analyses included χ2, multinomial, and multivariable logistic regressions. After review, 506 patients were included. NA (OR = 5.10; P = 0.002) and AWAD status (OR = 2.77; P = 0.01) before DFU development were predictive of major (below or above-knee) amputation during hospitalization, emergency department visits within 30-days (NA: OR = 4.19; P = 0.01, AWAD: OR = 3.09; P = 0.02), and mortality within one-year (NA: OR = 4.19; P = 0.01, AWAD: OR = 3.09; P = 0.02). AWAD status was also associated with increased risk of hospital readmission (OR = 2.89; P < 0.001) within 30-days and any amputation (OR = 1.73; P = 0.01) within 1 year. In patients with DFUs, NA and AWAD status were predictive of major amputation during hospitalization and are associated with poorer 1-year outcomes, including mortality. Ambulatory status assessment may be used to inform DFU treatment approaches.

Diabetic Foot Ulcers and Their Surgical Management: Our Experience at Hayatabad Medical Complex, Peshawar.

Surgeons face a therapeutic challenge while treating diabetic foot ulcers (DFUs), particularly in underdeveloped nations with limited healthcare resources and a high proportion of patients who arrive at medical institutions with advanced foot ulcers. To assess the effectiveness of treatment in patients with DFUs and to demonstrate how early surgical intervention and appropriate bedside medical care can improve results. This prospective study was carried out at Hayatabad Medical Complex, Peshawar, Pakistan, to assess how DFUs changed over a period between November 2021 and December 2022 at the wards and at the outpatient department of endocrinology and general surgery. A diabetic patient's foot is first screened for ulceration in the endocrinology department, and only those with active ulcers are referred to the surgical department. According to the Wagner classification, there were six (13.6%) cases in grade I, 11 (25%) in grade 2, 10 (22.7%) in grade 3, 13 (29.5%) in grade 4, and four (9%) in grade 5. Among comorbidities, a family history of diabetes mellitus was noted in 25 (56.8%) patients, followed by tobacco chewing and alcohol in 10 (22.7%) and hypertension in nine (20.4%) patients. Diabetes foot ulceration is the most common reason for non-traumatic lower limb amputation in people with diabetes mellitus and is a significant cause of morbidity and mortality.

#2889 CAROTID PLAQUE THICKNESS PREDICTS CARDIOVASCULAR EVENTS AND DEATH IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Classical risk scoring systems highly underestimate the elevated risk of cardiovascular (CV) disease in chronic kidney disease (CKD) (1). Coronary artery calcification score (CACS) has improved prediction of CV events in patients with CKD (2). Recently, ultrasound examination of the carotid arteries with measurement of maximal carotid plaque thickness (cPTmax) has demonstrated similar predictive value as CACS in the general population (3). This is the first study to investigate whether cPTmax can predict CV events in patients with CKD. We also compared the predictive value of cPTmax and CACS. Method Two hundred patients with CKD stage 3 from the Copenhagen CKD Cohort underwent ultrasound scanning of the carotid arteries in 2016 to 2017. The assessment consisted of finding areas with plaque, if there were any, and measuring the thickest part of the plaque, cPTmax, defined as the radial distance from the media–adventitia interface to the intima–lumen interface towards the center of the arterial lumen. For the statistical analysis only the anatomical side with the highest cPTmax was used. The intra-observer coefficient of variation was 9%. Based on the distribution of cPTmax, the subjects were divided into 3 groups: No plaques, cPTmax 1.0-1.9 mm and cPTmax &amp;gt; 1.9 mm (the median cPTmax in the group was 1.9 mm). One hundred and seventy-five of the patients underwent a non-contrast CT scan of the coronary arteries, which was used to measure CACS. The patients were divided into the following categories: no calcification, CACS = 1-100, CACS = 101-400 and CACS &amp;gt; 400. The follow-up time was time elapsed from the ultrasound scan and until a predefined end-date or the time of first event, which was defined as a composite of major CV events or death of any cause (MACE). CV events included: myocardial infarction, percutaneous coronary intervention, coronary bypass surgery, ischemic stroke, carotid endarterectomy or stenting, non-traumatic lower limb amputation, lower limb artery bypass graft, percutaneous transluminal angioplasty of a lower limb. Results The average follow-up time was 5.4 years. Twenty patients (10%) experienced a CV event and 28 patients died (14%). In a crude absolute risk plot (Figure), patients with no plaque at baseline showed the lowest risk of MACE, whereas patients with cPTmax 1.0-1.9 mm showed an intermediate risk, and patients with cPTmax &amp;gt;1.9 mm the highest risk (log rank test, p&amp;lt;0.0001). When using the group of patients with no plaque as the reference in an unadjusted Cox-regression analysis, the hazard ratio (HR) of MACE was significantly increased in patients with cPTmax = 1.0-1.9 mm (HR = 3.8 (CI: 1.5 - 9.9), p&amp;lt;0.01) and in patients with cPTmax &amp;gt;1.9 mm (HR = 8.4 (CI: 3.4 – 20.8), p&amp;lt;0.0001). After adjustment for age, sex, diabetes, smoking, hypertension, and hypercholesterolemia, only patients with cPTmax &amp;gt;1.9 mm showed a significantly increased HR of MACE (HR 3.2, CI 1.1-9.3), p&amp;lt;0.05. We applied C-statistics to assess which imaging technique had the best predictive value of MACE in this cohort. The differences in C-statistics were similar for the two imaging methods: cPTmax (0.21, p &amp;lt; 0.0001) and CACS (0.21, p &amp;lt; 0.0001). Conclusion Our results indicate that measurement of cPTmax may be a useful method for prediction of MACE in CKD. In the present small study, cPTmax and CACS showed equal potential for predicting MACE Ultrasound imaging is more convenient, more widely available, and without radiation exposure. To further assess the value of cPTmax in predicting CV risk in CKD, a larger study of patients with all CKD stages is needed.

Perilesional injections of human platelet lysate versus platelet poor plasma for the treatment of diabetic foot ulcers: A double-blinded prospective clinical trial.

Diabetic foot ulcer (DFU) is a major cause of morbidity, non-traumatic lower limb amputation in diabetic patients and a high-cost burden on the healthcare system. New therapeutic products are increasingly tested. Platelet-rich plasma (PRP) and human platelet lysate (hPL) are reported to be useful. This trial was conducted to test whether the healing effect of hPL in chronic DFU was due to plasma or platelet lysates in a prospective double-blind design. Autologous PRP was obtained from citrated blood, lysed, and used as drug 1 (active product). The platelet-poor plasma (PPP) was used as a drug 2 (placebo). Ten patients were enrolled in arm 1 and 9 in arm 2. The drugs were injected perilesionally every 2 weeks for a total of sixinjections. Adverse events were recorded until Week 14. The DFUs were scored per the Texas and Wegner systems. No patient showed any major adverse events. Some reported local pain post-injection. Wound healing was achieved in the hPL group in 9/10 of patients at a mean of 35.1 days. In the PPP group, no patient had healed by Day 84. The difference was statistically significant at P < 0.00001. We conclude that autologous hPL is safe and highly effective in healing chronic DFU and is superior to autologous PPP.

Epidemiology and Outcome of Nontraumatic Lower Limb Amputations.

In order to create a solid evidence base for the development of improved management methods, this study was performed to describe the epidemiology and outcome of nontraumatic lower limb amputations (LLAs). This descriptive case series was conducted over a period of 4 years. It included all patients of both sexes and all ages who underwent LLAs for nontraumatic indications. There were a total of 217 patients with 136 (62.67%) men and 81(37.32%) women. The age range was 7 to 71 years, with a mean of 54.25 ± 11.49 years. The most common indication for amputation (41.47%) was diabetic foot gangrene. The most common level of amputation (48.29%) was below knee amputation. Patients with diabetic foot gangrene, malignant tumors, and chronic neuropathic ulcers with osteomyelitis constituted the bulk of the amputees. Diabetes mellitus, obesity, and hypertension were the commonest comorbidities identified among them. Public awareness and education would ensure prompt and early health seeking at the appropriate time and help to prevent the need for major amputations in many instances. The amputees' improved reintegration into society and ability to become contributing members of society would be ensured by the provision of vigorous rehabilitation.

Prevalence and grade of diabetic peripheral neuropathy among known diabetic patients in rural Uganda.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). Approximately 50% of diabetic patients are estimated to develop DPN, depending on disease duration and diabetic control. Early diagnosis of DPN will avoid complications, including non-traumatic lower limb amputation, which is considered the most debilitating complication, as well as significant psychological, social, and economical problems. There is a paucity of literature on DPN from rural Uganda. This study aimed to deliver the prevalence and grade of DPN among DM patients in rural Uganda. A cross-sectional study that recruited 319 known DM patients was conducted in an outpatient clinic and a diabetic clinic at Kampala International University-Teaching Hospital (KIU-TH), Bushenyi, Uganda, between December 2019 and March 2020. Questionnaires were used to obtain clinical and sociodemographic data, a neurological examination was carried out to assess the DPN, and a blood sample was collected from each participant (for random/fasting blood glucose and glycosylated hemoglobin analyses). Data were analyzed using Stata version 15.0. The sample size was 319 participants. The mean age of study participants was 59.4 ± 14.6 years and there were 197 (61.8%) females. The prevalence of DPN was 65.8% (210/319) (95% CI 60.4% to 70.9%), and 44.8% of participants had mild DPN, 42.4% had moderate DPN, and 12.8% had severe DPN. The prevalence of DPN at KIU-TH was higher among DM patients and its stage might have a negative impact on the progression of Diabetes Mellitus. Therefore, clinicians should consider neurological examination as a routine during assessment of all DM patients especially in rural areas where resources and facilities are often limited so that complications related to Diabetic mellitus will be prevented.

The effect of amputation level on patient mental and psychological health, prospective observational cohort study.

Non-traumatic lower limb amputation is a commonly performed surgical procedure and is associated with a high prevalence of psychological morbidity including anxiety and depression. Many risk factors have been identified, including the indication for amputation, perioperative pain and sociodemographic factors. The aim of this study was to identify whether level of amputation has an impact on this psychological morbidity. A prospective observational study was conducted in a tertiary vascular unit including all adult non-traumatic amputations performed during a 6 month period. The Hospital Anxiety and Depression Scale (HADS) was used to score anxiety and depression pre and postoperatively. 49 patients met the inclusion criteria (22 trans-femoral amputations (AKA) and 27 trans-tibial amputations (BKA)). HADS scores for anxiety and depression were high in both groups both pre and postoperatively. A higher level of anxiety was noted in the BKA group, significantly decreasing postoperatively (p<0.05). No other statistically significant differences were found between the two groups. In non-traumatic amputations, there appears to be a higher rate of pre-operative anxiety in patients undergoing trans-tibial amputation compared with trans-femoral amputees. However, the level of amputation does not appear to have a significant effect on psychological status of patients with high rates of depression and anxiety demonstrated in both groups.

Engineering diabetic human skin equivalent for in vitro and in vivo applications

The prevalence of diabetes is increasing worldwide. Diabetes contributes to 70% of all non-traumatic lower-limb amputations, which are directly caused by diabetic foot ulcers (DFU) that are difficult to heal. Non-healing diabetic ulcers represent one of modern society’s most difficult medical challenges. One of the promising initiatives to treat DFU is the grafting of autologous skin or stimulating the skin cells at the edge of the wound to proliferate and close the wound. The present study was to engineer a diabetic human skin equivalent (DHSE) that contains fibroblasts and keratinocytes extracted from the skin collected from diabetic patients. The DHSE was used to investigate whether exposure to low-intensity electrical stimulation (ES) could promote diabetic cell activity. The ES was generated by a direct current (DC) electric field of 20 or 40 mV/mm. We demonstrated that the fibroblasts and keratinocytes could be extracted from older diabetics, cultured, and used to engineer DHSE. Interestingly, the exposure of DHSE to ES led to a structural improvement through tissue stratification, increased Ki-67 expression, and the deposition of basement membrane proteins (laminin and type IV collagen). The DHSE exposed to ES showed a high level of keratin 5 and 14 expressions in the basal and supra-basal layers. The keratinocyte proliferation was supported by an increased secretion of the keratinocyte growth factor (FGF-7). Exposure to ES decreased the activity of metalloproteinases (MMP) 2 and 9. In conclusion, we extracted keratinocytes and fibroblasts from the skin of diabetic-old donors. These cells were used to engineer skin equivalents and demonstrate that ES can promote diabetic wound healing. This DHSE can be a promising tool for various in vitro studies to understand the wound healing mechanisms under chronic inflammatory conditions such as diabetes. The DHSE could also be used as an autologous substrate to cover the DFU permanently.

Role of Jalauka Avacharan (Leech Therapy) in the Management of Non-Healing Ulcer: A Case Study

Non-healing ulcers are a serious health issue that affects people all over the world. They are expensive in terms of both human and material resources. Unavoidable and harmful to the lower limb, non-healing ulcers are a leading factor in non-traumatic lower limb amputations. Numerous studies have examined the potential effects of medicinal leech therapy (MLT), also known as hirudotherapy or Jalaukavcharan in Ayurveda on a variety of illnesses, including Skin disorders and inflammatory diseases, as well as various surgical ailments. Despite the lengthy history of complementary health practises, contemporary medicine has only recently focused on their potential mechanisms of action. Many bioactive compounds, including antistasin, eglins, guamerin, hirudin, saratin, and bdellins, as well as complement and carboxypeptidase inhibitors, are secreted by leeches. In addition to extracellular matrix degradative and antibacterial actions, they exhibit analgesic, anti-inflammatory, platelet inhibitory, anticoagulant, and thrombin regulating properties. However, with more research, the range of effects may broaden. The method has been shown to be affordable, efficient, simple to use, and effective. The aim of this study to evaluate the effectiveness of Jalaukavcharan to promote the healing processes in non-healing ulcer. The study was an observational single case design without control group; it was carried out in department of Shalya of Rajiv Gandhi Post Graduate Ayurvedic College, Paprola

The Efficacy of Autologous Platelet-Rich Gel and Traditional Chinese Medicine in Diabetic Foot Treatment: A Parallel Randomized Controlled Clinical Trial

Diabetic foot (DF) is a prevalent metabolic infection. DF wounds are the basis for all cases of nontraumatic lower limb amputations in diabetes. DF care approaches include debridement of wound, pressure relief in the wounded area, proper wound, infection, and ischemia management. However, there is a need for research to develop more effective therapeutic approaches. This study investigated the effectivity and safety of autologous platelet-rich gel combined with conventional treatment and traditional Chinese medicine (TCM) in DF ulcer therapy. Sixty DF ulcer patients were divided into treatment and control groups of 30 patients each. The treatment group involved a combination of autologous platelet-rich gel, conventional treatment, and TCM. The control group was only treated with a combination of conventional therapy and TCM. Laboratory variables, including platelets, hemoglobin (Hb), albumin, and HbA1c, were analyzed and compared between the treatment and the control groups at baseline and endpoint. Healing area, volume, and rates were compared in both groups. Basic patients' data and the wound conditions had no significant difference between the treatment and the control group. The treatment and control groups cure rates were 93.3% vs. 50%, respectively. The healing rate per 2weeks was significantly higher in the treatment than in the control group (0.78±0.05 vs. 0.43±0.04). There was no statistically significant difference in the platelets, Hb, albumin, and HbA1c levels in the treatment and control groups. Autologous platelet-rich gel combined with conventional treatment and TCM is effective and safe for DF ulcer treatment.

Feasibility of repeated session error-augmentation gait training for people with nontraumatic transtibial amputation.

Spatiotemporal gait asymmetries are a persistent problem for people with non-traumatic lower-limb amputation. To date, there is limited knowledge of multi-session gait training interventions targeting step length symmetry after non-traumatic amputation. The objective was to evaluate the feasibility and efficacy of an eight-session, treadmill-based error-augmentation gait training (EAT) protocol to improve spatiotemporal gait asymmetry in people with non-traumatic transtibial amputation (TTA). Pre-post, single group. Methods: The EAT protocol involved eight training sessions (twice per week, four weeks) of supervised split-belt treadmill walking with asymmetrical belt speeds for five, three-minute sets each session. Step length symmetry during overground walking at a self-selected gait speed was assessed prior to, weekly, and one-week after the EAT protocol. Feasibility outcomes included protocol fidelity, safety, participant acceptability, and efficacy. Seven of the eight participants (87.5%) completed the intervention at the prescribed dose. One participant developed a skin blister on their residual limb, which was possibly related to the intervention. No falls, musculoskeletal injuries, or increases in pain occurred. Participants rated EAT as acceptable based on scores on the Intrinsic Motivation Inventory - Interest/Enjoyment subscale (6.6 ± 0.5; mean ± SD). Average between-limb step length Normalized Symmetry Index improved (was reduced) one-week following EAT (2.41 ± 6.6) compared to baseline (5.47 ± 4.91) indicating a moderate effect size (d=0.53). An eight session EAT program delivered over four weeks using a split-belt treadmill is feasible for people with unilateral non-traumatic TTA and may reduce step length asymmetry up to a week after intervention.

Assessing the external validity of the SAFEHEART risk prediction model in patients with familial hypercholesterolaemia in an English routine care cohort

Background and aimsThe SAFEHEART tool has shown good discrimination in predicting cardiovascular events in a bespoke genotyped cohort with familial hypercholesterolaemia (FH). We assessed whether the tool could aid clinical decision making in an English routine care cohort with FH. MethodsA historical (2000–2017) open cohort of 3643 participants aged 18–79 years and ≥6-months since FH diagnosis was derived from the Clinical Practice Research Datalink. Individual 10-year cardiovascular risks were predicted using the SAFEHEART model, with multiple imputation used to manage missing data. Outcomes were the first occurrence of myocardial infarction, coronary revascularisation, ischaemic stroke, carotid revascularisation, peripheral arterial revascularisation, non-traumatic lower limb amputation, or cardiovascular death. Model performance was assessed using standard measures of calibration and discrimination, and decision curve analysis. Results147 outcome events were observed over a median 3.73 (IQR 1.59–6.48) years follow-up. While the model had some discriminatory value (Harrell's c-statistic 0.67 (95% CI 0.61–0.72)), observed outcome risks departed substantially from predicted risks. Calibration slopes for men and women by age decile were 10.09 (95% CI 7.40–12.77) and 2.85 (1.25–4.45), respectively. Recalibration-in-the-large led to closer alignment of observed and predicted risks (recalibration slopes 3.48 (2.55–4.41) and 1.14 (0.50–1.79), respectively). Decision curve analysis suggested the recalibrated model had net benefit at predicted risks of 10–30%. ConclusionsThe original SAFEHEART model has limited generalisability to the routinely identifiable English primary care FH population. With recalibration it appears to have moderate utility at 10–30% predicted risk. It may have greater validity in more bespoke genetically defined FH populations.

A Prospective Cohort Study on Diabetic Foot Infections with Emphasis on Identifiable Risk Factors in Patients Attending Tertiary Care Centre

Background: Foot infections are one of the most commonly observed complications in diabetic patients and are associated with high morbidity and risk of lower extremity amputation. Foot infections account for about 20% of all hospitalizations in people with diabetes and at least 50% of all non-traumatic lower-limb amputations performed annually.&#x0D; Objective: To identify the risk factors in patients with diabetic foot infections attending tertiary care centre.&#x0D; Method: It is a longitudinal prospective study in which patients attending the tertiary care centre with diabetic foot infections meeting the inclusion criteria were enrolled after obtaining the informed consent form.&#x0D; Results and discussion: The results of this study revealed that the overall prevalence of DFI was seen more in males (61.42%) when compared to females (38.57%). The results also showed that the risk of DFI was more with trauma(44.28%) followed by the long duration of DM (28.57%) &gt; wound (15.71%) &gt; uncontrolled DM &amp; prior foot ulcer (5.7%) which indicates a lack of awareness, longer duration of DM, poor glycemic control were the main risk factors causing diabetic foot problems. Conclusion: The results suggest that lack of awareness, poor glycemic control, and long duration of diabetes were the main risk factors causing DFI. Therefore, efforts to prevent infections should be targeted at people with traumatic foot wounds especially those that are chronic and recurrent. Foot care education would be the foremost important way of dealing with this serious problem.&#x0D; Keywords: Morbidity, lower-extremity amputation, trauma, glycemic control.

421-P: Differential Prognostic Burden of Lower-Limb Amputation and Cardiovascular Disease on the Risk of All-Cause Death in People with Type 1 Diabetes

Background: Nontraumatic lower-limb amputation (LLA) and cardiovascular disease (CVD) both result in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of LLA and CVD on the risk of all-cause death in people with type 1 diabetes. Methods: We used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1) absence of CVD (myocardial infarction and/or stroke) nor LLA, 2) history of CVD alone without LLA, 3) LLA alone without CVD or 4) CVD and LLA at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was all-cause death. Results: Among 1169 (male 55%, age 40 ± 13 years, diabetes duration 23 ± years) participants, LLA, CVD or 2 combined conditions were present at baseline in 62 (5.3%) , 49 (4.2%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 3 (26%) subjects during 17-year follow-up. The risk of all-cause death increased in subjects withbaseline history of LLA (adjusted HR 2.26 [95% CI, 1.56 - 3.28], p&amp;lt;0.0001) or CVD (2.00 [1.34 - 3.01], p=0.0008) versus no condition, with an additive effect in those with two combined conditions (5.32 [3.14 - 9.00], p&amp;lt;0.0001) . No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54 - 1.41]) . Compared with no condition, LLA and CVD were similarly associated with reduced life expectancy during follow-up: 3.38 (95% CI, 1.87 -4.88) and 2.79 (1.26 - 4.32) years, respectively. Combined conditions expose to 7. (4.76 - 9.31) less years of life expectancy (all p&amp;lt;0.0001) . Conclusion: LLA and CVD conferred a similar and heavy burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as it is usually done for those with CVD, in terms of management of risk factors, treatments and prevention. Disclosure M.Camoin: None. O.Bourron: Other Relationship; Novo Nordisk. A.Scheen: Advisory Panel; AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. R.Roussel: None. M.Marre: Board Member; AstraZeneca, Consultant; Novo Nordisk. K.Mohammedi: Board Member; Lilly, Novo Nordisk, Sanofi, Research Support; Cyclerion Therapeutics, Inc., Speaker's Bureau; Abbott, AstraZeneca. G.Velho: None. P.Saulnier: Consultant; Grünenthal Group, Research Support; AstraZeneca, Novo Nordisk, Sanofi. L.Potier: Board Member; Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Consultant; AstraZeneca, Sanofi. Y.Abouleka: None. C.Carpentier: None. S.Dubois: None. A.Larroumet: Consultant; Lilly Diabetes, Novo Nordisk, Sanofi. V.Rigalleau: None.

123-OR: Shotgun LC/MS Proteomics Uncovers Potential Markers of Diabetic Foot Osteomyelitis

Osteomyelitis is the leading cause of non-traumatic lower limb amputation in patients living with diabetes. The pathophysiology of diabetic foot osteomyelitis (DFO) is complex and incompletely understood. Using FFPE bone biopsies obtained from patients with suspicious clinical presentation of DFO, we characterized the proteome of bone infection in the diabetic microenvironment. A discovery LC/MS approach was used to identify molecules of interest in subjects diagnosed with DFO versus no DFO based on histopathology findings. In total, 2,135 proteins were identified across 18 DFO and 12 non-DFO TMT labeled samples. After applying data filtering and imputing missing values, 668 proteins were retained for statistical analysis. Of 66 significant proteins (p&amp;lt;0.05) , 8 demonstrated twofold abundance decreases in DFO with respect to non-DFO samples, while 8 proteins were enriched by at least onefold. Ontological analysis suggested that proteins regulating chemokine signaling and integrin mediated cascades are reduced in DFO, potentially resulting in suppression of downstream MAPK pathways, and impairing inflammatory response and cellular adhesion. Our analysis demonstrates that archived FFPE samples are a rich source for elucidating molecular mechanisms associated with diabetic foot infection and may improve accuracy of diagnosis, contribute to novel therapeutic approaches, and uncover new disease biomarkers. Disclosure A.Sherwood: None. K.L.Rubitschung: None. P.Crisologo: None. H.Hwang: None. L.A.Lavery: Advisory Panel; Acera Surgical Inc., Uluru, Research Support; Integra, Smith+Nephew, Tissue tech. O.K.Oz: None. Funding American Diabetes Association (1-17-ICTS-056) ;

Microvascular disease increases the risk of lower limb amputation - A Western Danish cohort study.

Peripheral artery disease is the leading cause of nontraumatic lower limb amputation. Microvascular disease (MVD) increases the risk of lower limb amputation in patients with peripheral artery disease (PAD). We estimated the risk of lower limb amputation associated with MVD and PAD in a Danish cohort. We included every resident without previous lower limb amputation in Western Denmark aged 50-75 years on 1 January 2012 and followed them for 7 years. Participants were stratified by MVD and PAD. We estimated adjusted hazard ratios of lower limb amputation using individuals with no MVD and no PAD as reference. We also provide a sex-specific analysis and estimated the population attributable fraction of the male sex. We included 933,597 individuals, of whom 16,741 had MVD only, 18,217 had PAD only and 1,827 had MVD and PAD. Both MVD only (adjusted hazard ratio 3.36, 95% CI 2.98-3.73) and PAD only (adjusted hazard ratio 7.32, 95% CI 6.62-8.08) increased the risk of lower limb amputation separately. Individuals with MVD and PAD had the highest risk of amputation (adjusted hazard ratio 12.27, 95% CI 10.43-14.80). Men had an increased absolute risk of amputation. The population attributable fraction associated with the male sex was 31%. Microvascular disease and PAD are independently associated with a threefold and sevenfold increase of amputation risk, respectively. Combined, they had an additive effect constituting a 12-fold amputation risk. The amputation risk was higher in men than women, and 3 in 10 amputations were attributed to the male sex.

Differential prognostic burden of cardiovascular disease and lower-limb amputation on the risk of all-cause death in people with long-standing type 1 diabetes

BackgroundCardiovascular disease (CVD) and nontraumatic lower-limb amputation (LLA) each results in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of CVD and LLA on the risk of mortality in people with type 1 diabetes.MethodsWe used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1/absence of CVD (myocardial infarction and/or stroke) nor LLA, 2/history of CVD alone without LLA, 3/LLA alone without CVD or 4/both conditions at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was any death occurring during follow-up, regardless of the causes.ResultsAmong 1169 participants (male 55%, age 40 ± 13 years, diabetes duration 23 ± 11 years), CVD, LLA or both were present at baseline in 49 (4.2%), 62 (5.3%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 304 (26%) participants during 17-year follow-up, corresponding to 18,426 person-years and an incidence rate of 16 (95%CI, 15–18) per 1000 person-years. The risk of death increased in individuals with baseline history of CVD (adjusted HR 2.00 [95% CI 1.34–3.01], p = 0.0008) or LLA (2.26 [1.56–3.28], p < 0.0001), versus no condition, with an additive effect in people with both conditions (5.32 [3.14–9.00], p < 0.0001). No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54–1.41]). Compared with no condition, CVD and LLA were similarly associated with reduced life expectancy during follow-up: 2.79 (95% CI 1.26–4.32) and 3.38 (1.87–4.88) years, respectively. Combined conditions expose to 7.04 (4.76–9.31) less years of life expectancy (all p < 0.0001).ConclusionsCVD and LLA conferred a similar burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as usually recommended for those with CVD, in terms of management of risk factors, treatments and prevention.