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Background This study investigated the effects of weight loss during follow-up on cardiovascular outcomes in a type 2 diabetes cohort and tested interactions with clinical and laboratory variables, particularly physical activity, that could impact the associations. Methods Relative weight changes were assessed in 651 individuals with type 2 diabetes and categorized as ≥5% loss,

Abstract Background Liver stiffness measurement (LSM, which reflects fibrosis) and controlled attenuation parameter (CAP, which reflects steatosis), two parameters derived from hepatic transient elastography (TE), have scarcely been evaluated as predictors of cardiovascular complications and mortality in individuals with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Methods Four hundred type 2 diabetic patients with NAFLD had TE examination (by Fibroscan®) performed at baseline. Multivariate Cox analyses evaluated the associations between TE parameters and the occurrence of cardiovascular events (CVEs) and mortality. TE parameters were assessed as continuous variables and dichotomized at low/high values reflecting advanced liver fibrosis (LSM > 9.6 kPa) and severe steatosis (CAP > 296 or > 330 dB/m). Improvements in risk discrimination were assessed by C-statistic and by the relative Integrated Discrimination Improvement (IDI) index. Results During a median follow-up of 5.5 years, 85 patients died (40 from cardiovascular causes), and 69 had a CVE. As continuous variables, an increasing LSM was a risk marker for total CVEs (hazard ratio [HR]: 1.05; 95% CI: 1.01–1.08) and all-cause mortality (HR: 1.04; 95% CI: 1.01–1.07); whereas an increasing CAP was a protective factor for both outcomes (HR: 0.93; 95% CI: 0.89–0.98; and HR: 0.92; 95% CI: 0.88–0.97; respectively). As dichotomized variables, a high LSM remained a risk marker of adverse outcomes (with HRs ranging from 2.5 to 3.0) and a high CAP was protective (with HRs from 0.3 to 0.5). The subgroup of individuals with low-LSM/high-CAP had the lowest risks while the opposite subgroup with high-LSM/low-CAP had the highest risks. Both LSM and CAP improved risk discrimination, with increases in C-statistics up to 0.037 and IDIs up to 52%. Conclusions Measured by hepatic TE, advanced liver fibrosis is a risk marker and severe steatosis is a protective factor for cardiovascular complications and mortality in individuals with type 2 diabetes and NAFLD.

Abstract Background The prognostic importance of several hematological parameters has been scarcely investigated in type 2 diabetes. So, we aimed to evaluate their prognostic importance for development of complications in a cohort of type 2 diabetes. Methods In a prospective study, 689 individuals with type 2 diabetes had blood red cell, platelet and leukocyte parameters obtained at baseline. Multivariate Cox analyses examined the associations between several hematological parameters (including neutrophyl-to-lymphocyte, lymphocyte-to-monocyte, platelet-to-lymphocyte, and monocyte-to-HDL ratios) and the occurrence of microvascular (retina, renal and peripheral neuropathy) and cardiovascular complications (total cardiovascular events [CVEs], and major adverse CVEs [MACEs]), and all-cause and cardiovascular mortality. Improvements in risk discrimination were assessed by C-statistics and Integrated Discrimination Improvement (IDI) index. Results During a median follow-up of 10.5 years, 212 patients had a CVE (174 MACEs), 264 patients died (131 cardiovascular deaths); 206 had a renal, 161 a retinopathy and 179 patients had a neuropathy outcome. In multivariate-adjusted analyses, the lymphocytes count and lymphocyte-to-monocyte ratio were protective (hazard ratios [HRs]: 0.77 and 0.72, respectively), whereas the neutrophyl-to-lymphocyte and platelet-to-lymphocyte ratios were associated with increased risks (HRs: 1.19 and 1.17) for all-cause mortality. For cardiovascular mortality, the monocytes count, the neutrophyl-to-lymphocyte and monocyte-to-HDL ratios were associated with increased risks and the lymphocyte-to-monocyte ratio was protective. Higher lymphocyte-to-monocyte ratio was protective for renal failure outcome. However, none of them improved risk discrimination. Conclusions Low lymphocytes count and leukocyte ratios that mainly included lymphocytes were predictors of macrovascular complications and mortality in individuals with type 2 diabetes. However, they did not improve risk prediction over traditional risk factors.

Abstract Background The prognostic importance of non-traditional risk factors for peripheral artery disease (PAD) development/progression is scarcely studied in diabetes. We investigated if carotid intima-media thickness (CIMT) and carotid-femoral pulse wave velocity (cf-PWV) added prognostic information beyond traditional cardiovascular risk markers for PAD outcomes. Methods Ankle-brachial index (ABI) was measured at baseline and after a median of 91 months of follow-up in 681 individuals with type 2 diabetes. Multivariate Cox regressions examined the associations between the candidate variables and the outcome. PAD development/progression was defined by a reduction in ABI ≥ 0.15 (to a level

Abstract Background The prognostic importance of an increased visit-to-visit blood pressure variability (BP-VVV) for the future development of micro- and macrovascular complications in type 2 diabetes has been scarcely investigated and is largely unsettled. We aimed to evaluate it in a prospective long-term follow-up study with 632 individuals with type 2 diabetes. Methods BP-VVV parameters (systolic and diastolic standard deviations [SD] and variation coefficients) were measured during the first 24-months. Multivariate Cox analysis, adjusted for risk factors and mean BP levels, examined the associations between BP-VVV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications (total cardiovascular events [CVEs], major adverse CVEs [MACE] and cardiovascular and all-cause mortality). Improvement in risk discrimination was assessed by the C-statistic and integrated discrimination improvement (IDI) index. Results Over a median follow-up of 11.3 years, 162 patients had a CVE (132 MACE), and 212 patients died (95 from cardiovascular diseases); 153 newly-developed or worsened diabetic retinopathy, 193 achieved the renal composite outcome (121 newly-developed microalbuminuria and 95 deteriorated renal function), and 171 newly-developed or worsened peripheral neuropathy. Systolic BP-VVV was an independent predictor of MACE (hazard ratio: 1.25, 95% CI 1.03–1.51 for a 1-SD increase in 24-month SD), but not of total CVEs, cardiovascular and all-cause mortality, and of any microvascular outcome. However, no BP-VVV parameter significantly improved cardiovascular risk discrimination (increase in C-statistic 0.001, relative IDI 0.9%). Conclusions Systolic BP-VVV was an independent predictor of MACE, but it did not improve cardiovascular risk stratification. The goal of anti-hypertensive treatment in patients with type 2 diabetes shall remain in controlling mean BP levels, not on decreasing their visit-to-visit variability.

Background and Aims: It remains unknown whether advanced liver fibrosis is associated with a higher risk of cardiovascular complications in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD).The aim was to evaluate the prognostic value of transient elastography (TE) by Fibroscan® as a predictor of mortality and cardiovascular outcomes in T2DM. Methods: On a prospective study, T2DM patients with no other cause of liver disease except NAFLD underwent TE at baseline and were followed-up for the evaluation of outcomes, including all-cause mortality and occurrence of any cardiovascular event. The associations between TE scores and outcomes were evaluated by Cox regressions adjusted for other potential confounders. Liver stiffness measurement (LSM) and Controlled attenuation parameter (CAP) were evaluated as continuous variables and categorized as advanced fibrosis if LSM >7.9 or 7.2 kPa (M-XL probe) and severe steatosis if CAP>296 dB/m. Results: 403 T2DM patients were included (64% female, mean age of 64±10 yrs) and followed for 94 months until March 2020. 395(98%) of the TE examinations were successful. At baseline, 104(26%) individuals had advanced fibrosis and 150(38%) had severe steatosis. During follow-up, 55(14%) patients died, 55(14%) had cardiovascular events, including 35 with coronary artery disease (CAD). As continuous variables, LSM (↑1 kPa) predicted all-cause mortality (HR 1.05, 95%CI 1.01-1.08,p=0.020) and CAP (↑20 dB/m) was associated with a significant reduced risk of cardiovascular mortality (HR 0.80,95%CI 0.66-0.96,p=0.014) and CAD (HR 0.81,95%CI 0.70-0.95,p=0.007). Increased LSM was associated with a significant 98% excess mortality risk (p=0.025), whereas a higher CAP was associated with a borderline 49% reduced risk (p=0.08). Conclusion: Advanced fibrosis is associated with all-cause mortality, independent of other potential risk factors. Severe steatosis could have some effect in the reduction of cardiovascular mortality and CAD events. Transient elastography may be useful to improve stratification risk of T2DM patients.

Abstract Background The prognostic importance of carotid atherosclerosis in individuals with diabetes is unsettled. We aimed to evaluate the relationships between parameters of carotid atherosclerosis and the future occurrence of micro- and cardiovascular complications in individuals with type 2 diabetes. Methods Ultrasonographic parameters of carotid atherosclerosis, intima-media thickness (CIMT) and plaques, were measured at baseline in 478 participants who were followed-up for a median of 10.8 years. Multivariate Cox analysis was used to examine the associations between carotid parameters and the occurrence of microvascular (retinopathy, renal, and peripheral neuropathy) and cardiovascular complications (total cardiovascular events [CVEs] and cardiovascular mortality), and all-cause mortality. The improvement in risk stratification was assessed by using the C-statistic and the integrated discrimination improvement (IDI) index. Results During follow-up, 116 individuals had a CVE and 115 individuals died (56 from cardiovascular diseases); 131 newly-developed or worsened diabetic retinopathy, 156 achieved the renal composite outcome (94 newly developed microalbuminuria and 78 deteriorated renal function), and 83 newly-developed or worsened peripheral neuropathy. CIMT, either analysed as a continuous or as a categorical variable, and presence of plaques predicted CVEs occurrence and renal outcomes, but not mortality or other microvascular complications. Individuals with an increased CIMT and plaques had a 1.5- to 1.8-fold increased risk of CVEs and a 1.6-fold higher risk of renal outcome. CIMT and plaques modestly improved cardiovascular risk discrimination over classic risk factors, with IDIs ranging from 7.8 to 8.4%; but more markedly improved renal risk discrimination, with IDIs from 14.8 to 18.5%. Conclusions Carotid atherosclerosis parameters predicted cardiovascular and renal outcomes, and improved renal risk stratification. Ultrasonographic carotid imaging may be useful in type 2 diabetes management.

Background The long‐term prognosis of refractory hypertension (RfHT), defined as failure to control blood pressure (BP) levels despite an antihypertensive treatment with ≥5 medications including a diuretic and mineraloreceptor antagonist, has never been evaluated. Methods and Results In a prospective cohort study with 1576 patients with resistant hypertension, patients were classified as refractory or nonrefractory based on uncontrolled clinic (or office) and ambulatory BPs during the first 2 years of follow‐up. Multivariate Cox analyses examined the associations between the diagnosis of RfHT and the occurrence of total cardiovascular events (CVEs), major adverse CVEs, and cardiovascular and all‐cause mortality, after adjustments for other risk factors. In total, 135 patients (8.6%) had RfHT by uncontrolled ambulatory BPs and 167 (10.6%) by uncontrolled clinic BPs. Over a median Follow‐Up of 8.9 years, 338 total CVEs occurred (288 major adverse CVEs, including 124 myocardial infarctions, and 96 strokes), and 331 patients died, 196 from cardiovascular causes. The diagnosis of RfHT, using either classification by clinic or ambulatory BPs, was associated with significantly higher risks of major adverse CVEs, cardiovascular mortality, and stroke incidence, with hazard ratios varying from 1.54 to 2.14 in relation to patients with resistant nonrefractory hypertension; however, the classification based on ambulatory BPs was better in identifying higher risk patients than the classification based on clinic BP levels. Conclusions Patients with RfHT, particularly when defined by uncontrolled ambulatory BP levels, had higher risks of major adverse CVEs and mortality in relation to patients with resistant but nonrefractory hypertension, supporting the concept of refractory hypertension as a true extreme phenotype of antihypertensive treatment failure.

Abstract Diabetic retinopathy (DR) is a chronic microvascular complication associated a worse prognosis. We aimed to evaluate the predictors of development/progression of DR in a cohort of 544 high-risk patients with type 2 diabetes who had annual ophthalmologic examinations over a median follow-up of 6 years. Ambulatory blood pressure (BP) monitoring and aortic stiffness by carotid-femoral pulse wave velocity were performed. Multivariate Cox survival analysis examined the independent predictors of development or progression of DR. During follow-up, 156 patients either newly-developed or worsened DR. Patients who developed/progressed DR had longer diabetes duration, higher ambulatory and clinic BP levels, higher aortic stiffness, and poorer glycemic control than patients who did not developed/progressed DR. After adjustments for baseline retinopathy prevalence, age and sex, a longer diabetes duration (p

Objectives. To investigate treatment adherence in patients with type 2 diabetes and to evaluate its associated factors. Methods. The Summary of Diabetes Self-Care Activities (SDSCA) questionnaire was used to assess treatment adherence. Good adherence was defined as ≥5 days a week in each SDSCA item. Pain, emotional, and physical domains of the SF-36 quality of life questionnaire and the Canadian Occupational Performance Measure (COPM) were also evaluated. Multivariable logistic regressions explored the independent correlates of good general adherence and of specific items of the SDSCA (diet, exercise, and medications). Results. Good adherence was 93.5% for medication use, 59.3% for foot care, 56.1% for blood glucose monitoring, 29.2% for diet, and 22.5% for exercise. Patients with general good adherence had lower BMI, better serum lipid profile, higher values of functional capacity, emotional and pain domains of SF-36, better occupational performance, and lower prevalence of pain or limitation in the upper and lower limbs than patients with worse adherence. The variables associated with good adherence were younger age, lower BMI, presence of macrovascular complications, better occupational performance and emotional domain of SF-36, and higher HDL cholesterol levels. The presence of pain/limitation in the upper limbs was associated with worse adherence. Good medication adherence was associated with longer diabetes duration, lower BMI, and lower HbA1c levels. Higher values of pain and emotional domains of the SF-36 and lower BMI were related to better exercise and diet adherence, while the presence of peripheral neuropathy and joint pain/limitation were associated with worse exercise adherence. Conclusions. Emotional and physical performances are important determinants of good diabetic treatment adherence. Good adherence has beneficial impact on BMI, lipid, and glycemic control.

BackgroundThe prognostic value of C‐reactive protein (CRP) is controversial in type 2 diabetes mellitus. We aimed to assess it in a cohort of high cardiovascular risk diabetic patients. Methods and ResultsCRP was measured at baseline and during the second year of follow‐up in 616 patients. The primary end points were a composite of total fatal and nonfatal cardiovascular events (CVEs), major CVEs, and all‐cause and cardiovascular mortalities. Association between baseline and second‐year CRP with end points were evaluated by multivariable Cox survival analyses. Baseline median CRP was 2.8 mg/L (interquartile range: 1.2–6.0 mg/L), and 47.8% of the patients either increased or persisted with high CRP levels during the first 2 years of follow‐up. After a median follow‐up of 8.4 years, 131 total CVEs occurred (89 major CVEs), and 129 patients died (53 of cardiovascular causes). Baseline and second‐year CRP, analyzed as a continuous variable and dichotomized at >3.0 mg/L, were significantly associated with total and major CVEs occurrence (with adjusted hazard ratios between 1.22 and 1.34 for increments of 1‐SD log of continuous CRP, and between 1.47 and 1.89 for dichotomized CRP), but not with mortality. Additionally, increasing CRP levels or persisting with high levels were associated with a 1.84 (95% CI: 1.10–3.06) excess risk of major CVEs, independent of baseline CRP values. ConclusionsBaseline and serial changes in CRP levels provide cardiovascular risk prediction independent of standard risk factors and glycemic control, and may be useful to refine cardiovascular risk stratification in high‐risk patients with type 2 diabetes mellitus.

Increased aortic stiffness has been recognized as a predictor of adverse cardiovascular outcomes in some clinical conditions, such as in patients with arterial hypertension and end-stage renal disease, in population-based samples and, more recently, in type 2 diabetic patients. Patients with type 2 diabetes have higher aortic stiffness than non-diabetic individuals, and increased aortic stiffness has been correlated to the presence of micro- and macrovascular chronic diabetic complications. We aimed to review the current knowledge on the relationships between aortic stiffness and diabetic complications, their possible underlying physiopathological mechanisms, and their potential applications to clinical type 2 diabetes management.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide. Liver inflammation and fibrosis related to NAFLD contribute to disease progression and increasing liver-related mortality and morbidity. Increasing data suggest that NAFLD may be linked to atherosclerotic vascular disease independent of other established cardiovascular risk factors. Central arterial stiffness has been recognized as a measure of cumulative cardiovascular risk marker load, and the measure of carotid-femoral pulse wave velocity (cf-PWV) is regarded as the gold standard assessment of aortic stiffness. It has been shown that increased aortic stiffness predicts cardiovascular morbidity and mortality in several clinical settings, including type 2 diabetes mellitus, a well-known condition associated with advanced stages of NAFLD. Furthermore, recently-published studies reported a strong association between NAFLD and increased arterial stiffness, suggesting a possible link in the pathogenesis of atherosclerosis and NAFLD. We sought to review the published data on the associations between NAFLD and aortic stiffness, in order to better understand the interplay between these two conditions and identify possible common physiopathological mechanisms.

Cutaneous metastases are rarely the initial manifestation of a previously undiagnosed malignancy and keratoacanthoma-like lesions are a notoriously unusual presentation pattern of cutaneous dissemination of a primary tumor. Herein, we report a 40-year-old woman presenting to our dermatology department with multiple keratoacanthoma-like scalp nodules. Subsequent investigation determined it to be the first manifestation of a disseminated endometrial epithelioid trophoblastic tumor, eventually causing the patient's death. Epithelioid trophoblastic tumor, a rare form of gestational trophoblastic disease, is a recently described neoplasm whose cutaneous metastasis has not been previously reported in the literature.

A 55-year-old man presented with a history of asymptomatic, bilateral, figurate dermatosis consisting of erythematous, annular, linear, andarciform, indurated nodules and plaques on the lateral walls of thorax, flanks, and hypogastrium. His medical history was positive for chronic hepatitis C. Skin biopsy was compatible with the diagnosisof interstitial granulomatous dermatitis. Additionalinvestigation revealed positive rheumatoid factor, antinuclear antibodies, and cryoglobulins. Thepatient started treatment with high-potency topical corticosteroid. After 12 weeks of treatment there was a partial clinical improvement of thedermatosis. Interstitial granulomatous dermatitis exhibits a distinct histopathological pattern with a diverse clinical appearance, which can be associated with autoimmune systemic diseases, neoplasms, several drugs, and infections. Optimal therapy for this condition is yet to be established, but topical corticosteroids have been a mainstay of treatment.

Objective: The objective of this study was to evaluate the effects of body weight variability (BWV) on the occurrence of adverse liver outcomes in individuals with type 2 diabetes (T2D) and metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods: A total of 549 patients with T2D and MASLD had BWV parameters assessed during the first 2 years of follow‐up. The associations between increasing BWV and liver outcomes (clinical cirrhosis or a liver stiffness measurement on transient elastography > 15 kPa, performed after a median of 7 years of cohort entry) were examined by multivariable logistic regressions. Interaction/subgroup analyses were performed according to participants' physical activity during the initial 2‐year period. Results: Individuals were followed up for an additional median 9.7 years, over which 34 liver outcomes occurred (14 with clinical cirrhosis and 20 with liver stiffness measurement > 15 kPa). A 1‐SD increase in weight SD and average real variability was associated with 52% higher (95% CI: 4%–128%) odds of having an adverse liver outcome. Otherwise, in interaction/subgroup analyses, an increased BWV was associated with a higher likelihood of outcomes only in sedentary individuals. Conclusions: Increased BWV was associated with adverse liver outcomes in individuals with T2D and MASLD; however, in those who were physically active, it was not hazardous. [ABSTRACT FROM AUTHOR]