Recent Trends in Diabetic and Nondiabetic Neuropathies: A Retrospective Hospital-based Nationwide Cohort Study.

OBJECTIVE: The aim of this study was to evaluate the trends in the incidence of diabetic neuropathy (DN) and nondiabetic neuropathy (non-DN) in a hospital-based cohort between 2010 and 2019 in Romania. METHODS: We retrospectively analyzed cases with a primary or secondary discharge International Classification of Diseases, Tenth Revision, diagnosis code of neuropathy reported throughout Romania. RESULTS: A total of 1 725 729 hospitalizations with a diagnosis of neuropathy (DN, 769 324 - 44.6%, and non-DN, 956 405- 55.4%) were identified. Women accounted for more DN cases (40 0 936- 52.1%), and men accounted for more non-DN cases (63 7 968- 61.0%). The incidence rate showed an increasing trend during the index period, by a mean rate of 4.3%/year for non-DN and 1.4%/year for DN. Type 2 diabetes was responsible for the overall increase in the incidence rate of DN, whereas in type 1 diabetes, the incidence rate decreased; in both types of diabetes, diabetic polyneuropathy was predominant, whereas autonomic neuropathy had an incidence rate of 10 to 20 times lower than polyneuropathy. The incidence rates of non-DNs increased mainly due to inflammatory polyneuropathies (+3.8%) and uremic neuropathy (+10.3%). CONCLUSION: Using a nationally representative database of hospital-admitted cases, we found that the incidence rates of DN and non-DN increased from 2010 to 2019. The main contributors were type 2 diabetes, inflammatory polyneuropathy, and uremic neuropathy.

Determinants of visfatin in type 2 diabetes patients with diabetic kidney disease: Relationship to inflammation, adiposity and undercarboxylated osteocalcin.

BACKGROUND: Visfatin is a proinflammatory molecule with possible actions on glucose metabolism. Interactions to bone metabolism and undercarboxylated osteocalcin (uOC) in diabetic patients (T2DP) with diabetic kidney disease (DKD) have not been reported. MATERIALS AND METHODS: We included 51 incident T2DP with DKD. History, laboratory evaluation, anthropometry, visfatin, uOC were obtained. Fifteen T2DP without DKD were used as controls. RESULTS: Visfatin was similar in DKD patients and controls: 1.56(0.97-3.03) versus 2.04(1.08-3.21) ng/mL, p = 0.51. In controls, visfatin positively correlated with diabetes duration (r = 0.63, p = 0.01) and negatively with uOC (r = -0.57, p = 0.03). In multivariate regression, diabetes duration remained significant (p = 0.01). In patients with DKD, visfatin was positively linked to C reactive protein (r = 0.27, p = 0.05), tricipital skin fold (TSF) (r = 0.41, p = 0.004) and leukocytes (r = 0.37, p = 0.01); the latter two parameters predicted visfatin in multivariate model (p = 0.001). In normoalbuminuric patients, visfatin was linked to body mass index (r = 0.32, p = 0.04), waist circumference (r = 0.42, p < 0.0001), LDL cholesterol (r = 0.33, p = 0.03), serum glucose (r = 0.36, p = 0.03) and glycated hemoglobin (r = 0.41, p = 0.007); there was a trend towards negative correlation to uOC (r = -0.28, p = 0.07); only glycaemia remained significant in multivariate analysis (p = 0.04). Albuminuric patients displayed a positive correlation of visfatin to waist to hip ratio (r = 0.41, p = 0.04) and leukocytes (r = 0.56, p = 0.04); the latter remained significant in multivariate regression (p = 0.005). CONCLUSION: The main determinant of visfatin in T2D patients with DKD is inflammation; in normoalbuminuric patients, a positive link to adiposity and altered glycemic control and a trend towards a negative correlation to uOC was observable; the latter relationship was evident in patients without DKD.

Relationship of endothelial cell selective adhesion molecule to markers of oxidative stress in type 2 diabetes.

BACKGROUND: Endothelial dysfunction is an important contributor to micro and macrovascular complications of type 2 diabetes (T2D) and is reflected by increased systemic oxidative stress. Endothelial cell selective adhesion molecule (ESAM) influences endothelial function. We aimed to assess, for the first time to our knowledge, the relationship of soluble ESAM to markers of systemic oxidative stress. MATERIALS AND METHODS: ESAM, malondialdehyde (MDA) level and catalase activity were determined in 54 T2D patients and 43 controls. RESULTS: T2D patients had significantly higher ESAM when compared to controls (16.07 ± 5.77 µg/L versus 8.57 ± 5.28 µg/L, p < 0.0001), they also had higher MDA level (3.88 ± 1.50 µmol/L vs. 1.58 ± 0.72 µmol/L, p < 0.0001) and lower catalase activity (3.07 (2.63-3.44) U/mg vs. 8.72 (4.55-10.46) U/mg, p < 0.0001). In T2D patients ESAM was inversely related to catalase activity (r = -0.27, p = 0.04), relationship to MDA level was direct but not significant (r = 0.16, p = 0.24). MDA concentration correlated inversely to catalase activity (r = -0.28, p = 0.04). In multiple regression catalase activity remained significantly correlated to ESAM (p = 0.02) and MDA level was significantly related to glycated hemoglobin (p = 0.01); there was trend towards a positive correlation of MDA level to ESAM (p = 0.08). When patients were divided according to oxidative stress, those with increased oxidative stress (defined as MDA concentration > 2.98 µmol/L and catalase activity < 3.38 U/mg) had higher ESAM than the rest of the patients (17.99 ± 5.02 µg/L vs. 14.29 ± 5.94 µg/L p = 0.01). CONCLUSION: ESAM is higher in T2D than in controls and parallels oxidative stress: ESAM is inversely related to catalase activity and higher ESAM is found in T2D patients with increased oxidative stress.

Five-Year Trends of Vascular Disease-Related Amputations in Romania: A Retrospective Database Study.

Background/Objectives: Lower extremity amputations (LEAs) are a burdensome complication of peripheral artery disease (PAD) and/or arterial embolism and thrombosis (AET). We assessed the trends in PAD- and/or AET-related LEAs in Romania. Methods: This retrospective study (2015-2019) analyzed data on minor and major LEAs in hospitalized patients recorded in the National School for Public Health, Management, and Health Education database. The absolute numbers and incidences of LEAs were analyzed by diagnosis type, year, age, sex, and amputation level. Results: Of 38,590 vascular disease-related amputations recorded nationwide, 36,162 were in PAD and 2428 in AET patients. The average LEA incidence in the general population was 34.73 (minimum: 31.96 in 2015; maximum: 36.57 in 2019). The average incidence of major amputations, amputations above the knee, hip amputations, amputations below the knee, and minor amputations was 16.21 (15.62 in 2015; 16.84 in 2018), 13.76 (13.33 in 2015; 14.28 in 2018), 0.29 (0.22 in 2017; 0.35 in 2019), 2.15 (2.00 in 2015; 2.28 in 2019), and 18.52 (16.34 in 2015; 20.12 in 2019), respectively. Yearly PAD- and/or AET-related amputations were significantly higher in men versus women. The overall number of LEAs increased with age, particularly in patients ≥ 70 years. The increase in the total number of amputations was mainly due to a constant rise in minor amputations for both groups, regardless of gender. Conclusions: PAD- and/or AET-related LEAs in Romania increased from 2015 to 2019, with men having a greater incidence than women. Raising awareness and effective management strategies are needed to prevent LEAs.

Lower Extremity Amputation and Peripheral Revascularisation Rates in Romania and Their Relationship with Comorbidities and Vascular Care.

(1) Background: This retrospective Romanian study aimed to calculate the rate of, and comparison between, amputation and revascularisation for patients with either cardiovascular or diabetic comorbidities. (2) Materials: In our hospital-based database, we analysed patient-level data from a series of 61 hospitals for 2019, which covers 44.9% of the amputation patients for that year. The national database is compiled by the national houses of insurance and was used to follow amputations and revascularisations between 2016 and 2021. (3) Results: During the six-year period, the mean number of amputations and revascularisations was 72.4 per 100,000 inhabitants per year for both groups. In this period, a decline in open-surgical revascularisation was observed from 58.3% to 47.5% in all interventions but was not statistically significant (r = -0.20, p = 0.70). The mean age of patients with amputation (hospital-based database) was 67 years. Of these patients, only 5.1% underwent revascularisation in the same hospital prior to amputation. The most common comorbidities in those undergoing amputations were peripheral arterial disease (76.8%), diabetes (60.8%), and arterial hypertension (53.5%). Most amputations were undertaken by general surgeons (73.0%) and only a small number of patients were treated by vascular surgeons (17.4%). (4) Conclusions: The signal from our data indicates that Romanian patients probably have a high risk of amputation > 5 years earlier than Western European countries, such as Denmark, Finland, and Germany. The prevalence of revascularisations in Romania is 64% lower than in the Western European countries.

Diabetes-Related Lower Extremity Amputations in Romania: Patterns and Changes between 2015 and 2019.

Lower extremity amputations (LEAs) are a feared complication of diabetes mellitus (DM). Here we evaluated the recent trends in DM-related LEAs in Romania. We collected data from a national database regarding minor and major LEAs performed between 2015 and 2019 in patients with DM admitted to a public hospital. Absolute numbers of LEAs were presented by year, diabetes type, sex and age; incidence rates of LEAs in the general population were also calculated. Over the study period, 40,499 LEAs were recorded nationwide (83.16% in persons with type 2 DM [T2DM]); on average, the number of LEAs increased by 5.7%/year. This trend was driven by an increased number of LEAs in patients with T2DM; in patients with type 1 DM (T1DM), LEAs decreased over the study period. In patients with T2DM, the increase in minor LEAs was more pronounced than that in major LEAs. The overall number of LEAs showed an increasing trend with age (r = 0.72), which was most pronounced in patients aged ≥70 years. Men had a higher frequency of LEAs than women, regardless of DM type. These data support renewed efforts to prevent and decrease the burden of amputations among patients with DM.

Hospitalization Costs of Lower Limb Ulcerations and Amputations in Patients with Diabetes in Romania.

In this retrospective case-control study conducted in Cluj-Napoca, Romania, we assessed the effect of ulcerations/amputations on hospitalization costs of patients with diabetes. Patients with (Group 1) or without (Group 2) ulcerations/amputations (case-control ratio 3:1) admitted to a single diabetes center between 2012-2017 were included. The effects of hospitalization days, age, duration of diabetes, body mass index and glycated hemoglobin (HbA1c) on total costs was explored using a multivariate linear regression analysis, enter model. Overall, 876 patients were included (Group 1: 682, 323 [47.4%] with amputations; Group 2: 194). Median (interquartile range) total expenses in Group 1 were 40% higher compared to Group 2 (€724 [504; 1186] vs €517 [362; 645], p < 0.001). Significant differences were observed between hospitalization costs (p < 0.001), cost of food (p < 0.001), medication (p = 0.044), drugs administered at the emergency room/intensive care unit (p < 0.001) and other expenses (p = 0.003). Hospitalization costs represented 80.5% of total expenses in Group 1 and 76.3% in Group 2. In multivariate analysis, hospitalization days influenced significantly the total costs in both groups (p < 0.001); in Group 2, the effect of HbA1c was also significant (p = 0.021). Diabetic foot ulcers and subsequent amputations most likely impose a significant economic burden on the Romanian public healthcare system.

HLA Polymorphisms and Haplotype Diversity in Transylvania, Romania.

Transylvania is a historical region in the northwestern part of Romanian with a rather heterogeneous population. Our study is the first to determine human leukocyte antigen (HLA) profiles in a large population sample from this region and to compare them with other European population groups. HLA genes were examined in 2,794 individuals using the Single Specific Primer-Polymerase Chain Reaction (SSP-PCR) and Polymerase Chain Reaction Sequence-Specific Oligonucleotide (PCR-SSO) methods. All samples were tested for the HLA-A locus, 2,773 for HLA-B, 1,847 for HLA-C, and 2,719 for HLA-DRB1 loci. HLA gene frequency data from several European population groups (as presented in studies involving more than 1,000 individuals) served as reference in comparison with the local sample. The distribution of HLA genes in the studied population group was heterogeneous, as the Hardy-Weinberg equilibrium was statistically significant (P value < 0.01). The most common genes found in our sample group were A∗02 (0.27%), B∗35 (0.14%), C∗07 (0.25%), and DRB1∗11 (0.19%). The most common haplotype was A∗01~B∗08~C∗07~DRB1∗03 (1.26% in 1,770 individuals with complete data). This analysis confirmed the known heterogeneity of the Transylvanian population. The study indicates that the European population groups located in close vicinity (those from Serbia, Hungary, Wallachia, and Croatia) are genetically closest to the Transylvanian population.

Skin autofluorescence: Correlation with measures of diabetic sensorimotor neuropathy.

OBJECTIVE: Advanced glycation end products (AGE) contribute to the development of diabetes complications. Their accumulation in skin can be non-invasively assessed by measurement of skin autofluorescence (SAF). Our study investigated whether SAF correlates with measures of diabetic peripheral neuropathy (DPN). METHODS: In a multi-center study (8 centers), 497 consecutive individuals with diabetes mellitus were investigated. Forearm SAF was measured using the AGE Reader (Groningen, The Netherlands). DPN was assessed using the Toronto Clinical Neuropathy Score (TCNS), the Neuropathy Symptoms Score (NSS) and the Neuropathy Disability Score (NDS). RESULTS (MEAN ±â€¯SD): According to the TCNS, SAF (arbitrary units - AU) was increased in individuals with DPN (TCNS > 5): 2.59 ±â€¯0.56 AU compared with those without DPN (TCNS ≤ 5): 2.45 ±â€¯0.53 AU, (p = 0.04) and significantly increased with the severity of DPN (p = 0.028). Higher SAF was detected in individuals with neuropathic deficits (NDS > 2): 2.58 ±â€¯0.56 AU vs. those without deficits (NDS ≤ 2): 2.45 ±â€¯0.53 AU, (p = 0.009) as well as in individuals with symptoms (NSS > 2): 2.54 ±â€¯0.56 AU vs. those without symptoms (NSS ≤ 2): 2.40 ±â€¯0.47 AU, (p = 0.022). CONCLUSIONS: Accumulation of AGE in skin is increased in individuals with DPN and progresses with the severity of DPN. Therefore, SAF measurement, an easy-to-use, quick and non-invasive method, might help in identifying subjects at high risk for having DPN.

Epidemiology of Diabetic Foot Ulcers and Amputations in Romania: Results of a Cross-Sectional Quality of Life Questionnaire Based Survey.

This is a post hoc analysis of quality of life in diabetic neuropathy patients in a cross-sectional survey performed in 2012 in Romania, using the Norfolk QOL-DN in which 21,756 patients with self-reported diabetes were enrolled. This current analysis aims to expand research on the diabetic foot and to provide an update on the number of foot ulcers found in Romania. Of the 21,174 patients included in this analysis, 14.85% reported a history of foot ulcers and 3.60% reported an amputation. The percentage of neuropathy patients with foot ulcers increased with age; the lowest percentage was observed in the 20-29-year age group (6.62%) and the highest in the 80-89-year age group (17.68%). The highest number of amputations was reported in the 70-79-year age group (largest group). Compared to patients without foot ulcers, those with foot ulcers had significantly higher scores for total DN and all its subdomains translating to worse QOL (p < 0.001). This analysis showed a high rate of foot ulcers and amputations in Romanian diabetic patients. It underscores the need for implementation of effective screening and educational programs.

Delay between Onset of Symptoms and Seeking Physician Intervention Increases Risk of Diabetic Foot Complications: Results of a Cross-Sectional Population-Based Survey.

We present a post hoc analysis of 17,530 questionnaires collected as part of the 2012 screening for neuropathy using Norfolk Quality of Life tool in patients with diabetes in Romania, to assess the impact on foot complications of time between the onset of symptoms of diabetes/its complications and the physician visit. Odds ratios (ORs) for self-reporting neuropathy increased from 1.16 (95% CI: 1.07-1.25) in those who sought medical care in 1-6 months from symptoms of diabetes/its complications onset to 2.27 in those who sought medical care >2 years after symptoms onset. The ORs for having a history of foot ulcers were 1.43 (95% CI: 1.26-1.63) in those who sought medical care in 1-6 months and increased to 3.08 (95% CI: 2.59-3.66) in those who sought medical care after >2 years from symptoms of diabetes/its complications onset. The highest ORs for a history of gangrene (2.49 [95% CI: 1.90-3.26]) and amputations (2.18 [95% CI: 1.60-2.97]) were observed in those who sought medical care after >2 years following symptoms onset. In conclusion, we showed that waiting for >1 month after symptoms onset dramatically increases the risk of diabetic foot complications. These results show the need for accessible educational programs on diabetes and its chronic complications and the need to avoid delays in reporting.

Detection of undisclosed neuropathy and assessment of its impact on quality of life: a survey in 25,000 Romanian patients with diabetes.

AIMS: The objective of this cross-sectional survey was to capture undiagnosed neuropathy in Romanian patients with self-reported diabetes using Norfolk QoL-DN as a screening tool and to assess its impact on quality of life (QoL). METHODS: 25,000 Romanian-translated, validated Norfolk QoL-DN questionnaires were distributed between June and December 2012. 21,261 patients who self-reported diabetes and answered questions related to neuropathy, ulceration, gangrene and amputation were included in the analysis. RESULTS: 52% of diabetic patients (n = 6615) who answered "no" to the question "Do you have neuropathy?" had total QoL scores above the cut-off, suggesting the presence of diabetic neuropathy. 13,854 (65.2%) patients answered "yes" to the question "Do you have neuropathy?" and 3,150 (14.8%) reported at least one episode of ulceration, gangrene or amputation. Total QoL score was 3-fold higher (worse) for patients who answered "yes" to the question "Do you have neuropathy?" than for those who answered "no" (38.39 vs. 13.71; p < 0.001) and 1.4-fold worse for patients who reported ulceration, gangrene or amputation than for those who did not report any of these (50.38 vs. 34.87; p < 0.001). CONCLUSIONS: We found a high prevalence of undisclosed diabetic neuropathy in this population and showed that neuropathy severity has an increasing impact on total QoL and its domains.

Circulating osteoprotegerin and asymptomatic carotid atherosclerosis in postmenopausal non diabetic women.

PURPOSE: Osteoprotegerin (OPG) is a bone metabolism regulator but it is also involved in vascular calcification. Its role in the development of atherosclerosis is still a subject of debate. Postmenopausal women seem to have an increased risk for cardiovascular disease. The aim of the study is to evaluate the relationship between serum OPG and asymptomatic carotid atherosclerosis in postmenopausal non-diabetic women. MATERIAL/METHODS: Carotid artery examination was performed in 100 postmenopausal women without diabetes mellitus and overt cardiovascular disease, using B-mode ultrasonography to determine the carotid intima-media thickness (CIMT) and the presence of plaques. Serum OPG was measured in all study participants and its relationship with clinical, biochemical and vascular parameters was evaluated. RESULTS: CIMT correlated with age (r=0.45, p<0.001), years since menopause (r=0.30, p=0.003), abdominal circumference (r=0.25, p=0.01) and OPG (r=0.23, p=0.02). Carotid plaques correlated with age (p<0.001), obesity (p=0.03), abdominal circumference (p=0.03) and CIMT (p<0.001), but not with serum OPG (p=0.86). In regression analyses the independent predictors for CIMT were age (ß=0.717, p<0.001), OPG (ß=0.214, p=0.02), and years since menopause (ß=-0.334, p=0.04) and for the presence of carotid plaques were obesity (p=0.04, OR=3.90), CIMT (p<0.001, OR=6408.86) and smoking (p=0.02, OR=687.93). CONCLUSION: OPG is associated with cardiovascular risk factors, CIMT, but not with the presence of asymptomatic carotid plaques in non diabetic postmenopausal women. OPG may be a marker of cardiovascular risk.