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Today, 463 million people worldwide suffer from diabetes, while 374 million have prediabetes. Unfortunately, this number is expected to double by 2030. However, data about the prevalence of diabetes are influenced by the age group to which it refers. For example, in 2000, 12% of people between 65 and 70 years old as well as 15% of the over 80s were affected by diabetes. Nowadays, the percentage of over 65s with diabetes is about 20-25%, with some geographical differences. Dementia is another critical health problem which is greatly increasing especially among the elderly. While it is well known that diabetes is a significant risk factor for worsening vision, renal function, and increased risk of cardiovascular disease, a number of recent epidemiological evidence reported that diabetes can also be considered a risk factor for cognitive dysfunction. Therefore, while basic research and trials on human models are focused on understanding the pathophysiological mechanisms underlying the development of cognitive decline in individuals with diabetes, in clinical practice the prevention of cognitive decline in the individual with diabetes is critically important. In this paper, we will discuss the pathogenetic mechanisms, clinical approach, and diagnostic strategies that can be used in a clinical-ambulatory setting for early diagnosis of cognitive decline in patients with diabetes.

Background and aims It is known that the highest COVID-19 mortality rates are among patients who develop severe COVID-19 pneumonia. However, despite the high sensitivity of chest CT scans for diagnosing COVID-19 in a screening population, the appearance of a chest CT is thought to have low diagnostic specificity. The aim of this retrospective case–control study is based on evaluation of clinical and radiological characteristics in patients with COVID-19 (n = 41) and no-COVID-19 interstitial pneumonia (n = 48) with mild-to-moderate symptoms. Methods and results To this purpose we compared radiological, clinical, biochemical, inflammatory, and metabolic characteristics, as well as clinical outcomes, between the two groups. Notably, we found similar radiological severity of pneumonia, which we quantified using a disease score based on a high-resolution computed tomography scan (COVID-19 = 18.6 ± 14.5 vs n-COVID-19 = 23.2 ± 15.2, p = 0.289), and comparable biochemical and inflammatory characteristics. However, among patients without diabetes, we observed that COVID-19 patients had significantly higher levels of HbA1c than n-COVID-19 patients (COVID-19 = 41.5 ± 2.6 vs n-COVID-19 = 38.4 ± 5.1, p = 0.012). After adjusting for age, sex, and BMI, we found that HbA1c levels were significantly associated with the risk of COVID-19 pneumonia (odds ratio = 1.234 [95%CI = 1.051–1.449], p = 0.010). Conclusions In this retrospective case–control study, we found similar radiological and clinical characteristics in patients with COVID-19 and n-COVID-19 pneumonia with mild-to-moderate symptoms. However, among patients without diabetes HbA1c levels were higher in COVID-19 patients than in no-COVID-19 individuals. Future studies should assess whether reducing transient hyperglycemia in individuals without overt diabetes may lower the risk of SARS-CoV-2 infection.

BACKGROUND/AIM: The COVID-19 lockdown includes restrictive measures and temporary health system reorganization. Resources were shifted to COVID-19 patients, screening programs were temporary suspended, and oncological care suffered slow-down. The aim of the study was to evaluate the impact of these measures on breast cancer patients. PATIENTS AND METHODS: All breast cancer patients referred to our unit from February 21, 2019 to February 21, 2021 were enrolled. Type of treatments and surgery, TNM, tumor diameter, and predictive and prognostic factors were analyzed. RESULTS: Out of 445 patients with a breast cancer diagnosis, 182 (40.9%) were enrolled in the COVID-19 group (from February 21, 2010 to February 21, 2021). These patients were compared with 263 (59.1%) patients pre-COVID-19. Tumor diameters were bigger in the COVID-19 group. Type of surgery and N staging were statistically significantly different. Extreme advanced disease incidence was significantly different between the groups (2.7% COVID-19 group vs. 0 pre-COVID-19 group, p=0.011). Incidence of post-surgical radiation-therapy was higher in the COVID-19 group. Other variables analyzed were comparable without a statistically significant difference. CONCLUSION: COVID-19 led to increased tumor dimensions, advanced N-staging, and increased need for adjuvant treatments in breast cancer.

Night shift work has been associated with cardiovascular and metabolic disease, endocrine and immunological disorders. Published studies have reported that a reduced total sleep time with sleep-wake cycle alterations were associated with a reduced rate of humoral response following vaccination. Our study aimed to evaluate the association between night shift work and serological status for HBV among workers employed in a university hospital in Rome. We evaluated medical records of 986 HCWs working at Tor Vergata Policlinic of Rome. We screened all study subjects for anti-HBs IgG, anti-HBc IgG and HBsAg. Serological protection for HBV was evaluated in relation to sex, age group, job task, risk setting and night shift work status. Protective titer was found in 856 (86.8%) study participants and the mean titer was significantly high in females, in subjects aged less than 40 years, in night shift workers and in high-risk setting workers. After adjustment for study covariates, night shift work was no longer associated with an HBV-protective titer. This finding suggests that a vaccination strategy for dampening HBV transmission should be carefully addressed in health care workers (HCWs) doing night shift.

Aims Disturbances in circadian rhythms may promote cardiometabolic disorders in rotating night shift workers (r-NSWs). We hypothesized that timed light therapy might reverse disrupted circadian rhythms and glucose intolerance observed among r-NSWs). Methods R-NSWs were randomly assigned to a protocol that included 12 weeks on followed by 12 weeks off light therapy (n = 13; 6 men; mean age, 39.5 ± 7.3 years) or a no-treatment control group (n = 9; 3 men; mean age 41.7 ± 6.3 years). Experimental and control participants underwent identical metabolic evaluations that included anthropometric, metabolic (including oral glucose tolerance tests), lipid, and inflammation-associated parameters together with an assessment of sleep quality and expression of circadian transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs) at baseline, 12 weeks, and 24 weeks of the protocol. Results Twelve weeks of warm white-light exposure (10,000 lx at 35 cm for 30 min per day) had no impact on sleep, metabolic, or inflammation-associated parameters among r-NSWs in the experimental group. However, our findings revealed significant decreases in REV-ERBα gene expression (p = 0.048) and increases in the REV-ERBα/BMAL1 ratio (p = 0.040) compared to baseline in PBMCs isolated from this cohort. Diminished expression of REV-ERBα persisted, although the REV-ERBα/BMAL1 ratio returned to baseline levels after the subsequent 12-day wash-out period. Conclusions Our results revealed that intermittent light therapy had no impact on inflammatory parameters or glucose tolerance in a defined cohort of r-NSWs. However, significant changes in the expression of circadian clock genes were detected in PBMCs of these subjects undergoing light therapy.

The main health effect of exposure to ionizing radiation on the eyes is lens opacities and cataracts. Recent findings have raised questions about the pathogenesis of lenticular damage and the exact threshold dose for the onset of this effect. Occupational dose limits for the lens have been therefore recently reduced to 0.02 Gy/year averaged over 5 years with no single year exceeding 0.05 Gy/year. Healthcare workers can be exposed to ionizing radiation during interventional and other medical procedures. The aim of our study was to evaluate the annual dose to the lens in a large group of healthcare workers exposed to ionizing radiation who are working in a university hospital in Rome and to evaluate a dose-response relationship between lens exposure and the onset of lenticular opacities. We reviewed the exposure data of 702 subjects; the average annual dose to the crystalline lens was calculated using a physical algorithm. Moreover, the clinical records of 107 radiation exposed workers were reviewed: the presence of radiation-compatible opacities were assessed for all operators according to the Lens Opacities Classification System (LOCS) III and Merriam-Focht classification. Annual doses exceeding 0.02 Gy were found in 2.1% of the exposed population. Incipient lenticular opacities were observed in 18.6% of the study population. The presence of alterations was associated with higher lens dose (>0.0092 Gy). Based on our results, optimization of procedures and protection of the lens from ionizing radiation by means of personal protection equipment are strongly recommended in higher exposure scenarios.

This is a prospective and comparative study including 76 consecutive patients performing EUS-FNB for pancreatic and extrapancreatic solid lesions, randomized by alternate allocation to macroscopic on-site evaluation (MOSE) (40 patients) or to a conventional technique (40 patients), with three passes each. MOSE samples were differentiated into score 0: no visible material, score 1: only necrotic or haematic material, score 2: white core tissue ≤ 2 mm, or score 3: white core tissue > 2 mm. The conventional technique consisted in pushing all the needle content into a test tube for evaluation by the pathologist. In both groups, a 22–25 Gauge Franseen-tip needle (Acquire, Boston Scientific Co., Natick, MA, USA) was used. The study evaluated the diagnostic accuracy and adequacy of MOSE compared to the conventional technique and whether MOSE could optimize the number of passes during EUS-FNB. Results: The analysis was performed on 76 patients (38 MOSE, 38 conventional). The overall diagnostic adequacy was 94.7% (72/76) and accuracy was 84.2% (64/76). The diagnostic accuracy was similar in the two groups: MOSE 86.8% (33/38 lesions), vs. conventional 81.6%, 31/38 lesions, p = 0.76). Regarding diagnostic adequacy, the MOSE technique was 97.4% (111/114 passes) compared to 92.1% (105/114 passes) with the conventional technique, p = 0.06. The accuracy increased according to the MOSE score evaluation: it was 43.5%, 65.5% and 78.3% in patients with score 1, score 2, and score 3, respectively. Moreover, if in the first two passes the MOSE score was 2 or 3, the accuracy was 82.6% (20/23), and upon adding a third pass, the accuracy increased to 87% (20/23), which was not significantly different from the general accuracy of the MOSE samples (86.8%) (p = 0.86). Conclusions: The MOSE score showed a comparable diagnostic accuracy to the conventional technique. However, MOSE allows endoscopists to perform an inspective evaluation of the material, tends to perform better than the conventional technique in terms of diagnostic adequacy, and may potentially reduce the number of passes.

The COVID-19 pandemic has led to health, social and economic consequences for public health systems. As a result, the development of safe and effective vaccines, in order to contain the infection quickly became a priority. The first vaccine approved by the Italian Agency for Drugs Authorization (AIFA) was the BNT162b2 mRNA vaccine, developed by BioNTech and Pfizer (Comirnaty). Comirnaty contains a molecule called messenger RNA (mRNA), which is a nucleoside-modified RNA that encodes the SARS-CoV-2 spike glycoprotein. Even if data from phase I suggest that vaccine induced antibodies can persist for up to six months following the second shot of BNT vaccine, data regarding the real duration of immunological protection are lacking. In this study, we aimed to evaluate the duration of serological protection by detecting the presence of anti-S-RBD (receptor-binding domain) antibodies for SARS-CoV-2 among a large group of healthcare workers (HCWs) three months after vaccination. 99% of HCWs had a detectable titre of anti-S SARS-CoV-2 antibodies 90 days after the second vaccine shot. Elderly operators showed significantly lower levels of protective antibodies when compared to the younger ones, thus they could become unprotected earlier than other operators.

Background/Aim: This study investigated the correlation of chest computed tomography (CT), findings, graded using two different scoring methods, with clinical and laboratory features and disease outcome, including a novel clinical predictive score, in patients with novel coronavirus-infected pneumonia (NCIP). Patients and Methods: In this retrospective, observational study, CT scan of 92 NCIP patients admitted to Policlinico Tor Vergata, were analyzed using a quantitative, computed-based and a semiquantitative, radiologist-assessed scoring system. Correlations of the two radiological scores with clinical and laboratory features, the CALL score, and their association with a composite adverse outcome were assessed. Results: The two scores correlated significantly with each other (ρ=0.637, p

Objective To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms. Design and methods We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock. Results Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p Conclusions We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression.

BACKGROUND/AIM: Due to the SARS-CoV-2 pandemic, many scientific committees proposed neoadjuvant therapy (NACT) bridging treatment as a novel strategy and indication. The aim of the study was to evaluate the impact of COVID-19 pandemic on breast cancer patients undergoing NACT. PATIENTS AND METHODS: All breast cancer patients referred to two Breast Units during COVID-19-pandemic were enrolled. RESULTS: Out of 814 patients, 43(5.3%) were enrolled in the COVID-19-group and compared with 94 (7.9%) similar Pre-COVID-19 patients. We observed a reduction in the number of patients undergoing NACT, p=0.0019. No difference was reported in terms of clinical presentation, indications, and tumor response. In contrast, a higher number of vascular adverse events was reported (6.9% vs. 0% p=0.029). Immediate breast cancer reconstructions following invasive surgery suffered a significant slowdown (5.9% vs. 47.7%, p=0.019). CONCLUSION: COVID-19 caused a reduction in the number of patients undergoing NACT, with no changes in terms of indications, clinical presentation, and tumor response. Furthermore, there was an increased incidence of vascular events.

BACKGROUND/AIM: Knowledge of Coronavirus 19 (COVID19) pathogenetic mechanisms is necessary to provide new treatment strategies. This study aims to assess how oncological disease impacts on the clinical course of COVID-19 patients. PATIENTS AND METHODS: From 1st March to 30th April 2020, 96 COVID-19 patients were classified according to clinical outcome as severe (n=67) and moderate (n=29). Demographic data, medical history, admission lymphocytes, procalcitonin (PCT), c-reactive-protein (CRP), D-dimer, and Interleukin-6 (IL-6) were collected. RESULTS: A statistically significant association was found between hypertension (p=0.007) and three or more comorbidities with severe outcomes (p=0.034). No statistical differences were found between the severe and moderate groups with regards to the rate of patients with past oncological history. However, no patient allocated in the moderate group had received oncological treatment within 12 months. Higher values of CRP, IL-6, D-Dimer and lower values of lymphocytes were reported in the severe group (p=0.0007, p=0.00386, p=0.041, and p=0.007, respectively). Using binary logistic regression, higher values of CRP (OR=8.861; p=0.012) and PCT were associated with a higher risk of severe outcome (OR=21.075; p=0.008). Within the oncological population, D-Dimer and IL-6 did not confirm their prognostic significance as in the general population (p>0.05). CONCLUSION: Specific prognostic factors for oncological patients should be designed for COVID-19 clinical practice.

Nurse's job involves staying close to the patient for an extended time period and a high risk of transmission for airborne pathogens, including measles. Previous studies found high rate of operators unprotected for measles. We evaluated the immunization status for measles in nurses of a large hospital in Rome.We retrospectively evaluated the clinical records of nurses working in Tor Vergata hospital who underwent the occupational health screening program. Gender, age, work area and levels measles-specific IgG were evaluated.This study included 358 nurses. 77.7% (217) had a protective measles-specific IgG antibodies level. Protection rate was higher among workers aging 40 years (82.6% vs 68.7%; p0.01). The mean value of the anti-measles IgG was 217.2±91.1 AU/ml. Males showed higher values than females (253.3 vs 214.6; p0.01).Our study revealed a non-protective anti measles IgG level in a high percentage of nurses, even among those working in high risk areas.

Varicella is a potentially serious infectious disease caused by Varicella-Zoster Virus (VZV). In Italy childhood varicella vaccine have gradually introduced into national immunization program since 2003 and from 2017 a two-doses schedule has been stated nationally for all newborns and has become compulsory for school attendance. VZV exposures among healthcare workers (HCWs) and patients can be really dangerous and expensive. According to Centers of Disease Control and Italian national immunization plan health care, institutions should verify that all HCWs have clear evidence of immunity to VZV and should ensure that susceptible subjects will receive 2 doses of VZV vaccine. Currently, the vaccination of HCWs is not compulsory in Italy and the risk of varicella infection among these subjects is not well known. We evaluated the clinical records of 840 HCWs (256 male and 584 female) who underwent the annual occupational screening, from 1st January to 31st August 2018. HCWs were divided into three subgroups according to their age: 18–30, 31–40, and over 40 years old. We compared the mean values of IgG-specific antibodies between the age group through analysis of variance (ANOVA). A total of 784 (93.33%) HCWs were protected for VZV IgG antibodies level. There wasn’t a significant difference between male and female while was found between age group (P

The multidimensional prognostic index (MPI) is a sensitive and specific prognosis estimation tool that accurately predicts all-cause mortality in frail older patients. It has been validated to assess the risk of 1-month to 2-year mortality in frail older patients during hospitalization and after hospital discharge. However, whether the MPI is a valid prognostic tool for follow-up periods of different lengths remains to be validated. To this end, we followed up 80 hospitalized patients (female=37, male 43) at least 75 years of age (mean age=82.6±4.4, range=75-94 years) to assess the 3-month all-cause mortality (mean follow-up=61.0 ± 31.7 months [range 4-90 days]). Accordingly, patients were subdivided into low (MPI-1, score 0-0.33), moderate (MPI-2, score 0.34-0.66) and high (MPI-3, score 0.67-1) mortality risk classes. Moreover, baseline biochemical, inflammatory and metabolic parameters, as well as anamnestic and clinical characteristics, were obtained. Although the MPI-3 score was significantly associated with 3-month all-cause mortality in univariate analysis (HR=5.79, 95%CI=1.77-18.92, p=0.004), a multivariate model indicated that only low albumin (HR=0.33, 95%CI=0.16-0.68, p=0.003) and high IL6 (HR=1.01, 95%CI=1.00-1.02, p=0.010) levels were significantly associated with 3-month all-cause mortality. In conclusion, we suggest that measurement of IL6 as well as albumin, rather than the MPI score, may help in providing tailored therapeutic interventions to decrease short term mortality in older hospitalized individuals.

The objective of this work was to evaluate the magnitude of COVID-19 spread and the related risk factors among hospital nurses employed in a COVID hospital in Rome, before the beginning of the vaccination programmes commenced in 2021. Participants periodically underwent (every 15–30 days) nasopharyngeal swab and/or blood sample for SARS-CoV-2 IgG examination. From 1 March 2020 to 31 December 2020, we found 162 cases of COVID-19 infection (n = 143 nasopharyngeal swab and n = 19 IgG-positive) in a total of 918 hospital nurses (17.6%). Most SARS-CoV-2-infected hospital nurses were night shift workers (NSWs), smokers, with higher BMI and lower mean age than that of individuals who tested negative. After adjusting for covariates, age (OR = 0.923, 95% C.I. 0.895–0.952), night shift work (OR = 2.056, 95% C.I. 1.320–2.300), smoking status (OR = 1.603, 95% C.I. 1.080–2.378) and working in high-risk settings (OR = 1.607, 95% C.I. 1.036–2.593) were significantly associated with SARS-CoV-2 hospital infection, whereas BMI was not significantly related. In conclusion, we found a high prevalence of SARS-CoV-2 infection among hospital nurses at a Rome COVID hospital in the pre-vaccination period. Smoking, young age, night shift work and high-risk hospital settings are relevant risk factors for hospital SARS-CoV-2 infection; therefore, a close health surveillance should be necessary among hospital nurses exposed to SARS-CoV-2.

Older people with type 2 diabetes (T2D) often have several comorbidities and take multiple drugs. This study tested a deprescribing strategy in older T2D patients, replacing a hypoglycemic therapeutic scheme with a single drug combination (iDegLira). In this 6-month, real-world, single-arm, open interventional study, we enrolled patients ≥ 75 years with T2D taking ≥ 2 medications for diabetes. Patients on a basal-bolus insulin regimen (n = 13), on a basal-insulin regimen plus oral glucose-lowering drugs (n = 9), and those on oral glucose-lowering drugs (n = 18) were switched to daily iDegLira. The primary clinical endpoint of the study was an improvement in CASP-19 and/or DTSQ score after 6 months. We also evaluated changes in glucose metabolism, depression, cognitive function, level of independence, and markers of inflammation. Thirty-five patients (12 women, mean age=81.4 y) completed the protocol. Results shown here are given as estimated mean difference (95%CI). DTSQ score improved [11.08 (7.13/15.02); p = 0.0001], whereas CASP-19 did not after 6 months of iDegLira treatment. We observed reductions in BMI [− 0.81 (− 1.27/0.35); p

The O subfamily of forkhead (FoxO) 1 is a crucial regulator of cell metabolism in several tissues, including the heart, where it is involved in cardiac regulation of glucose and lipid metabolic pathways, and endothelium, controlling the levels of some relevant biomarkers in atherosclerotic process. Despite the growing understanding of FoxO1 biology, the metabolic consequences of FoxO1 modifications and its implication in CVD, atherosclerosis and T2DM are still not incompletely described. In this review we discuss how FoxO1 affects cardiovascular pathophysiology and which of its effects should be restrained or enhanced to preserve endothelial and heart functions.

Objective To evaluate results of the ‘pSORRIDI’ experience (which is a prevention campaign to evaluate the prevalence of comorbidities, multidisciplinary needs and appropriateness of the therapeutic approach for comorbidities) in patients already being treated for psoriasis. Methods Telephone interviews were conducted in patients with psoriasis, who then underwent comprehensive evaluation and investigation of comorbidities. If necessary, patients were referred to specialist cardiology, endocrinology and/or rheumatology services. Results Overall, 72.0% (54/75) of patients required a multidisciplinary consultation. Among patients referred to cardiology, therapeutic adjustment was needed in 33.3% (five of 15) patients and a redefined diagnosis in 26.7% (four of 15) cases. Among patients undergoing endocrinology evaluations, therapeutic adjustment and a redefined diagnosis were needed in 61.1% (11/18) and 33.3% (six of 18) patients, respectively; for rheumatology evaluations, therapeutic adjustment and a redefined diagnosis were needed in 76.2% (16/21) and 19.0% (four of 21) of patients, respectively. Conclusions Among patients with psoriasis, there may be a need for an improvement in the diagnosis of underlying comorbid conditions, and in disease management of both psoriasis and any comorbid conditions.

Inflammation plays a role in the development and progression of type 2 diabetes macroangiopathy. Interleukin 33 (IL-33) drives production of Th2-associated cytokines. The soluble form of suppression of tumorigenicity 2 (sST2) acting as a decoy receptor blocks IL-33 and tones down Th2 inflammatory response. We investigated the role of sST2 as a predictor of CV and all-cause mortality in a cohort of patients affected by established atherosclerotic disease. 399 patients with atherosclerotic disease from the Tor Vergata Atherosclerosis Registry performed follow-up every year by phone interview. The primary endpoint was cardiovascular death and the secondary endpoint was death for any other disease. sST2 plasma levels were significantly increased from normal glucose-tolerant patients to patients with history of type 2 diabetes (p

Objective Tissue inhibitor of metalloproteinase 3 (TIMP3) is an extracellular matrix (ECM) bound protein, which has been shown to be downregulated in human subjects and experimental models with cardiometabolic disorders, including type 2 diabetes mellitus, hypertension and atherosclerosis. The aim of this study was to investigate the effects of TIMP3 on cardiac energy homeostasis during increased metabolic stress conditions. Methods ApoE−/−TIMP3−/− and ApoE−/− mice on a C57BL/6 background were subjected to telemetric ECG analysis and experimental myocardial infarction as models of cardiac stress induction. We used Western blot, qRT-PCR, histology, metabolomics, RNA-sequencing and in vivo phenotypical analysis to investigate the molecular mechanisms of altered cardiac energy metabolism. Results ApoE−/−TIMP3−/− revealed decreased lifespan. Telemetric ECG analysis showed increased arrhythmic episodes, and experimental myocardial infarction by left anterior descending artery (LAD) ligation resulted in increased peri-operative mortality together with increased scar formation, ventricular dilatation and a reduction of cardiac function after 4 weeks in the few survivors. Hearts of ApoE−/−TIMP3−/− exhibited accumulation of neutral lipids when fed a chow diet, which was exacerbated by a high fat, high cholesterol diet. Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids. Using whole heart mRNA sequencing, we identified apelin as a putative modulator of these metabolic defects. Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE−/−TIMP3−/− mice. Injection of apelin restored the hitherto identified metabolic defects of lipid oxidation. Conclusion TIMP3 regulates lipid metabolism as well as oxidative stress response via apelin. These findings therefore suggest that TIMP3 maintains metabolic flexibility in the heart, particularly during episodes of increased cardiac stress., Graphical abstract, Highlights • Loss of TIMP3 leads to increased mortality in ApoE−/− mice. • ApoE−/−TIMP3−/− mice reveal arrhythmias and greater myocardial infarction size. • TIMP3 modulates oxidative stress, sphingolipid and lipid pathways in the heart. • Myocardial and circulating apelin levels are reduced by loss of TIMP3. • Supplementation of apelin rescues metabolic phenotype of TIMP3 −/−.

Atherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable.We tested the association of ADAM17 (A Disintegrin and Metallo Protease Domain 17) circulating substrates (sICAM-1, sVCAM-1, sIL6R and sTNFR1) with a second major cardiovascular events [MACEs] (cardiovascular death, peripheral artery surgeries, non-fatal myocardial infarction and non-fatal stroke) in 298 patients belonging to the Vascular Diabetes (AVD) study. To evaluate ADAM17 activity we create ADAM17 score through a RECPAM model. Finally we tested the discrimination ability and the reclassification of clinical models. At follow-up (mean 47 months, range 1-118 months), 55 MACEs occurred (14 nonfatal MI, 14 nonfatal strokes, 17 peripheral artery procedures and 10 cardiovascular deaths) (incidence = 7.8% person-years). An increased risk for incident events was observed among the high ADAM17 score individuals both in univariable (HR 19.20, 95% CI 15.82-63.36, p0.001) and multivariable analysis (HR 3.42, 95% CI 1.55-7.54, p0.001). Finally we found that ADAM17 score significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 9%, p = 0.012) and correctly reclassifying 10% of events and 41% of non-events resulting in a cNRI = 0.51 (p = 0.005).We demonstrated a positive role of ADAM17 activity to predicting CV events. We think that an approach that targets strategies beyond classic cardiovascular risk factors control is necessary in individuals with an established vascular atherosclerosis.

BACKGROUND AND AIMS We aimed to identify novel biomarkers for cardiovascular mortality through a non-targeted metabolomics approach in patients with established atherosclerotic disease from the Tor Vergata Atherosclerosis Registry (TVAR). METHODS We compared the serum baseline metabolome of 19 patients with atherosclerosis suffering from cardiovascular death during follow-up with the baseline serum metabolome of 20 control patients matched for age, gender, body mass index (BMI) and atherosclerotic disease status, who survived during the observation period. RESULTS Three metabolites were significantly different in the cardiovascular mortality (CVM) group compared to controls: 2-hydroxycaproate, gluconate and sorbitol. 2-hydroxycaproate (otherwise known as alpha hydroxy caproate) was also significantly correlated with time to death. The metabolites performed better when combined together rather than singularly on the identification of CVM status. CONCLUSIONS Our analysis led to identify few metabolites potentially amenable of translation into the clinical practice as biomarkers for specific metabolic changes in the cardiovascular system in patients with established atherosclerotic disease.

Insulin resistance and type 2 diabetes are independent risk factors for cardiovascular diseases. Levels of C-peptide are increased in these patients and its role in the atherosclerosis progression was studied in vitro and in vivo over the past years. To evaluate the possible use of C-peptide as cardiovascular biomarkers, we designed an observational study in which we enrolled patients with mono- or poly-vascular atherosclerotic disease.We recruited 431 patients with stable atherosclerosis and performed a yearly follow-up to estimate the cardiovascular and total mortality and cardiovascular events.We performed a mean follow-up of 56 months on 268 patients. A multivariate Cox analysis showed that C-peptide significantly increased the risk of cardiovascular mortality [Hazard Ratio: 1.29 (95% confidence interval: 1.02-1.65, p0.03513)] after adjustment for age, sex, diabetes treatment, estimated glomerular filtration rate and known diabetes status. Furthermore, levels of C-peptide were significantly correlated with metabolic parameters and atherogenic factors.C-peptide was associated with cardiovascular mortality independently of known diabetes status in a cohort of patients with chronic atherosclerotic disease. Future studies using C-peptide into a reclassification approach might be undertaken to consider its potential as a cardiovascular disease biomarker.

Objective : We have previously reported the combined effect of SNPs perturbing insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. Methods : We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. Results : In the first sample, individuals carrying 1 or ≥2 risk alleles had 33% ( p = 0.06) and 51% ( p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08–1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13–1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. Conclusion : Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.

Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity.1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs).1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009).Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.