Charcot Foot: An Update on Diagnosis, Treatment, and Areas of Uncertainty.

BACKGROUND AND AIMS: Charcot neuroosteoarthropathy (CN) is considered a rare complication of diabetic neuropathy. Due to its insidious mode of presentation, CN may be difficult to diagnose timely and a high index of suspicion is required from both, the diabetic patient (especially those with neuropathy) and their physicians for the early diagnosis and treatment to prevent major complications. METHODS: We planned a narrative review and searched MEDLINE database to identify evidence regarding CN incidence, treatment options, and recent guidelines. As practitioners do not commonly treat CN, a characteristic clinical case is also presented. RESULTS: The available evidence for diagnosis and treatment remains of low quality. On the one hand, there is an urgent need for action to increase awareness of the disease in both practitioners and people with diabetes. On the other hand, prospective nationwide registries of patients with diabetic neuropathy will help clarify the prognostic factors that may predispose to this complication, and more randomized clinical trials are needed to identify whether medical treatment may improve CN outcomes. For the time being, offloading of the foot to stop the perpetuation of trauma, and inflammation, and importantly to arrest the progression to a deformed nonfunctional foot is the cornerstone of medical therapy of CN. Multidisciplinary assessment between diabetologists and radiologists is fundamental for prompt diagnosis. CONCLUSIONS: To avoid potentially deleterious delays in diagnosis and treatment, every physician should bear in mind that every patient with diabetic neuropathy presenting with a warm swollen foot should be treated as having CN until proven otherwise.

Treatment with Umbilical Cord Blood Platelet Lysate Gel Improves Healing of Diabetic Foot Ulcer.

BACKGROUND: This study was conducted to examine the hypothesis that umbilical cord blood platelet lysate (UCB-PL) gel has a significant impact on the healing rate of DFU. Μethods: In this open-labeled, randomized controlled trial, 110 patients were randomized to treatment with UCB-PL gel (UCB-PL group, n = 52) every three days for one month or dressing with normal saline (control group, n = 58). All participants were followed up for 20 weeks post treatment. Ulcer surface area was assessed with the imitoMeasure application at two, four, and six weeks, and two, four and six months. This study's main outcome was the reduction in ulcer size over the six-month study period. RESULTS: The mean ulcer area at baseline was 4.1 cm2 in the UCB-PL group and 1.7 cm2 in the control group. At six months post treatment, patients on the UCB-PL treatment displayed a significant reduction in ulcer size compared to baseline 0.12 (0-8.16) in contrast to a more modest change in the control group 1.05 (0-24.7). The ulcer area was decreased at the end of the study in 40 patients (97.6%) in the UCB-PL group and 27 (73%) in the control group (Fisher's p = 0.002). CONCLUSIONS: The application of UCB-PL gel in DFU resulted in a significant reduction in ulcer size compared to regular saline dressing.

Diabetic Sensorimotor Polyneuropathy: An Overview on Epidemiology, Risk Factors, Classification, Diagnosis, and Treatment.

Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) is a common complication of diabetes with devastating consequences. Hyperglycaemia is the major aetiological factor, while emerging data demonstrate that cardiometabolic risk factors also contribute to its development. Diagnosis of DSPN involves interview of medical and neurological history, foot inspection, and sensory and motor function examination with specific tests such as temperature and pinprick perception for small nerve fibers, and vibration and light touch assessments for large nerve fibers. Management includes optimised glycaemic control, treatment of cardiovascular risk factors, and symptomatic treatment aiming at improving life quality. This article provides an overview on epidemiology, risk factors, classification, diagnosis and current treatment of DSPN.

The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity.

BACKGROUND: Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. METHODS: This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. RESULTS: Genotype distribution of the studied VDR SNPs in the control group was in Hardy-Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2-5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17-8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. CONCLUSIONS: The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.

7-year follow-up atherosclerotic plaque progression in patients with antiphospholipid syndrome versus diabetes mellitus and healthy controls.

OBJECTIVES: Patients with antiphospholipid syndrome (APS) carry a substantial burden of cardiovascular disease and subclinical atherosclerosis. We aimed to assess a 7-year follow-up atherosclerotic plaque progression in APS patients vs diabetes mellitus (DM) and healthy controls (HC). METHODS: Eighty-six patients with thrombotic APS, 86 with DM and 86 HC (all age- and sex-matched) who underwent a baseline ultrasound of carotid and femoral arteries were invited for a 7-year follow-up ultrasonography examination. We compared atherosclerosis progression among the three groups and examined determinants of plaque progression in APS patients. RESULTS: Sixty-four APS patients (75% females, 43.8% with primary APS), 58 patients with DM and 66 HC were included in the 7-year ultrasound re-evaluation. New plaque was detected in 51.6%, 36.2% and 25.8% of APS, DM and HC subjects, respectively. After adjusting for traditional cardiovascular risk factors (CVRFs) and baseline plaque presence, APS patients showed a 3-fold (OR = 3.07, p= 0.007) higher risk for atherosclerosis progression vs HC and 2-fold (OR = 2.25, p= 0.047) higher risk than DM patients. In multivariate analysis in the APS group, plaque progression was independently associated with systemic lupus erythematosus (SLE) co-existence (OR = 7.78, p= 0.005) and number of CVRFs (OR = 3.02, p= 0.002), after adjusting for disease-related parameters and CVRF-related medications. Sustained low-density lipoprotein target attainment reduced plaque progression risk (OR = 0.34, p= 0.021). CONCLUSION: Half of APS patients develop new atherosclerotic plaques over a 7-year follow-up, having a three-times higher risk vs HC. Concomitant SLE and number of traditional CVRFs are associated with plaque progression, supporting the need for thorough CVRF assessment and control.

Sodium-glucose linked transporter 2 inhibitors in liver cirrhosis: Beyond their antidiabetic use.

Type 2 diabetes mellitus (T2DM) and liver cirrhosis are clinical entities that frequently coexist, but glucose-lowering medication options are limited in cirrhotic patients. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a class of glucose-lowering medication that act independently of insulin, by causing glycosuria in the proximal convoluted tubule. In this review, we aimed to briefly present the main data and to provide insight into the pathophysiology and potential usefulness of SGLT2 inhibitors in cirrhotic patients with or without T2DM. SGLT2 inhibitors have been proven useful as antidiabetic treatment in patients with metabolic liver disease, with most robust data from patients with metabolic dysfunction-associated steatotic liver disease (MASLD), where they also showed improvement in liver function parameters. Moreover, it has been suggested that SGLT2 inhibitors may have effects beyond their antidiabetic action. Accordingly, they have exhibited cardioprotective effects, expanding their indication in patients with heart failure without T2DM. Since decompensated liver cirrhosis and congestive heart failure share common pathophysiological features, namely renin-angiotensin-aldosterone axis and sympathetic nervous system activation as well as vasopressin secretion, SGLT2 inhibitors could also be beneficial in patients with decompensated cirrhosis, even in the absence of T2DM.

Bariatric surgery, through beneficial effects on underlying mechanisms, improves cardiorenal and liver metabolic risk over an average of ten years of observation: A longitudinal and a case-control study.

BACKGROUND: Bariatric surgery has long-term beneficial effects on body weight and metabolic status, but there is an apparent lack of comprehensive cardiometabolic, renal, liver, and metabolomic/lipidomic panels, whereas the underlying mechanisms driving the observed postoperative ameliorations are still poorly investigated. We aimed to study the long-term effects of bariatric surgery on metabolic profile, cardiorenal and liver outcomes in association with underlying postoperative gut hormone adaptations. METHODS: 28 individuals who underwent bariatric surgery [17 sleeve gastrectomy (SG), 11 Roux-en-Y gastric bypass (RYGB)] were followed up 3, 6 and 12 and at 10 years following surgery. Participants at 10 years were cross-sectionally compared with an age-, sex- and adiposity-matched group of non-operated individuals (n = 9) and an age-matched pilot group of normal-weight individuals (n = 4). RESULTS: There were durable effects of surgery on body weight and composition, with an increase of lean mass percentage persisting despite some weight regain 10 years postoperatively. The improvements in metabolic and lipoprotein profiles, cardiometabolic risk markers, echocardiographic and cardiorenal outcomes persisted over the ten-year observation period. The robust improvements in insulin resistance, adipokines, activin/follistatin components and postprandial gastrointestinal peptide levels persisted 10 years postoperatively. These effects were largely independent of surgery type, except for a lasting reduction of ghrelin in the SG subgroup, and more pronounced increases in proglucagon products, mainly glicentin and oxyntomodulin, and in the cardiovascular risk marker Trimethylamine-N-oxide (TMAO) within the RYGB subgroup. Despite similar demographic and clinical features, participants 10 years after surgery showed a more favorable metabolic profile compared with the control group, in conjunction with a dramatic increase of postprandial proglucagon product secretion. CONCLUSIONS: We demonstrate that cardiorenal and metabolic benefits of bariatric surgery remain robust and largely unchanged ten years postoperatively and are associated with durable effects on gastrointestinal- muscle- and adipose tissue-secreted hormones. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04170010.

Arterial stiffness tested by pulse wave velocity and augmentation index for cardiovascular risk stratification in antiphospholipid syndrome.

OBJECTIVES: Cardiovascular disease is a major cause of morbidity and mortality in Antiphospholipid syndrome (APS). Arterial stiffness (ArS) has emerged as a predictor of future cardiovascular events in the general population. We aimed to assess ArS in patients with thrombotic APS versus diabetes mellitus (DM) and healthy controls (HC) and identify predictors of increased ArS in APS. METHODS: ArS was evaluated by carotid-femoral pulse wave velocity (cfPWV) and augmentation index normalized to 75 beats/min (AIx@75) using the SphygmoCor device. Participants also underwent carotid/femoral ultrasound for atherosclerotic plaque detection. We used linear regression to compare ArS measures among groups and assess ArS determinants in the APS group. RESULTS: We included 110 patients with APS (70.9% female, mean age 45.4 years), 110 DM patients and 110 HC, all age/sex matched. After adjustment for age, sex, cardiovascular risk factors and plaque presence, APS patients exhibited similar cfPWV [ß = -0.142 (95% CI -0.514, 0.230), p = 0.454] but increased AIx@75 [ß = 4.525 (95% CI 1.372, 7.677), p = 0.005] compared with HC and lower cfPWV (p < 0.001) but similar AIx@75 (p = 0.193) versus DM patients. In the APS group, cfPWV was independently associated with age [ß = 0.056 (95% CI 0.034, 0.078), p < 0.001], mean arterial pressure (MAP) [ß = 0.070 (95% CI 0.043, 0.097), p < 0.001], atherosclerotic femoral plaques [ß = 0.732 (95% CI 0.053, 1.411), p = 0.035] and anti-ß2-glycoprotein I IgM positivity [ß = 0.696 (95% CI 0.201, 1.191), p = 0.006]. AIx@75 was associated with age [ß = 0.334 (95% CI 0.117, 0.551), p = 0.003], female sex [ß = 7.447 (95% CI 2.312, 12.581), p = 0.005] and MAP [ß = 0.425 (95% CI 0.187, 0.663), p = 0.001]. CONCLUSION: APS patients exhibit elevated AIx@75 vs HC and similar to DM patients, indicating enhanced arterial stiffening in APS. Given its prognostic value, ArS evaluation may help to improve cardiovascular risk stratification in APS.

Effects of Hypericin on Cultured Primary Normal Human Dermal Fibroblasts Under Increased Oxidative Stress.

INTRODUCTION: Wound healing is a dynamic process that begins with inflammation, proliferation, and cell migration of a variety of fibroblast cells. As a result, identifying possible compounds that may improve fibroblast cell wound healing capacity is crucial. Hypericin is a natural quinine that has been reported to possess a wide range of pharmacological profiles, including antioxidant and anti-inflammatory, activities. Herein we examined for the first time the effect of hypericin on normal human dermal fibroblasts (NHDFs) under oxidative stress. METHODS: NHDF were exposed to different concentrations of hypericin (0-20 µg/mL) for 24 h. For the oxidative stress evaluation, H2O2 was used as a stressor factor. Cell viability and proliferation levels were evaluated. Immunohistochemistry and flow cytometry were performed to assess cell apoptosis levels and with confocal microscopy we identified the mitochondrial superoxide production under oxidative stress and after the treatment with hypericin. Scratch assay was performed under oxidative stress to evaluate the efficacy of hypericin in wound closure. To gain an insight into the molecular mechanisms of hypericin bioactivity, we analyzed the relative expression levels of genes involved in oxidative response and in wound healing process. RESULTS: We found that the exposure of NHDF to hypericin under oxidative stress resulted in an increase in cell viability and ATP levels. We found a decrease in apoptosis and mitochondrial superoxide levels after treatment with hypericin. Moreover, treatment with hypericin reduced wound area and promoted wound closure. The levels of selected genes showed that hypericin upregulated the levels of antioxidants genes. Moreover, treatment with hypericin in wound under oxidative stress downregulated the levels of proinflammatory cytokines, and metalloproteinases; and upregulated transcription factors and extracellular matrix genes. CONCLUSION: These findings indicated that hypericin possesses significant in vitro antioxidant activity on NHDF and provide new insights into its potential beneficial role in the management of diabetic ulcers.

Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center.

Familial partial lipodystrophy (FPLD) is a rare syndrome in which a patient's phenotype is not merely dependent on the specific genetic mutation, but it is also defined by a combination of other demographic, environmental and genetic factors. In this prospective observational study in a Greek referral center, we enrolled 39 patients who fulfilled the clinical criteria of FPLD. A genetic analysis was conducted, which included sequence and deletion/duplication analyses of the LMNA and PPRARG genes, along with anthropometric and metabolic parameters. The treatment responses of patients who were eligible for treatment with metreleptin were evaluated at 3 and 12 months. In most of the patients, no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. On the contrary, various changes were detected at the intron level, especially in introns 7 and 10, whose clinical significance is considered unknown. In addition, treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, an effect which was sustained at the 12-month follow-up. More large-scale studies are necessary to clarify the genetic and allelic heterogeneity of the disease, along with other parameters which could predict treatment response.

COVID-19 Outcomes and Diabetes Mellitus: A Comprehensive Multicenter Prospective Cohort Study.

The link between type 2 diabetes (T2D) and the severe outcomes of COVID-19 has raised concerns about the optimal management of patients with T2D. This study aimed to investigate the clinical characteristics and outcomes of T2D patients hospitalized with COVID-19 and explore the potential associations between chronic T2D treatments and adverse outcomes. This was a multicenter prospective cohort study of T2D patients hospitalized with COVID-19 in Greece during the third wave of the pandemic (February-June 2021). Among the 354 T2D patients included in this study, 63 (18.6%) died during hospitalization, and 16.4% required ICU admission. The use of DPP4 inhibitors for the chronic management of T2D was associated with an increased risk of in-hospital death (adjusted odds ratio (adj. OR) 2.639, 95% confidence interval (CI) 1.148-6.068, p = 0.022), ICU admission (adj. OR = 2.524, 95% CI: 1.217-5.232, p = 0.013), and progression to ARDS (adj. OR = 2.507, 95% CI: 1.278-4.916, p = 0.007). Furthermore, the use of DPP4 inhibitors was significantly associated with an increased risk of thromboembolic events (adjusted OR of 2.249, 95% CI: 1.073-4.713, p = 0.032) during hospitalization. These findings highlight the importance of considering the potential impact of chronic T2D treatment regiments on COVID-19 and the need for further studies to elucidate the underlying mechanisms.

The Role of Vitamin D in Health and Disease: A Narrative Review on the Mechanisms Linking Vitamin D with Disease and the Effects of Supplementation.

Vitamin D insufficiency or deficiency (VDD) is a very prevalent condition in the general population. Vitamin D is necessary for optimal bone mineralization, but apart from the bone effects, preclinical and observational studies have suggested that vitamin D may have pleiotropic actions, whereas VDD has been linked to several diseases and higher all-cause mortality. Thus, supplementing vitamin D has been considered a safe and inexpensive approach to generate better health outcomes-and especially so in frail populations. Whereas it is generally accepted that prescribing of vitamin D in VDD subjects has demonstrable health benefits, most randomized clinical trials, although with design constraints, assessing the effects of vitamin D supplementation on a variety of diseases have failed to demonstrate any positive effects of vitamin D supplementation. In this narrative review, we first describe mechanisms through which vitamin D may exert an important role in the pathophysiology of the discussed disorder, and then provide studies that have addressed the impact of VDD and of vitamin D supplementation on each disorder, focusing especially on randomized clinical trials and meta-analyses. Despite there already being vast literature on the pleiotropic actions of vitamin D, future research approaches that consider and circumvent the inherent difficulties in studying the effects of vitamin D supplementation on health outcomes are needed to assess the potential beneficial effects of vitamin D. The evaluation of the whole vitamin D endocrine system, rather than only of 25-hydroxyvitamin D levels before and after treatment, use of adequate and physiologic vitamin D dosing, grouping based on the achieved vitamin D levels rather than the amount of vitamin D supplementation subjects may receive, and sufficiently long follow-up are some of the aspects that need to be carefully considered in future studies.

Effects of Advanced Glycation End Products via Oxidative Stress on Beta Cells: Insights from in vitro and in vivo Studies and Update on Emerging Therapies.

BACKGROUND: Protein, lipid, and nucleic acid glycation reactions begin and continue as a result of persistent hyperglycemia in patients with diabetes mellitus. Advanced glycated end products (AGEs) are a complex group of chemical moieties that are formed as a result of the glycation process and play an important role in the pathogenesis of diabetes mellitus. When AGEs interact with their cellular receptor (RAGE), numerous signaling pathways, including nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), are activated, increasing oxidative stress. OBJECTIVE: The aim of this review was to summarize in vitro and in vivo studies underlining the involvement of AGEs on beta cell dysfunction and death via oxidative stress. METHODS: A literature search of publications published between 1912 and December 2022 was conducted using MEDLINE, EMBASE, and the Cochrane Library, with restrictions on articles written in English. RESULTS: Recent insights have revealed that oxidative stress has a crucial role in the development of beta cell dysfunction and insulin resistance, the major hallmarks of type 2 diabetes mellitus. Studies also revealed that AGEs decrease insulin synthesis and secretion in the pancreatic beta cells and induce cell apoptosis. CONCLUSION: Experimental data have shown that both AGEs and oxidative stress contribute to beta cell dysfunction and development as well as to the progression of diabetic complications. Many anti- AGE therapies are being developed; however, it remains to be seen whether these therapies can help maintain beta cell function and prevent diabetes complications.

Highlights from the 82nd ADA Scientific Sessions and the 58th EASD Meeting on Diabetic Neuropathy.

Diabetic neuropathy is one of the commonest diabetic complications. It affects 30-50% of people with diabetes mellitus (DM) and may cause severe pain and foot ulcers. Distal symmetric polyneuropathy and diabetic autonomic neuropathy are the main manifestations of diabetic neuropathy. The American Diabetes Association's (ADA) 82nd Scientific Sessions took place in June 2022 in New Orleans, Louisiana, and the 58th European Association for the Study of Diabetes (EASD) Annual Meeting was held in September 2022 in Stockholm, Sweden. Herein, we describe interesting studies in the field of diabetic neuropathy presented in these two meetings.

Positive contribution of hydroxytyrosol-enriched wheat bread to HbA1c levels, lipid profile, markers of inflammation and body weight in subjects with overweight/obesity and type 2 diabetes mellitus.

PURPOSE: The aim of the present study was to assess the impact of the daily consumption of bread enriched with hydroxytyrosol on HbA1c and blood lipid levels, inflammatory markers and weight loss. METHODS: Sixty adults with overweight/obesity and type 2 diabetes mellitus (29 male, 31 female) participated in a 12-week dietary intervention based on the Mediterranean diet and consumed daily 60 g of conventional whole wheat bread (WWB) or whole wheat bread enriched with hydroxytyrosol (HTB). Anthropometric characteristics were measured and venous blood samples were collected at baseline and at the end of the intervention. RESULTS: Both groups experienced significant weight loss, body fat and waist circumference decrease (p < 0.001). Nonetheless, a greater body fat mass decrease was observed in the HTB group compared to the WWB group (14.4 ± 1.6 vs 10.2 ± 1.1%, p = 0.038). Significant reductions were also reported in fasting glucose, HbA1c and blood pressure in both groups (p < 0.05). Regarding glucose and HbA1c, greater decreases were observed in the intervention group (101.4 ± 19.9 vs. 123.2 ± 43.4 mg/dL, p = 0.015 and 6.0 ± 0.6 vs. 6.4 ± 0.9%, p = 0.093, respectively). At HTB group, significant reductions in blood lipid, insulin, TNF-αand adiponectin levels (p < 0.05) and a marginally significant reduction in leptin levels (p = 0.081) were also reported. CONCLUSION: Enrichment of bread with HT resulted in significant body fat mass reduction and positive effects on fasting glucose, insulin and HbA1c levels. It also contributed to reductions in inflammatory markers and blood lipid levels. Incorporation of HT in staple foods, like bread, may improve their nutritional profile and, in terms of a balanced diet, may contribute to the management of chronic diseases. TRIAL REGISTRATION: The study was prospectively registered in clinicaltrials.gov (24th May 2021). CLINICALTRIALS: gov Identifier: NCT04899791.

Common Pathogenetic Pathways of Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are two cardinal manifestations of the metabolic syndrome, which is becoming a growing global pandemic and a health care burden. They constitute a pathogenetic duo, with complex interplay through interrelated, but still partly understood, pathophysiological pathways, which mainly involve lipid toxicity (expressed through increased hepatic de novo lipogenesis, hepatic and peripheral insulin resistance, upregulated lipolysis, lipoprotein abnormalities, hyperinsulinemia), impaired autophagy, mitochondrial dysfunction, endoplasmic reticulum stress, adipose tissue dysfunction with a consequent latent inflammatory state, inflammasome activation, genetic and epigenetic factors, altered gut microbiota and finally dietary factors. In this review, based on data from recent studies and focusing mainly on common molecular mechanisms, we will highlight the common pathophysiological grounds and the interplay between NAFLD and T2DM.

Impact of Glucagon-like peptide 1 receptor agonists on peripheral arterial disease in people with diabetes mellitus: A narrative review.

Peripheral arterial disease (PAD) is a common macrovascular complication of diabetes mellitus (DM). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are among the latest class of antidiabetic medications that stimulate insulin synthesis and secretion and have been used for the management of type 2 DM. Apart from the effect on glycaemic control, GLP-1RAs also have a robust impact on weight reduction and have shown favorable effects on cardiovascular morbidity and mortality in cardiovascular outcome trials (CVOTs). The aim of this review was to examine the impact of GLP1-RAs on PAD among people with DM based on CVOTs, randomized controlled trials, observational studies as well as systematic reviews and meta-analyses. Data from retrospective studies and meta-analyses have shown superiority of these agents in comparison with other antidiabetic medications such as sodium-glucose cotransporter type 2 inhibitors and dipeptidyl peptidase-4 inhibitors in terms of PAD-related events. Nevertheless, data from CVOTs regarding the impact of GLP-1RAs on PAD are scarce and hence, safe conclusions regarding their effects cannot be drawn. Further prospective studies are needed to examine the impact of GLP-1RAs on PAD-related incidents including major adverse limb events, lower limb amputations and revascularization procedures.

Evaluation of Vitamin D Levels in Patients With Diabetic Foot Ulcers.

Low vitamin D levels have been associated with several diseases as its receptors are expressed in almost all tissues of the human body. Literature data have shown delayed diabetic foot ulcer (DFU) healing in patients with low vitamin D; however, data on the association between vitamin D levels and DFU in Mediterranean countries are scarce. In this cross-sectional study we examined for differences in serum vitamin D levels between patients with DFU, people with diabetes mellitus (DM) without DFU and healthy individuals in a Southern European country. A total of 96 subjects (33 patients with DFU, 35 patients without DFU and 28 healthy controls) were recruited. Medical and dietary history was obtained and total serum 25-hydroxyvitamin D [25(OH)D] levels were determined. Serum vitamin D levels differed significantly among the three groups of participants; sub-analysis showed that healthy individuals had higher vitamin D levels when compared with patients with and without DFU, while vitamin D levels did not differ between patients with and without DFU (17.9 ± 6.7 vs. 19.8 ± 8.7 ng/mL, P = 0.329, respectively). More than half of patients with DM with or without DFU had vitamin D levels <20 ng/ml. A positive correlation was found between vitamin D and sun exposure duration in participants without DFU. In conclusion, although serum vitamin D levels did not differ between people with and without DFU, the prevalence of deficiency and insufficiency was high in both groups in a Mediterranean country. This finding highlights the need for screening and supplementation with vitamin D in individuals with DM.

The Performance and Interrater Agreement of Vibration Perception for the Diagnosis of Loss of Protective Sensation in People With Diabetes Mellitus.

This study examined the performance of VibraTip for the diagnosis of loss of protective sensation (LOPS) and the interrater agreement of different neurological modalities performed by 3 health care professionals, a consultant diabetologist, a diabetes specialist nurse, and a podiatrist. Diagnosis of LOPS was based on 10-g Semmes Weinstein monofilament testing performed by a consultant diabetologist (reference method), while examination with a 128-Hz tuning form was also performed. The performance of VibraTip for the diagnosis of LOPS was examined using the receiver operating characteristic curves analysis. Interrater agreement was determined by weighted kappa (κ) statistics. Diagnosis of LOPS (%) was 37.5%. Receiver operating characteristic curve analysis showed that VibraTip examination versus 10-g monofilament, both performed by a consultant, could diagnose LOPS (P < .001). Sensitivity, specificity, positive predictive value, and negative predictive value of VibraTip versus 10-g monofilament, both performed by a consultant (value, 95% confidence interval), was 0.705 (0.591-0.803), 0.836 (0.758-0.897), 0.733 (0.642-0.808), and 0.816 (0.757-0.863), respectively. The interrater agreement among the health care professionals for 10-g monofilament, VibraTip, and 128-Hz tuning fork in neurological assessment was good with κ > 0.61. VibraTip can be used as a screening tool for the detection of LOPS. There was good overall agreement in the results of neurological examination using 10-g monofilament, 128-Hz tuning fork, and VibraTip among health care professionals.

Real world data from a multi-centre study on the effects of cilostazol on pain symptoms and walking distance in patients with peripheral arterial disease.

OBJECTIVE: to assess the effects of cilostazol on pain-free walking distance in PAD patients with IC at 3 and 6 months in a real world, prospective, observational study. We included 1015 PAD patients presenting with IC (71.3% men, 93.5% white, mean age 69.2 ± 8.7 years). Patients were followed up for 6 months by their physicians. RESULTS: Cilostazol significantly increased pain-free walking distance by a median of 285 and 387 m at 3 and 6 months, respectively (p < 0.01 for all comparisons). This effect was significant for patients 50-74 years (but not for those aged ≥ 75 years) and independent of smoking status, changes in physical activity, comorbidities and concomitant medication for PAD (i.e., acetylsalicylic acid and clopidogrel). Furthermore, significant reductions were observed in systolic (from 139 ± 16 to 133 ± 14 mmHg; p < 0.001) and diastolic blood pressure (from 84 ± 9 mmHg to 80 ± 10 mmHg; p < 0.001). Smoking cessation and increased physical activity were reported by the majority of participants. In conclusion, cilostazol was shown to safely decrease pain symptoms and improve pain-free walking in PAD patients with IC in a real world setting. Benefits also occurred in terms of BP and lifestyle changes.