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There are several activated forms of macrophages: 2 main groups are designated M1 and M2. While M1 macrophages have proinflammatory, bactericidal, and phagocytic functions and are the dominant phenotype observed in the early stages of inflammation, M2 macrophages are involved in constructive processes such as tissue repair; they play a role in wound healing and are required for revascularization and re-epithelialization. Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis. Its pathogenesis is not well understood, but it is not considered a neoplastic entity. JXGs possibly appear as a reaction to a nonspecific injury such as trauma or viral infection, although a genetic predisposition has been suggested in some cases. Tissue damage leads to a histiocytic response. JXGs appear, evolve toward maturation, and then most of them spontaneously regress. Young JXGs are characterized by small macrophages scattered in the dermis, in apposition close to the epidermis. As the lesion matures, the number of foamy macrophages and Touton cells increases and other cell types such as plasma cells, lymphocytes, and polymorphs are observed. Regressing xanthogranulomas will show numerous spindle cells in Significant values are in bold.a storiform distribution, interstitial fibrosis, and few foamy and Touton cells. In this study, we studied the immunophenotypic profile of macrophages found in cutaneous JXGs according to their stage of maturation. We examined the skin biopsies from 25 patients; all were embedded in paraffin and stained with hematoxylin and eosin and for immunohistochemistry. Typically, all JXGs were positive for factor XIIIa and CD4, and were negative for CD1a. The following histiocyte markers were used: CD68, CD204, CD163, MAC387, and HAM56. Images were analyzed by Image J software; data were statistically evaluated by SAS 9.0 software. The cases showed a slight predominance of males and the preference of the JXGs for the axial skin. Lesions occupied the papillary and reticular dermis in 85% of the cases and extended to the subcutaneous fat in the remainder. Compared with mature and regressing JXGs, younger lesions had a higher density of M1 macrophages, stained with MAC387. This antibody labels the histiocytes that have recently arrived in the areas of inflammation. As the lesions matured, there was an overwhelming predominance of M2 macrophages. These cells tended to cluster against the epidermis, except in the 2 cases in phase of regression. This suggests that there is a cross-talk between the epidermis and macrophages and that receptors, cytokines, chemokines, and adhesion molecules may play a role in the development and evolution of JXGs. These results indicate that, for most of their life, JXGs are formed by repairing M2 macrophages and are not just an M1 macrophagic response to a local antigen. The process appears to be influenced by chemical-mediator epidermal-macrophage cross-talking, considering the tendency of these cells to accumulate against the dermoepidermal junction.

Background and aims Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macroangiopathies, particularly cardiovascular (CV) diseases, seem closely related to diabetes microvascular complications. Aspirin represents the most prescribed compound in CV prevention. Aspirin impact on DR is still object of debate. As it is already recommended among diabetics at high CV risk, aim of this study was to assess a potential relationship between DR and aspirin therapy, in a type 2 diabetes cohort of patients screened through telemedicine. Methods and results NO Blind is a cross-sectional, multicenter, observational study, which involved nine Italian outpatient clinics. Primary endpoint was the assessment of the relationship between aspirin treatment and DR. 2068 patients were enrolled in the study, subsequently split in two subpopulations according to either the presence or absence of DR. Overall, 995 subjects were under aspirin therapy. After adjusting for most common potential confounders, age and gender, aspirin reveals significantly associated with DR (OR: 1.72, 95%CI: 1.58–2.89, p = 0.002) and proliferative DR (PDR) (OR: 1.89, 95%CI: 1.24–2.84, p = 0.003). Association comes lost further adjusting for MACEs (OR: 1.28, 95%CI: 0.85–1.42, p = 0.157) (Model 4) and eGFR (OR: 0.93; 95%CI: 0.71–1.22; p = 0.591) (Model 5). Conclusion In this multicenter cross-sectional study including a large sample of outpatients with T2DM, we showed that aspirin was not associated with DR after adjustment for several cardio-metabolic confounders. However, as partially confirmed by our findings, and related to the well-known pro-hemorrhagic effect of aspirin, its use should be individually tailored, even by telemedicine tools.

Background and aims: HCV is associated with an increased risk of cardiovascular events (CV). Whether HCV clearance by direct-acting antivirals (DAA) reduces incident CV disease is poorly understood. We investigate whether HCV eradication reduces CV events. Methods: In a prospective multicentre study, 2204 HCV patients (F0–F2:29.5%, F3–F4: 70.5%) were enrolled. Males were 48%, median age was 68 (59–74) years and BMI 25.9 (23.1–28); 24.7% were smokers, 18% had diabetes, 13.2% had cholesterol levels >200 mg/dl and 9.1% took statins, 44% had hypertension. During an overall median follow-up of 28 (24–39) months, incident CV events, such as ischemic heart disease (IHD) and ischemic cerebral stroke (ICS), were recorded. An overall of 2204 patients were evaluated as control group and 1668 patients after HCV elimination were followed as a case group. Factors associated with CV events were evaluated by uni- and multi-variate analyses. Results: Incident CV rates per 100 patient years in pre-treatment and untreated controls and treated cases were 1.12, 1.14 and 0.44 (p = 0.0001 vs. controls), respectively, and a decreased of relative risk (RR = 0.379; p = 0.0002) was observed. CV risk was 2.0–3.5 times lower then in controls (HR 3.671; 95%C.I.:1.871–7.201; p < 0.001). The calculated number of patients to be treated to get a benefit in a patient was 55.26. The annual incidence reduction of CV events was 0.68%. HCV clearance was independently associated with CV events reduction (OR, 4.716; 95% C.I.:1.832–12.138; p = 0.001). Conclusions: HCV clearance by DAA reduces CV events (IHD and ICS) with both clinical and socio-economic benefits.

Objective The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19. Methods We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated. Results Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3–2.95 vs median, 0.82 nmol/L; interquartile range, 0.57–1.03; P Conclusion We found that MR-proADM could represent a prognostic biomarker of COVID-19.

Introduction: Some abnormal electrocardiographic findings were independently associated with increased mortality in patients admitted for COVID-19; however, no studies have focussed on the prognosis impact of the interatrial block (IAB) in this clinical setting. The aim of our study was to assess the prevalence and clinical implications of IAB, both partial and advanced, in hospitalized COVID-19 patients. Materials: We retrospectively evaluated 300 consecutive COVID-19 patients (63.22±15.16years; 70% males) admitted to eight Italian Hospitals from February 2020 to April 2020 whounderwent twelve lead electrocardiographic recording at admission. The study population has been dichotomized into two groups according to the evidence of IAB at admission, both partial and advanced. The differences in terms of ARDS in need of intubation, in-hospital mortality and thromboembolic events (a composite of myocardial infarction, stroke and transient ischaemic attack) have been evaluated. Results: The presence of IAB was noticed in 64 patients (21%). In the adjusted logistic regression model, the partial interatrial block was found to be an independent predictor of ARDS in need of intubation (HR: 1.92; p:.04) and in-hospital mortality (HR: 2.65; p:.02); moreover, the advanced interatrial block was an independent predictor of thrombotic events (HR: 7.14; p&nbsp

Immunosurveillance by evaluating anti-spike protein receptor-binding domain (S-RBD) antibodies represents a useful tool to estimate the long immunity against Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection. The aim of this study was to evaluate the kinetics of antibody response in vaccine recipients. We measured anti-S-RBD IgG levels by indirect chemiluminescence immunoassay on Maglumi 800 (SNIBE, California) in 1013 healthy individuals naïve to SARS-CoV2 infection after two and three COVID-19 vaccine doses. We found that anti-S-RBD IgG levels are higher in females than males. Antibody levels gradually decrease to a steady state after four months since the peak, and the decay is independent of age, sex, vaccine doses, and baseline antibodies titer. The third dose induces a high anti-S-RBD IgG reactivity in individuals with previous high responses and triggers a moderate-high anti-S-RBD IgG reactivity. The assessment of anti-S-RBD IgG levels is essential for monitoring long-term antibody response. A third SARS-CoV-2 vaccine dose is associated with a significant immunological response. Thus, our results support the efficacy of the vaccine programs and the usefulness of the third dose.

Type 2 Diabetes Mellitus (T2DM) is associated with an elevated incidence of cardiovascular and renal diseases, responsible for mortality rates significantly higher than in the general population. The management of both cardiovascular risk and progression of kidney disease thus seem crucial in the treatment of the diabetic patient. The availability of new classes of drugs which positively affect both cardiovascular and renal risk, regardless of the glycemic control, represents a revolution in the treatment of T2DM and shifts the attention from the intensive glycemic control to a holistic management of the diabetic patient. Among these, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with a remarkable reduction of cardiovascular and renal mortality, lower hospitalization rates for heart failure and lower progression of renal damage and albuminuria. Thus, their use in selected subpopulations seems mandatory. Aim of this review was the assessment of the current evidence on SGLT2i and their related impact on the cardiovascular and renal profiles.

Objectives Olfactory dysfunction is a frequent feature of COVID-19. Despite the growing evidence, current knowledge on the subject remains insufficient, so that data obtained with different tools, from multiple centers and in distinct scenarios are welcome. Yet, the predictive value of olfactory dysfunction in terms of the overall prognosis of COVID-19 is unknown. This study aims to evaluate the olfactory function of hospitalized patients with COVID-19 and the impact of the results on their clinical outcomes. Methods Patients with severe acute respiratory distress syndrome (ARDS) admitted to a university tertiary hospital were recruited and divided into those with ARDS due to COVID-19, and those with ARDS of any other cause. Sociodemographic and clinical data were collected at baseline and the patients had their objective olfactory function evaluated by the Alcohol Sniff Test on admission and during hospital stay. The participants were then followed up until reaching an endpoint: hospital discharge, endotracheal intubation, transfer to the intensive care unit, or death. Patients with COVID-19 were also subgrouped and compared according to their olfactory thresholds and to their overall clinical outcomes. The obtained data was analyzed using R software. Level of significance was set at 0.05. Results Eighty-two patients were included (of which 58 had COVID-19). 87.93% of the patients with COVID-19 had diminished olfactory dysfunction on admission. The mean length of hospital stay among patients with olfactory dysfunction was greater (7.84 vs 6.14 days) and nine individuals in this subgroup had poor overall outcomes. None of those with normal olfactory function developed critical COVID-19. The mean olfactory function was significantly worse among patients with COVID-19 and poor outcomes (3.97 vs 7.90 cm, P = .023). Conclusion Objective olfactory dysfunction is frequent in ARDS caused by SARS-CoV-2 infection. Patients with longitudinal poorer outcomes present worse olfactory thresholds on admission.

Despite evidence that pregnancy planning improves outcomes, in Italy, as in many other countries worldwide,50% of women with diabetes prepare their pregnancy. The aim of this study was to document training and knowledge on diabetes and pregnancy (DP) among diabetes professionals.We administered an anonymous online questionnaire, focused on diabetes and pregnancy planning, to diabetes team members. Between Nov-2017 and Jul-2018, n = 395 professionals (60% diabetes/endocrinology/internal medicine specialists, 28% fellows) completed the survey. Fifty-nine percent of the specialists, mainly (78%) those completing their fellowship after 2006, reported having received training on DP during fellowship. Considering specialists reporting training, 43% correctly identified fetal risks of inadequate preconceptional glucose control and 55% maternal risks, 38% identified risks associated with overweight/obesity, and 39% would prescribe hormonal contraception to women with diabetes only if glucose control is good.The results of our survey suggest the need to improve training and awareness of professionals in the area of diabetes and pregnancy.

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.

Background and aims: Beyond type 2 diabetes, even a condition of prediabetes is associated with an increased cardiovascular (CV) risk, and HCV infection coexistence represents an exacerbating factor. CV prognosis improvement in prediabetes represents a challenge, due to the increasing prevalence of this metabolic condition worldwide. Hence, we aimed to prospectively assess how direct acting antivirals (DAAs) could affect major cardiovascular events (MACE) in a prediabetic HCV positive cohort. Methods and results: In this prospective multicenter study, we enrolled HCV patients with overt prediabetes. We compared a subgroup of patients treated with DAAs with untreated prediabetic controls. We recorded all CV events occurred during an overall median follow-up of 24 months (IQR 19–34). 770 HCV positive prediabetic patients were enrolled, 398 untreated controls and 372 DAAs treated patients. Overall, the CV events annual incidence was much higher among prediabetic treated patients (1.77 vs. 0.62, p < 0.001), and HCV clearance demonstrated to significantly reduce CV events (RR: 0.411, 95%CI 0.148–1.143; p < 0.001), with an estimated NNT for one additional patient to benefit of 52.1. Moreover, an independent association between a lower rate of CV events and HCV clearance after DAAs was observed (OR 4.67; 95%CI 0.44–53.95; p = 0.016). Conclusions: HCV eradication by DAAs allows a significant reduction of MACEs in the prediabetic population, and therefore represents a primary objective, regardless of the severity of liver disease and CV risk factors.

Objectives We aimed to assess the value of liver biopsy in the evaluation of abnormal liver tests. Methods We analyzed consecutive liver biopsy specimens performed for evaluation of unexplained abnormal liver tests from 2014 to 2018. Diagnoses were categorized histologically and clinically. We determined whether histologic examination led to a specific diagnosis and whether prebiopsy laboratory variables predicted the underlying etiology. Results Among the 383 liver biopsy specimens included, chronic hepatitis was the most common histologic (25%) and clinical (17%) diagnosis. Liver biopsy led to a clinical diagnosis in 87% of patients. The most likely clinical diagnoses were autoimmune hepatitis, nonalcoholic fatty liver disease, and drug-induced liver injury (38, 33, and 32 patients, respectively). Using sensitivity, specificity, and positive and negative predictive values, we found that liver tests were not predictive of a specific diagnosis. In patients with no history of liver disease or clinical features of portal hypertension, biopsy specimens revealed histologic cirrhosis in 5% of patients. Conclusions Histopathologic diagnoses were made in 85% of patients undergoing liver biopsy for investigation of unexplained liver tests, leading to a clinical diagnosis in 87% of patients. However, neither liver tests themselves nor their patterns were useful in predicting histologic or clinical diagnoses.

BACKGROUND: Despite improvements in imaging techniques that have enhanced the ability to diagnose hepatocellular carcinoma (HCC), histopathological evaluation of many other types of liver masses is critical. AIMS: To evaluate the utility of liver biopsy in patients with radiologically undiagnosed liver masses. METHODS: We retrospectively analyzed 293 consecutive patients who had a liver biopsy for evaluation of an undiagnosed liver mass between January 2014 and January 2018. RESULTS: Out of 293 biopsies, 246 patients were found to have malignancy (84%), including 210 (72%) patients with metastatic malignancy and 36 with primary hepatic malignancies (20 HCC and 16 others). In the 47 patients without malignancy, 17 patients had necrotic abscess/granuloma, 16 patients had normal histology, eight patients had hepatic fibrosis/cirrhosis without malignant foci, and six patients had benign tumors. The most common primary lesion in patients with liver metastasis was breast carcinoma (32/293, 11%), followed by colon and pancreas (31 (each)/293, 11%), and lung (9%) adenocarcinomas. Histopathological analysis confirmed the presence of metastasis in 165/200 (83%) patients with a history of oncological malignancy and in 45/93 (48%) patients who had no malignancy history. CONCLUSIONS: In patients with a radiologically identified liver mass of unclear etiology, liver biopsy/histology made a diagnosis in 95% (277/293) of patients, including 84% (246/293) found to have an oncological malignancy. Liver biopsy/histology also identified malignancy in a high proportion of patients without known underlying cancer. We conclude that liver biopsy is valuable for evaluation of radiologically identified liver masses of unclear etiology.

In this study we evaluated the effect of pharmacological treatment with AnxA1-derived peptide AcMale rats were divided into Sham (control), Cisplatin (received intraperitoneal injections of 10 mg/kg/day of cisplatin for 3 days) and AcAfter 6 h of the last dose of cisplatin, an acute inflammatory response was observed characterized by a marked increase in the number of neutrophils and GM-CSF, IL-β, IL-6, IL-10 and TNF-α plasma levels. These findings were associated with increased AnxA1 protein levels in liver and kidneys, as well as positive AnxA1/Fpr2 circulating leukocytes. Treatment with AcDespite activation of the anti-inflammatory AnxA1/Fpr axis during cisplatin administration, treatment with Ac

In the last decades, an important role of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) diagnosis has emerged. The evaluation of the triad consisting of 42 aminoacid-long amyloid-beta peptide (Aβ42), total Tau (tTau) and Tau phosphorylated at threonine 181 (pTau) have been recently integrated into the research diagnostic criteria of AD. For a long time, the enzyme-linked immunosorbent assay (ELISA) has represented the most commonly used method for the measurement of CSF biomarkers levels. This study aimed to assess the diagnostic accuracy of CSF biomarkers, namely Aβ42, tTau and pTau and their ratio, measured by fully automated CLEIA assay (Lumipulse). We included 96 patients clinically diagnosed as AD (48) and non-AD (48). All CSF biomarkers levels were measured on Lumipulse G1200 fully automated platform (Fujirebio Inc. Europe, Gent, Belgium). Aβ42 levels, 42/40 ratio, 42/tTau ratio, 42/PTau ratio were significantly reduced, and tTau and PTau levels were significantly increased in AD patients in comparison with non-AD patients. The receiving operator curve (ROC) analysis showed good diagnostic accuracy of all CSF biomarkers and their ratios for discriminating AD patients from non-AD patients, with 42/40 ratio having the best AUC (0.724, 95%CI 0.619–0.828; p < 0.001). Our findings support the use of CSF biomarkers measured by CLEIA method on a fully automated platform for AD diagnosis.

Objective We evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients. Methods Plaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up. Results Compared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P, Highlights • The identification of novel molecular targets of atherosclerosis progression is of utmost importance in diabetic patients. • The occurrence of SGLT2 receptors on the endothelial cells of atherosclerotic plaques may be an attractive therapeutic option for atherosclerosis in patients with diabetes. • SGLT2/SIRT6 represents an attractive option, given its crucial involvement in atherosclerosis progression. • The endothelial SGLT2 inhibition increases the endothelial expression of SIRT6, yielding an improved atherosclerotic plaque phenotype and 2-year outcome. • The impairment of the endothelial SGLT2/SIRT6 pathway worsens outcomes in atherosclerotic patients with diabetes; this may be a potential preventive target.

OBJECTIVE: We aimed to assess the correlation between LUS Soldati proposed score and clinical presentation, course of disease and the possible need of ventilation support/intensive care. PATIENTS AND METHODS: All consecutive patients with laboratory confirmed SARS-CoV-2 infection and hospitalized in two COVID Centers were enrolled. All patients performed blood gas analysis and lung ultrasound (LUS) at admission. The LUS acquisition was based on standard sequence of 14 peculiar anatomic landmarks with a score between 0-3 based on impairment of LUS picture. Total score was computed with their sum with a total score ranging 0 to 42, according to Soldati LUS score. We evaluated the course of hospitalization until either discharge or death, the ventilatory support and the transition in intensive care if needed. RESULTS: One hundred and fifty-six patients were included in the final analysis. Most of patients presented moderate-to-severe respiratory failure (FiO2

Many patients with inflammatory bowel disease (IBD) restrict dairy products to control their symptoms. The aim of the study was to investigate the prevalence of lactose intolerance assessed with hydrogen breath test (H-BT) in IBD patients in clinical remission compared to a sex, age and BMI matched control population. We further detected the prevalence of three single nucleotide polymorphisms of the lactase (LCT) gene: the lactase non persistence LCT-13910 CC (wildtype) and the intermediate phenotype LCT-22018 CT and LCT-13910 AG, finally, we assess the correlation between genotype and H-BT. A total of 54 IBD patients and 69 control who underwent clinical evaluation, H-BT and genetic test were enrolled. H-BT was positive in 64.8% IBD patients and 62.3% control (p = 0.3). The wild-type genotype was found in 85.2% IBD patients while CT-22018, AG-13910 and CT-22018/AG-13910 polymorphisms were found in 9.3%, 1.8% and 3.7%. In the control group, the wild-type genotype, CT-22018, AG-13910 and CT-22018/AG-13910 polymorphisms were found in 87%, 5.8%, 5.8% and 1.4% of cases, respectively. Therefore, the wild-type and polymorphisms’ prevalence did not differ between IBD population and control group (85.2% vs. 87%, p = 0.1) (14.8% vs. 13%, p = 0.7). The correlation between positive H-BT and genetic analysis showed that the wild-type genotype was associated with higher rate of lactose intolerance in the total population (OR 5.31, 95%CI 1.73–16.29, p = 0.003) and in the IBD (OR 7.61, 95%CI 1.36–42.7, p = 0.02). The prevalence of lactose intolerance in IBD patients did not differ from that of control. Despite suggestive symptoms, about 1/3 of IBD patients are not lactose intolerant, thus not needing “a priori” elimination diet. This may encourage a rationale and balanced dietary management in IBD.

Introduction Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. Methods We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/- mice for FD, 5 NAGLU-/- mice for MPS IIIB, 5 GAA-/- mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. Results Compared to their correspondent WT mice: GAA-/- mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs 1.02mm, p-value 0.04); GLA-/- mice showed greater diameters of aortic annulus (1.35mm vs. 1.22mm, p-value = 0.01), sinus of Valsalva (1.6mm vs. 1.38mm, p-value

OBJECTIVE To evaluate the effect of metformin therapy on coronary endothelial function and major adverse cardiac events (MACE) in patients with prediabetes with stable angina and nonobstructive coronary stenosis (NOCS). RESEARCH DESIGN AND METHODS Metformin therapy may be needed to reduce coronary heart disease risk in patients with prediabetes. A total of 258 propensity score–matched (PSM) patients with stable angina undergoing coronary angiography were enrolled in the study. Data from 86 PSM subjects with normoglycemia (NG), 86 PSM subjects with prediabetes (pre-DM), and 86 PSM subjects with prediabetes treated with metformin (pre-DM metformin) were analyzed. During coronary angiography, NOCS was categorized by luminal stenosis 0.80. In addition, we assessed the endothelial function, measuring coronary artery diameter of left anterior descending coronary (LAD) at baseline and after the infusion of acetylcholine, by means of an intracoronary Doppler guide wire. MACE, as cardiac death, myocardial infarction, and heart failure, was evaluated at 24 months of follow-up. RESULTS At baseline, NG patients had a lower percentage of LAD endothelial dysfunction compared with pre-DM patients (P < 0.05). The pre-DM patients had a higher percentage of endothelial LAD dysfunction as compared with the pre-DM metformin patients (P < 0.05). At the 24th month of follow-up, MACE was higher in pre-DM versus NG (P < 0.05). In pre-DM metformin patients, MACE was lower compared with pre-DM patients (P < 0.05). CONCLUSIONS Metformin therapy may reduce the high risk of cardiovascular events in pre-DM patients by reducing coronary endothelial dysfunction.

Objective:To evaluate if genetic polymorphisms in the oestrogen receptor 1 ( ESR1) and oestrogen receptor 2 ( ESR2) genes encoded for oestrogen receptors alpha (ERα) and beta (ERβ) are involved in permanent tooth size.Design:Cross-sectional study.Setting:Orthodontic Clinic at School of Dentistry of Ribeirão Preto, University of São Paulo.Participants:A total of 108 orthodontic patients.Materials and Methods:Pre-treatment orthodontic records were evaluated. Dental casts were used to determine the maximum crown measurements of fully erupted permanent teeth in the mesiodistal dimensions. Second and third molars were not included in the analysis. Genomic DNA samples were used for the genotyping of four genetic polymorphisms: ESR1 (rs9340799 and rs2234693) and ESR2 (rs1256049 and rs4986938). The associations between tooth size and sex were evaluated using t test. The associations between tooth size and genotype were analysed with linear regression and adjusted by sex at an alpha of P⩽0.05.Results:Female patients presented smaller tooth size than male patients. A statistically significant difference was observed in almost all teeth ( PConclusion:This study provides evidence that genetic polymorphisms in ESR1 and ESR2 could be associated with tooth size in permanent teeth.

Purpose There are conflicting reports as to whether there is a binocular advantage or disadvantage when reading with central vision loss. This study examined binocular reading summation in patients with macular degeneration. Methods Seventy‐one patients with bilateral central vision loss [mean age: 63 (S.D. = 21) years] participated. Reading performances during binocular and monocular viewing with the better eye (i.e., the eye with the best monocular visual acuity) were evaluated using different versions of the Italian MNREAD reading chart (www.precision‐vision.com). Fixation stability and preferred retinal loci (PRLs) were recorded monocularly for each eye. The overall sample was split into inhibition, equality, and summation groups based on the binocular ratio (i.e., binocular/monocular) of the maximum reading speed. Results 41% of patients experienced binocular inhibition, 42% summation, and 17% equality. Binocular reading speed of the inhibition group was approximately 30 words per minute slower than those of the equality and summation groups, although the inhibition group had the best visual acuity. These patients generally had monocular PRLs in non‐corresponding locations temporal or nasal to the scotoma, had the largest interocular acuity difference and lacked residual stereopsis. The three groups did not differ in fixational control, contrast sensitivity or critical print size. Conclusions Equal proportions of patients with central vision loss show binocular reading summation and inhibition. Patients with binocular reading inhibition have poorer reading performance and different clinical characteristics than those with binocular reading summation and equality.

Objective: To assess the correlation of serum protein biomarkers with disease activity across different domains of psoriatic arthritis (PsA).Material and methods: A cross-sectional cohort of 45 adult patients with PsA fulfilling the classification for psoriatic arthritis (CASPAR) criteria was recruited from University of California San Diego (UCSD) Arthritis Clinics. Clinical data and serum samples were collected and serum was analyzed for protein biomarkers hypothesized to be relevant to disease activity in PsA. Correlations were evaluated for clinical disease activity measures across disease domains.Results: Biomarkers with the highest correlation to the composite indices and disease domains were SAA, IL-6, YKL-40, and ICAM-1. In addition, several biomarkers were moderately correlated with individual composite indices and/or disease domains. Low or no correlation was observed with some biomarkers, e.g. MMP-3, MMP-1, EGF, VEGF, and IL-6R. In contrast, the correlation of all biomarkers with certain disease domains was low; specifically, pain, percent body surface area of psoriasis, and patient global assessment. The multi-biomarker disease activity score (MBDA) developed for rheumatoid arthritis (RA) showed high correlations with most composite indices and some disease domains in PsA.Conclusions: These data suggest biomarker analysis can reflect disease activity across disease domains in PsA. Certain domains would likely benefit from the evaluation of additional biomarkers.

One type of parental effect occurs when changes in parental phenotype or environment trigger changes to offspring phenotype. Such nongenetic parental effects can be precisely triggered in response to an environmental cue in time-locked fashion, or in other cases, persist for multiple generations after the cue has been removed, suggesting multiple timescales of action. For parental effects to serve as reliable signals of current environmental conditions, they should be reversible, such that when cues change, offspring phenotypes change in accordance. Social hierarchy is a prevalent feature of the environment, and current parental social status could signal the environment in which offspring will be born. Here, we sought to address parental effects of social status and their timescale of action in mice. We show that territorial competition in seminatural environments affects offspring growth. Although dominant males are not heavier than nondominant or control males, they produce faster growing offspring, particularly sons. The timing, effect-size, and sex-specificity of this association are modulated by maternal social experience. We show that a change in paternal social status is sufficient to modulate offspring weight: from one breeding cycle to the next, status-ascending males produce heavier sons than before, and status-descending males produce lighter sons than before. Current paternal status is also highly predictive of liver transcription in sons, including molecular pathways controlling oxidative phosphorylation and iron metabolism. These results are consistent with a parental effect of social experience, although alternative explanations are considered. In summary, changes in paternal social status are associated with changes in offspring growth and metabolism.

Background and aims: To evaluate the change in circulating serum irisin and interleukin-6 (IL-6), in patients with type 2 diabetes mellitus (T2DM) after 6 and 12 months of GLP-1 treatment. Methods and results: Eighty-five patients with T2DM inadequately controlled with insulin or other hypoglycaemic drugs were added to dulaglutide (N° = 44) and liraglutide (N° = 41) treatment. After 6 months of GLP-1 analogues a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (p < 0.001), HbA1c (p < 0.001), total cholesterol (p < 0.001), LDL-cholesterol (p = 0.003), triglycerides (p = 0.017), IL-6 (p = 0.045) and a significant increase in serum irisin (p < 0.001) were observed compared to baseline. After 12 months of treatment no significant differences were found compared to the levels at 6 months. The change in irisin from baseline (Δ_irisin) was significantly related to the changes in total-cholesterol (Δ_total-cholesterol) (r = −0.293; p = 0.020), while the change in IL-6 (Δ_IL-6) was significantly related to the changes in WC (Δ_WC) (r = 0.347; p = 0.006). Conclusions: Additive treatment with GLP1-analogues results in an increase in serum circulating irisin levels and a decrease in IL-6. The post-treatment change in irisin was correlated with a decrease in total cholesterol, while the change in IL-6 was correlated with a decrease in WC.

Optimal dual antiplatelet therapy (DAPT) strategy in high-bleeding risk (HBR) patients presenting with acute coronary syndrome remains debated. We sought to investigate the use of clopidogrel versus ticagrelor in HBR patients with acute coronary syndrome and their impact on ischemic and bleeding events at 1year. In the START-ANTIPLATELET registry (NCT02219984), consecutive patients with ≥ 1 HBR criteria were stratified by DAPT type in clopidogrel versus ticagrelor groups. The primary endpoint was net adverse clinical endpoints (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. Of 1209 patients with 1-year follow-up, 553 were defined at HBR, of whom 383 were considered eligible for the study as on DAPT with clopidogrel (174 or 45.4%) or ticagrelor (209 or 54.6%). Clopidogrel was more often administered in patients at increased ischemic and bleeding risk, while ticagrelor in those undergoing percutaneous coronary intervention. Mean DAPT duration was longer in the ticagrelor group. At 1year, after multivariate adjustment, no difference in NACEs was observed between patients on clopidogrel versus ticagrelor (19% vs. 11%, adjusted hazard ratio 1.27 [95% CI 0.71–2.27], p = 0.429). Age, number of HBR criteria, and mean DAPT duration were independent predictors of NACEs. In a real-world registry of patients with acute coronary syndrome, 45% were at HBR and frequently treated with clopidogrel. After adjustment for potential confounders, the duration of DAPT, but not DAPT type (stratified by clopidogrel vs. ticagrelor), was associated with the risk of ischemic and bleeding events at 1year.

Aims: Peripheral neuropathy (PN) affects two-thirds of type 2 diabetes patients (T2DM). According to diabetic PN length-dependent pattern, neurophysiological evaluation of foot-sole nerves might increase NCS diagnostic sensitivity, hence allowing early diagnosis of PN. Thus, we aim to assess the ability of whole plantar nerve (WPN) conduction in diabetic PN early diagnosis. Methods: This is a single center prospective observational cohort study on 70 T2DM patients referred to Internal Medicine Unit of A.O.U. “Luigi Vanvitelli” between October 2019/October 2020. Primary endpoint was WPN efficacy assessment in PN early detection. As secondary, we evaluated (i) a potential cut-off of SNAPs amplitude by WPN and (ii) WPN diagnostic accuracy vs. gold-standard distal sural nerve conduction. Results: ROC curve analysis allowed to establish two potential cut-offs for people aged ≤60 years (AUROC: 0.83, 95%CI: 0.69–0.96, p < 0.001) and ≤60 years (AUROC: 0.76, 95%CI: 0.59–0.93, p = 0.017). In depth, we fixed a cut-off of WPN-SNAP amplitude of 4.55 μV and 2.65 μV, respectively, with subsequent 48 patients classified as PN-T2DM. Conclusions: Our data support WPN conduction study reliability in characterizing the most distal sensory nerve fibers at lower limbs. Thus, WPN may represent an extremely useful diagnostic tool for diabetic PN early detection.

Introduction During COVID-19 pandemic, the use of several drugs has represented the worldwide clinical practice. However, though the current increase of knowledge about the disease, there is still no effective treatment for the usage of drugs. Thus, we retrospectively assessed use and effects of therapeutic regimens in hospitalized patients on in-hospital mortality. Methods COVOCA is a retrospective observational cohort study on 18 COVID centres throughout Campania Region Hospitals. We included adult patients with confirmed SARS-CoV-2 infection, discharged/dead between March/June 2020. Results 618 patients were included, with an overall in-hospital cumulative mortality incidence of 23.1%. Most prescribed early treatments were antivirals (72%), antibiotics (65%) and hydroxychloroquine/anticoagulants (≈50%). Tocilizumab, indeed, was largely prescribed late during hospitalization. Multivariable models, with a cut-off at day 2 for early COVID-19 therapy administration, did not disclose any significant association of a single drug administration on the clinical outcome. Discussion COVOCA represents the first multicenter database in Campania region. None drug class used during the pandemic significantly modified the outcome, regardless of therapy beginning, both overall and net of those already in non-invasive ventilation (NIV)/ orotracheal intubation (OTI) at hospitalization. Our cumulative incidence of mortality seems lower than other described during the same period, particularly in Northern Italy.

Objectives: We examined the association of the coronary thrombus microbiota and relative metabolites with major adverse cardiovascular events (MACE) in hyperglycemic patients with ST segment elevation myocardial infarction (STEMI). Background: Hyperglycemia during STEMI may affect both development and progression of coronary thrombus via gut and thrombus microbiota modifications. Methods: We undertook an observational cohort study of 146 first STEMI patients treated with primary percutaneous coronary intervention (PPCI) and thrombus-aspiration (TA). Patients were clustered, based on admission blood glucose levels, in hyperglycemic (≥140 mg/dl) and normoglycemic (

Objective To evaluate the efficacy of Perceptual Learning in improving the peripheral reading performance of patients with Stargardt disease (STGD). Design Prospective observational randomized study. Participants Fourteen consecutive patients (7 females, 7 males; median age of 50.4 ± 12.8 years) with STGD were analyzed and divided into two groups: Group A received “Win-flash” as Perceptual Learning training and Group B was used as control. Methods Subjects underwent an ophthalmic evaluation at baseline, after perceptual learning training and at 6 months of follow-up. Outcomes measured included reading speed, contrast sensitivity and fixation stability. Results Reading speed improved of 51,7% after training in group A. Visual acuity, contrast sensitivity and fixation stability enhanced in group A after training from 0.89 (±0.09) LogMAR to 0.75 (±0.2) LogMAR (t(6)= 3.6, p= 0.001), from 0.8 (±0.3) LogC (0.6 − 0.9) to 1.3 (±0.3) LogC (t(13)=3.17, p= 0.003) and from 59.3 % (± 24.3) to 71.5 % (± 20.4) (t(13)=1.8 p= 0.04), respectively. No changes were found in group B. At 6-monts of follow-up, visual acuity and contrast sensitivity decreased in group A. Conclusions STGD patients receiving “Win-flash training”, as PL technique, showed an improvement of reading performance on a real-world task. Early follow-up for perceptual learning re-intervention should be considered.

Objective: To evaluate if temporomandibular disorders (TMDs) are associated with genetic polymorphisms in ESR1 and ESR2, which are genes encoding oestrogen receptor alpha (ERα) and beta (ERβ). Also...

International audience; The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) (P < 10-4). For CAPA, the presence of several mycological criteria was associated with death (P < 10-4). Serum galactomannan was rarely positive (

OBJECTIVE To investigate gender inequity in the scientific production of the University of Sao Paulo. METHODS Members of the University of Sao Paulo faculty are the study population. The Web of Science repository was the source of the publication metrics. We selected the measures: total publications and citations, average of citations per year and item, H-index, and history of citations between 1950 and 2019. We used the name of the faculty member as a proxy to the gender identity. We use descriptive statistics to characterize the metrics. We evaluated the scissors effect by selecting faculty members with a high H-index. The historical series of citations was projected until 2100. We carry out analyses for the general population and working time subgroups: less than 10 years, 10 to 20 years, and 20 years or more. RESULTS Of the 8,325 faculty members, we included 3,067 (36.8%). Among those included, 1,893 (61.7%) were male and 1,174 (38.28%) female. The male gender presented higher values in the publication metrics (average of articles: M = 67.0 versus F = 49.7; average of citations/year: M = 53.9 versus F = 35.9), and H-index (M = 14.5 versus F = 12.4). Among the 100 individuals with the highest H-index (≥ 37), 83% are male. The male curve grows faster in the historical series of citations, opening a difference between the groups whose separation is confirmed by the projection. DISCUSSION Scientific production at the Universidade de São Paulo is subject to a gender bias. Two-thirds of the faculty are male, and hiring over the past few decades perpetuates this pattern. The large majority of high impact faculty members are male. CONCLUSION Our analysis suggests that the Universidade de São Paulo will not overcome gender inequality in scientific production without substantive affirmative action. Development does not happen by chance but through choices that are affirmative, decisive, and long-term oriented. RESUMO OBJETIVO Investigar desigualdades de gênero na produção científica de docentes da Universidade de São Paulo. MÉTODOS A população consiste em professores(as) da Universidade de São Paulo. O repositório Web of Science foi a fonte das métricas de publicação. Selecionamos as medidas: total de publicações e citações, média de citações por ano e por item, índice H e histórico de citações entre 1950 e 2019. Usamos o nome do(a) docente como um proxy para a identidade de gênero. Usamos estatísticas descritivas para caracterizar as métricas. Avaliamos o efeito tesoura selecionando os(as) professores(as) com índice H alto. A série histórica de citações foi projetada até 2100. Realizamos análises para a população geral e subgrupos de tempo de trabalho: menos de 10 anos, de 10 a 20 anos e 20 anos ou mais. RESULTADOS Dos 8.325 docentes, incluímos 3.067 (36,8%). Dentre os incluídos, 1.893 (61,7%) eram professores e 1.174 (38,28%) professoras. O gênero masculino apresentou valores mais altos nas métricas de publicação (média de artigos: M = 67,0 versus F = 49,7; média de citações/ano: M = 53,9 versus F = 35,9) e índice H (M = 14,5 versus F = 12,4). Entre os 100 indivíduos com maior índice H (≥ 37), 83% são do gênero masculino. Na série histórica de citações, a curva masculina cresce mais rápido, abrindo uma diferença entre os grupos com afastamento confirmado pela projeção. DISCUSSÃO A produção científica na Universidade de São Paulo está sujeita a um viés de gênero. Dois terços do corpo docente são do gênero masculino, e as contratações das últimas décadas perpetuam esse padrão. A grande maioria dos membros com alto impacto no corpo docente é do sexo masculino. CONCLUSÃO Nossas análises sugerem que a Universidade de São Paulo não superará a desigualdade de gênero na produção científica sem uma ação afirmativa substancial. O desenvolvimento não acontece por acaso, mas por meio de escolhas afirmativas, decisivas e de longo prazo.

Introduction Microsporidiosis is an emerging opportunistic infection in renal transplantation (RT) recipients. We aimed to describe its clinical presentation and treatment. Materials and methods We collected microsporidiosis cases identified in RT recipients between 2005 and 2019 in six French centers from the Crystal, Divat and Astre prospective databases. Results We report 68 RT recipients with intestinal microsporidiosis; the patients were predominantly male (61.8%), with a median age of 58 (46-69) years. Infection occurred at a median time of 3 (0.8-6.8) years posttransplant. Only Enterocytozoon bieneusi was found. Microsporidiosis manifested as diarrhea (98.5% of patients) with weight loss (72.1%) and acute renal injury (57.4%) without inflammatory biological parameters. The therapeutic approaches were no treatment (N = 9), reduction of the immunosuppressive regimen (∆IS) (N = 22), fumagillin alone (N = 9), fumagillin and ∆IS (N = 19), and albendazole or nitazoxanide and ∆IS (N = 9). Overall clinical remission was observed in 60 patients (88.2%). We observed no acute kidney rejection, renal transplant failure or death within 6 months after microsporidiosis. Conclusion E. bieneusi is an underestimated opportunistic pathogen in RT recipients, and infection with E. bieneusi leads to diarrhea with important dehydration and acute renal injury. The treatment is based on the reduction of the immunosuppressive regimen and the administration of fumagillin if available. This article is protected by copyright. All rights reserved.

Background Italy has been the first Western country to be heavily affected by the spread of SARS-COV-2 infection and among the pioneers of the clinical management of pandemic. To improve the outcome, identification of patients at the highest risk seems mandatory. Objectives Aim of this study is to identify comorbidities and clinical conditions upon admission associated with in-hospital mortality in several COVID Centers in Campania Region (Italy). Methods COVOCA is a multicentre retrospective observational cohort study, which involved 18 COVID Centers throughout Campania Region, Italy. Data were collected from patients who completed their hospitalization between March-June 2020. The endpoint was in-hospital mortality, assessed either from data at discharge or death certificate, whilst all exposure variables were collected at hospital admission. Results Among 618 COVID-19 hospitalized patients included in the study, 143 in-hospital mortality events were recorded, with a cumulative incidence of about 23%. At multivariable logistic analysis, male sex (OR 2.63, 95%CI 1.42–4.90; p = 0.001), Chronic Liver Disease (OR 5.88, 95%CI 2.39–14.46; p Conclusion Mortality of patients hospitalized for COVID-19 appears strongly affected by both clinical conditions on admission and comorbidities. Originally, we observed a very poor outcome in subjects with a chronic liver disease, alongside with an increase of hepatic damage.

Background Monocyte distribution width has been recently proposed as a sepsis biomarker in the emergency department. The aim of this study was to assess the role of monocyte distribution width as a diagnostic biomarker of sepsis in the intensive care unit. Methods In this prospective observational study, we included all consecutive patients admitted to the intensive care unit of the University Hospital “P. Giaccone” of Palermo. Patients were classified into three groups according to Sepsis-3 criteria: (1) patients without sepsis; (2) patients developing sepsis during their hospital stay; (3) patients admitted with sepsis. Monocyte distribution width was measured at admission (groups 1, 2, 3) and daily until the developing of sepsis (group 2) or the end of hospitalization (group 1). Results Monocyte distribution width was significantly higher in group 3 than group 1 and group 2 (30.9 [25.6–36.0] vs. 20.3 [18.3–23.6] and 21.4 [19.4–25.2]). Among patients belonging to group 2, monocyte distribution width values, measured at the day when sepsis was clinically diagnosed, were significantly higher than those found at admission: 29.4 (26.7–36.0) vs. 21.4 (19.4–25.2), P = 0.001. Conclusion Monocyte distribution width could represent a reliable biomarker of sepsis in the intensive care unit.