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Elena Pacella,1 Anna Rita Vestri,2 Roberto Muscella,1 Maria Rosaria Carbotti,1 Massimo Castellucci,1 Luigi Coi,1 Paolo Turchetti,3 Fernanda Pacella1 1Department of Sense Organs, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy; 2Department of Public Health and Infectious Diseases, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy; 3National Institute for Health, Migration and Poverty (INMP/NIHMP), Rome, ItalyBackground: To evaluate the efficacy and safety of an intravitreal dexamethasone implant (Ozurdex®; Allergan Inc, Irvine, CA, USA) in patients with persistent diabetic macular edema (DME) over a 6-month follow-up period.Methods: Seventeen patients (20 eyes) affected by DME were selected. The mean age was 67 ± 8 years, and the mean duration of DME was 46.3 ± 18.6 months. The eligibility criteria were: age ≥18, a best-corrected visual acuity between 5 and 40 letters, and macular edema with a thickness of ≥275 μm. Thirteen patients had also previously been treated with anti-vascular endothelial growth factor medication.Results: The mean ETDRS (Early Treatment Diabetic Retinopathy Study) value went from 18.80 ± 11.06 (T0) to 26.15 ± 11.03 (P = 0.04), 28.15 ± 10.29 (P = 0.0087), 25.95 ± 10.74 (P = 0.045), 21.25 ± 11.46 (P = 0.5) in month 1, 3, 4, and 6, respectively. The mean logMAR (logarithm of the minimum angle of resolution) value went from 0.67 ± 0.23 (at T0) to 0.525 ± 0.190 (P = 0.03), 0.53 ± 0.20 (P = 0.034), and 0.56 ± 0.22 (P = 0.12) in month 1, 3, and 4, respectively, to finally reach 0.67 ± 0.23 in month 6. The mean central macular thickness value improved from 518.80 ± 224.75 μm (at T0) to 412.75 ± 176.23 μm, 292.0 ± 140.8 μm (P < 0.0001), and 346.95 ± 135.70 (P = 0.0018) on day 3 and in month 1 and 3, respectively, to then increase to 476.55 ± 163.14 μm (P = 0.45) and 494.25 ± 182.70 μm (P = 0.67) in month 4 and 6.Conclusion: The slow-release intravitreal dexamethasone implant, Ozurdex, produced significant improvements in best-corrected visual acuity and central macular thickness from the third day of implant in DME sufferers, and this improvement was sustained until the third month.Keywords: macular edema, diabetes, intravitreal implant, Ozurdex®

Purpose: Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists., Methods: PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations., Results: The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19 months of age (CI: 3.00-20.00), while the mean age at diagnosis was 15 years (CI: 10.00-30.00). Therefore, the diagnostic delay amounted to 13.42 years (CI: 8.00-23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion., Conclusion: Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In Italy, nephrology residency is available in twenty-one nephrology schools, each with its own strengths and weaknesses. The present study is aimed at exploring the residents' satisfaction with their training programs., Methods: Between April 20th and May 19th, 2021, a questionnaire on residency satisfaction consisting of 49 items was sent to 586 residents and 175 recently certified specialists (qualified to practice as nephrologists in 2019 and 2020), with a response rate of 81% and 51%, respectively. The teaching organization was contextualized with a survey involving 13 European nephrology schools., Results: Most residency fellowship programs received a good rating with regard to "satisfaction", in particular for the following items: number of hospitalizations followed-up, chronic hemodialysis training, follow-up of transplanted patients, diagnosis and treatment of glomerulonephritis. The teachings that were identified as being of lower quality or insufficient intensity included vascular access management, ultrasound diagnostics and renal nutrition. The need for improvement in formal teaching programs was underlined. Young nephrologists were rather satisfied with their salary and with the quality of the work they were doing, but only few were interested in an academic career since it was generally held that it is "too difficult" to obtain a university position. Many young nephrologists who filled in the questionnaire felt that lack of experience in peritoneal dialysis and vascular access management was a barrier to finding an ideal job. Compared to other European training programs, the Italian program differs with regard to longer exposure to nephrology (as compared to internal medicine), and greater flexibility for internships in different settings, including abroad., Conclusions: This first nationwide survey on the satisfaction of residents in nephrology indicates that, despite rather good overall satisfaction, there is room for improvement to make nephrology a more appealing choice and to fulfill the needs of a growing number of renal disease patients., (© 2024. The Author(s).)

After a huge decline in sperm concentration between 1938 and 1991 was reported, many researchers investigated the possibility of a worsening of human sperm quality. Despite massive efforts, published evidence is still controversial. Similarly, the role of lifestyle factors on semen parameters is debated. We conducted a monocentric Italian study to evaluate the total sperm number trend over the last 10 years (from 2010 to 2019). Additionally, we evaluated the association between lifestyle factors and total sperm number in order to identify possible damaging factors. We performed a retrospective study analyzing subjects aged 18-55 years who had their semen analyzed between 2010 and 2019. A total of 3329 subjects were included: 1655 subjects referred to our department (Department of Experimental Medicine, Sapienza University of Rome, Roma, Italy) for idiopathic infertility and 1674 subjects referred for preconceptional or andrological screening with no confirmed andrological diseases. Semen samples were examined according to World Health Organization (WHO) 2010 criteria by two seminologists with the same training and the same equipment. For statistical evaluations, only total sperm number (×10 6 per ejaculate) was taken into consideration. We detected no significant changes in mean total sperm number during the last decade, in either the entire population or the two subgroups (infertile group and control group). In a multivariate analysis total sperm number was significantly associated with the history of infertility, body mass index (BMI) and cigarette smoking. Our results suggest that infertile men are "vulnerable" subjects, particularly susceptible to several negative factors, many of which still remain unknown. Our study highlights the need for studies addressing men's lifestyle in order to find and reduce deleterious agents., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Objectives: Acute gastrointestinal graft-versus-host disease (GI-aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Diagnosis relies on clinical, endoscopic, and pathological investigations. Our purpose is to assess the value of magnetic resonance imaging (MRI) in the diagnosis, staging, and prediction of GI-aGVHD-related mortality., Methods: Twenty-one hematological patients who underwent MRI for clinical suspicion of acute GI-GVHD were retrospectively selected. Three independent radiologists, blinded to the clinical findings, reanalyzed MRI images. The GI tract was evaluated from stomach to rectum by analyzing fifteen MRI signs suggestive of intestinal and peritoneal inflammation. All selected patients underwent colonoscopy with biopsies. Disease severity was determined on the basis of clinical criteria, identifying 4 stages of increasing severity. Disease-related mortality was also assessed., Results: The diagnosis of GI-aGVHD was histologically confirmed with biopsy in 13 patients (61.9%). Using 6 major signs (diagnostic score), MRI showed 84.6% sensitivity and 100% specificity in identifying GI-aGVHD (AUC = 0.962; 95% confidence interval 0.891-1). The proximal, middle, and distal ileum were the segments most frequently affected by the disease (84.6%). Using all 15 signs of inflammation (severity score), MRI showed 100% sensitivity and 90% specificity for 1-month related mortality. No correlation with the clinical score was found., Conclusion: MRI has proved to be an effective tool for diagnosing and scoring GI-aGVHD, with a high prognostic value. If larger studies will confirm these results, MRI could partly replace endoscopy, thus becoming the primary diagnostic tool for GI-aGVHD, being more complete, less invasive, and more easily repeatable., Key Points: • We have developed a new promising MRI diagnostic score for GI-aGVHD with a sensitivity of 84.6% and specificity of 100%; results are to be confirmed by larger multicentric studies. • This MRI diagnostic score is based on the six MRI signs most frequently associated with GI-aGVHD: small-bowel inflammatory involvement, bowel wall stratification on T2-w images, wall stratification on post-contrast T1-w images, ascites, and edema of retroperitoneal fat and declivous soft tissues. • A broader MRI severity score based on 15 MRI signs showed no correlation with clinical staging but high prognostic value (100% sensitivity, 90% specificity for 1-month related mortality); these results also need to be confirmed by larger studies., (© 2023. The Author(s).)

Background:  Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-related pneumonia is associated with venous and arterial thrombosis. Aim of the study was to find out a new score for predicting thrombosis in patients with SARS-CoV-2., Methods:  We included a cohort of 674 patients affected by SARS-CoV-2, not requiring intensive care units, and followed-up during the hospitalization until discharge. Routine analyses performed at in-hospital admission included also serum albumin and D-dimer while arterial and venous thromboses were the endpoints of the study., Results:  During the follow-up, 110 thrombotic events were registered; patients with thrombotic events were older and had lower albumin and higher D-dimer, compared with thrombotic event-free ones. On multivariable logistic regression with step-by-step procedure age, serum albumin, and D-dimer were independently associated with thrombotic events. The linear combination of age, D-dimer, and albumin allowed to build-up the ADA (age-D-dimer-albumin) score, whose area under the curve (AUC) was 0.752 (95% confidence interval [CI], 0.708-0.795). ADA score was internally validated by bootstrap sampling procedure giving an AUC of 0.752 (95% CI: 0.708-0.794)., Conclusion:  Combination of age, D-dimer, and albumin in the ADA score allows identifying SARS-CoV-2 patients at higher risk of thrombotic events., Competing Interests: None declared., (Thieme. All rights reserved.)

Research is lacking on the reversibility of antimicrobial resistance (AMR). Thus, we aimed to determine the influence of previous antibiotic use on the development and decay over time of third generation cephalosporin (3GC)-resistance of E. coli . Using the database of hospital laboratories of the Autonomous Province of Bolzano/Bozen (Italy), anonymously linked to the database of outpatient pharmaceutical prescriptions and the hospital discharge record database, this matched case-control study was conducted including as cases all those who have had a positive culture from any site for 3GC resistant E. coli (3GCREC) during a 2016 hospital stay. Data were analyzed by conditional logistic regression. 244 cases were matched to 1553 controls by the date of the first isolate. Male sex (OR 1.49, 95% CI 1.10-2.01), older age (OR 1.11, 95% CI 1.02-1.21), the number of different antibiotics taken in the previous five years (OR 1.20, 95% CI 1.08-1.33), at least one antibiotic prescription in the previous year (OR 1.92, 95% CI 1.36-2.71), and the diagnosis of diabetes (OR 1.57, 95% CI 1.08-2.30) were independent risk factors for 3GCREC colonization/infection. Patients who last received an antibiotic prescription two years or three to five years before hospitalization showed non-significant differences with controls (OR 0.97, 95% CI 0.68-1.38 and OR 0.85, 95% CI 0.59-1.24), compared to an OR of 1.92 (95% CI 1.36-2.71) in those receiving antibiotics in the year preceding hospitalization. The effect of previous antibiotic use on 3GC-resistance of E. coli is highest after greater cumulative exposure to any antibiotic as well as to 3GCs and in the first 12 months after antibiotics are taken and then decreases progressively.

Evidences of an association between air pollution and Covid-19 infections are mixed and inconclusive. We conducted an ecological analysis at regional scale of long-term exposure to air-borne particle matter and spread of Covid-19 cases during the first wave of epidemics. Global air pollution and climate data were calculated from satellite earth observation data assimilated into numerical models at 10 km resolution. Main outcome was defined as the cumulative number of cases of Covid-19 in the 14 days following the date when > 10 cumulative cases were reported. Negative binomial mixed effect models were applied to estimate the associations between the outcome and long-term exposure to air pollution at the regional level (PM 10 , PM 2.5 ), after adjusting for relevant regional and country level covariates and spatial correlation. In total we collected 237,749 Covid-19 cases from 730 regions, 63 countries and 5 continents at May 30, 2020. A 10 μg/m 3 increase of pollution level was associated with 8.1% (95% CI 5.4%, 10.5%) and 11.5% (95% CI 7.8%, 14.9%) increases in the number of cases in a 14 days window, for PM 2.5 and PM 10 respectively. We found an association between Covid-19 cases and air pollution suggestive of a possible causal link among particulate matter levels and incidence of COVID-19.

CD44v6, the CD44 isoform mostly involved in cancer cell migration and invasion, has been identified as a functional biomarker and therapeutic target in colon cancer stem cells. We here provide evidence that baseline CD44v6-positive CTC predict treatment failure in patients with metastatic colorectal cancer undergoing first-line chemotherapy. We suggest that CD44v6-positive CTC can be used to early detect intrinsic drug resistance in this cancer type., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright: © 2020 Nicolazzo et al.)

Background: Uniportal video-assisted thoracoscopic surgery (VATS) lobectomy has become a common approach for the treatment of early stage lung cancer. Here, we aimed to establish whether the length of uniportal incision could affect postoperative pain and surgical outcomes in consecutive patients undergoing uniportal VATS lobectomy for early stage lung cancer., Methods: This was a unicenter Randomized Control Trial (NCT03218098). Consecutive patients undergoing uniportal VATS lobectomy for Stage I lung cancer were randomly assigned to a Small Incision group or Long Incision group in 1:1 ratio based on whether patients received a 4 cm or 8 cm incision. The endpoints were to compare the intergroup difference regarding (i) postoperative pain measured by brief pain inventory (BPI) questionnaire (first endpoint); (ii) operative time; (iii) length of chest drainage; (iv) length of hospital stay; (v) postoperative complications; and (vi) pulmonary functional status (secondary endpoints)., Results: A total of 48 patients were eligible for the study. Four patients were excluded; the study population included 44 patients: 23 within the Small Incision group, and 21 within the Long Incision group. The 11 BPI scores between the two groups showed no significant difference. Small Incision group presented higher operative time than Long Incision group (138.69 vs. 112.14 minutes; P = 0.0001) while no significant differences were found regarding length of hospital stay (P = 0.95); respiratory complications (P = 0.92); FEV1% (P = 0.63), and 6-Minute Walking Test (P = 0.77)., Conclusions: A larger incision for uniportal VATS lobectomy significantly reduced the operative time due to better exposure of the anatomical structures without increasing postoperative pain or affecting the surgical outcome., Key Points: A larger incision for uniportal VATS lobectomy significantly reduced the operative time due to better exposure of the anatomical structures without increasing postoperative pain or affecting the surgical outcome. To perform a larger incision could be a valuable strategy, particularly in nonexpert hands or when the patient's anatomy or tumor size make exposure of anatomic structures through smaller incisions difficult., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: To identify differences between two cohorts of adult and pediatric patients affected by Crohn's disease (CD), with regard to lesion location in the small intestine and colon-rectum, lesion activity, and prevalence of perianal disease (PD), using MRI as the main diagnostic tool., Methods: We retrospectively reviewed 350 consecutive MRI examinations performed between 2013 and 2016 in outpatients or inpatients with histologically proven CD, monitored by the Gastroenterology and Pediatric Units of our Hospital. The magnetic resonance enterography (MRE) protocol for adult and pediatric CD patients routinely includes evaluation of nine different intestinal segments (from jejunum to rectum) and of the anal canal. Intestinal activity was also calculated using a validated score. Perianal disease (PD) was staged. Fisher's exact test was used and the odds ratio (OR) was calculated., Results: Two hundred and nineteen out of 350 MRI studies (118 adults and 101 children) were included. The prevalence of PD was 34.6% in children and 16.1% in adults (OR = 2.8; p = 0.0017). Pediatric patients showed more frequent rectal involvement (29.7% vs 13.5%, OR = 2.7; p = 0.0045) and higher risk of PD in the presence of rectal disease (p = 0.043; OR = 4.5). In pediatric patients with severe colorectal disease, the prevalence of PD was twofold (86.7% vs 40%; p = 0.072). Using the clinical Montreal classification for lesion location, no significant differences emerged between the two patient populations., Conclusions: MRI showed a significantly higher prevalence of rectal involvement and perianal disease in the pediatric population. These results may have a relevant clinical impact and deserve further investigation., Key Points: • To our knowledge, this is the largest morphological comparative study available in the literature using MRI as the main diagnostic tool to compare adult patients and children with Crohn's disease. • Our study showed significant differences between adults and children: a higher prevalence of rectal and perianal fistulous disease (PD) in pediatric patients and an increased prevalence of PD in the presence of severe colon-rectum involvement. • The association of rectal and perianal disease implies a poorer clinical prognosis and a higher risk of disabling complications in pediatric patients.

Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

In the original publication, one of the ARAPACIS collaborators Dr. "Leonardo Di Gennaro" name has been erroneously mentioned as "Leonardo De Gennaro".

Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.

Chronic obstructive pulmonary disease (COPD) increases the risk of mortality in non-valvular atrial fibrillation (NVAF) patients. Data on the relationship of COPD to major cardiovascular events (MACE) in AF have not been defined. The aim of the study is to assess the predictive value of COPD on incident MACE in NVAF patients over a 3-year follow-up. In the Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study (ARAPACIS) cohort, we evaluate the impact of COPD on the following clinical endpoints: MACE (including vascular death, fatal/non-fatal MI and stroke/TIA), cardiovascular (CV) death and all-cause mortality. Among 2027 NVAF patients, patients with COPD (9%) are more commonly male, elderly and at higher thromboembolic risk. During a median 36.0 months follow-up, 186 patients experienced MACE: vascular death (n = 72), MI (n = 57), stroke/TIA (n = 57). All major outcomes (including stroke/TIA, MI, vascular death, and all-cause death) are centrally adjudicated. Kaplan-Meier curves show that NVAF patients with COPD are at higher risk for MACE (p < 0.001), CV death (p < 0.001) and all-cause death (p < 0.001). On Cox proportional hazard analysis, COPD is an independent predictor of MACE (Hazard ratio [HR] 1.77, 95% Confidence Intervals [CI] 1.20-2.61; p = 0.004), CV death (HR 2.73, 95% CI 1.76-4.23; p < 0.0001) and all-cause death (HR 2.16, 95% CI 1.48-3.16; p < 0.0001). COPD is an independent predictor of MACE, CV death and all-cause death during a long-term follow-up of NVAF patients.

Influenza virus replicates intracellularly exploiting several pathways involved in the regulation of host responses. The outcome and the severity of the infection are thus strongly conditioned by multiple host factors, including age, sex, metabolic, and redox conditions of the target cells. Hormones are also important determinants of host immune responses to influenza and are recently proposed in the prophylaxis and treatment. This study shows that female mice are less susceptible than males to mouse-adapted influenza virus (A/PR8/H1N1). Compared with males, PR8-infected females display higher survival rate (+36%), milder clinical disease, and less weight loss. They also have milder histopathological signs, especially free alveolar area is higher than that in males, even if pro-inflammatory cytokine production shows slight differences between sexes; hormone levels, moreover, do not vary significantly with infection in our model. Importantly, viral loads (both in terms of viral M1 RNA copies and tissue culture infectious dose 50%) are lower in PR8-infected females. An analysis of the mechanisms contributing to sex disparities observed during infection reveals that the female animals have higher total antioxidant power in serum and their lungs are characterized by increase in (i) the content and biosynthesis of glutathione, (ii) the expression and activity of antioxidant enzymes (peroxiredoxin 1, catalase, and glutathione peroxidase), and (iii) the expression of the anti-apoptotic protein Bcl-2. By contrast, infected males are characterized by high expression of NADPH oxidase 4 oxidase and phosphorylation of p38 MAPK, both enzymes promoting viral replication. All these factors are critical for cell homeostasis and susceptibility to infection. Reappraisal of the importance of the host cell redox state and sex-related effects may be useful in the attempt to develop more tailored therapeutic interventions in the fight against influenza.

Purpose: The aim of the present study is to assess impairment of spermatogenesis induced by varicocele in, to our knowledge, the largest single-centre caseload available to date., Materials and Methods: We conducted a retrospective study on 4230 consecutive patients attending our Department for andrological outpatient assessment and preconception check-ups between 2011 and 2014. A total of 2113 patients had varicocele (Group V), while the remaining 2117 were selected as the control group (Group C). All patients were divided into age classes (<17, 18-28, 29-39 and ≥40 years), and Group V patients were classified as "low" (I-II) or "high" (III-IV) grade., Results: Varicocele patients had a higher mean height than controls, as well as lower BMI. There was also a statistically significant reduction in the concentration/mL and the total sperm number in Group V against Group C. When stratified by age, values for all semen parameters were significantly worse in the older than in the younger age classes in both Group V and Group C, except for concentration/mL and total sperm number in the 29-39 and ≥40 age classes in both groups. A multivariable logistic regression analysis showed that factors independently predicting the presence of varicocele were older age, higher BMI and smoking for more than 10 years., Conclusions: Varicocele patients show worse semen parameters compared to controls, although their values were still within WHO reference limits. Semen quality is further worsened by increased age, grade and chronic smoking.

Background and Aims: Vascular disease (VD), as assessed by history of myocardial infarction or peripheral artery disease or aortic plaque, increases stroke risk in atrial fibrillation (AF), and is a component of risk assessment using the CHA 2 DS 2 -VASc score. We investigated if systemic atherosclerosis as detected by ultrasound carotid plaque (CP) could improve the predictive value of the CHA 2 DS 2 -VASc score., Methods: We analysed data from the ARAPACIS study, an observational study including 2027 Italian patients with non-valvular AF, in whom CP was detected using Doppler Ultrasonography., Results: VD was reported in 351 (17.3%) patients while CP was detected in 16.6% patients. Adding CP to the VD definition leaded to higher VD prevalence (30.9%). During a median [IQR] follow-up time of 36months, 56 (2.8%) stroke/TIA events were recorded. Survival analysis showed that conventional VD alone did not increase the risk of stroke (Log-Rank: 0.009, p=0.924), while addition of CP to conventional VD was significantly associated to an increased risk of stroke (LR: 5.730, p=0.017). Cox regression analysis showed that VD+CP was independently associated with stroke (HR: 1.78, 95% CI: 1.05-3.01, p=0.0318). Reclassification analysis showed that VD+CP allowed a significant risk reclassification when compared to VD alone in predicting stroke at 36months (NRI: 0.192, 95% CI: 0.028-0.323, p=0.032)., Conclusions: In non-valvular AF patients the addition of ultrasound detection of carotid plaque to conventional VD significantly increases the predictive value of CHA 2 DS 2 -VASc score for stroke., (Copyright © 2017. Published by Elsevier B.V.)

Background: Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc., Methods: Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells., Results: Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes., Conclusion: This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells.

Purpose: To assess correlations between periodontal status, maternal age and adverse pregnancy outcomes, such as pre-term and low birth weight in a sample of pregnant women., Methods: Study population was represented by outpatient pregnant women, gestational age > 26 weeks. Medical history questionnaires were administered to all participants who underwent clinical evaluation; clinical obstetric outcome records were collected after delivery. A questionnaire was administered regarding personal information, socio-economic status, oral hygiene habits, and oral health conditions. A clinical oral examination was performed to collect Simplified Oral Hygiene Index (OHI-S) and Community Periodontal Index (CPI). Pregnancy outcome records included: delivery week, kind and causes of delivery, any relevant complications, and birth weight. Descriptive statistics were used to depict the data from the questionnaire while the relationship between delivery week, birth weight, maternal age and periodontal status was evaluated through multivariate tests of significance., Results: 88 pregnant women were enrolled in the study. The results showed a statistically significant correlation (P< 0.001) among participants older than 40 years of age, between periodontal disease and adverse pregnancy outcomes. No statistical correlation was found among pre-term and low birth weight, smoking, ethnicity and educational level of mothers. The results highlight the importance of including a routine oral and periodontal health examination in pregnant women older than 40 years of age., Clinical Significance: The correlation between periodontal status and adverse pregnancy outcomes in older mothers indicates the need for routine oral health examination and periodontal status assessment and care in pregnant women older than 40 years of age., Competing Interests: The authors declared no conflict of interest.

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helios(high) and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression.

Atrial fibrillation (AF) patients are at high risk for thrombotic and vascular events related to their cardiac arrhythmia and underlying systemic atherosclerosis. Ankle-Brachial Index (ABI) is a non-invasive tool in evaluating systemic atherosclerosis, useful in predicting cardiovascular events in general population; no data are available in AF patients. ARAPACIS is a prospective multicentre observational study performed by the Italian Society of Internal Medicine, analysing association between low ABI (≤ 0.90) and vascular events in NVAF out- or in-patients, enrolled in 136 Italian centres. A total of 2,027 non-valvular AF (NVAF) patients aged > 18 years from both sexes followed for a median time of 34.7 (interquartile range: 22.0-36.0) months, yielding a total of 4,614 patient-years of observation. Mean age was 73 ± 10 years old with 55 % male patients. A total of 176 patients (8.7 %) experienced a vascular event, with a cumulative incidence of 3.81 %/patient-year. ABI≤ 0.90 was more prevalent in patients with a vascular event compared with patients free of vascular events (32.2 vs 20.2 %, p< 0.05). On Cox proportional hazard analysis, ABI≤ 0.90 was an independent predictor of vascular events (hazard ratio (HR): 1.394, 95 % confidence interval (CI): 1.042-1.866; p=0.02), vascular death (HR: 2.047, 95 % CI: 1.255-3.338; p=0.004) and MI (HR: 2.709, 95 % CI: 1.485-5.083; p=0.001). This latter association was also confirmed after excluding patients with previous MI (HR: 2.901, 95 % CI: 1.408-5.990, p=0.004). No association was observed between low ABI and stroke/transient ischaemic attack (p=0.91). In conclusion, low ABI is useful to predict MI and vascular death in NVAF patients and may independently facilitate cardiovascular risk assessment in NVAF patients.

Objectives: In 2012, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published novel guidelines on celiac disease (CD) diagnosis. Symptomatic children with serum anti-transglutaminase (anti-tTG) antibody levels ≥10 times upper limit of normal (ULN) could avoid duodenal biopsies after positive HLA test and serum anti-endomysial antibodies (EMAs). So far, both asymptomatic and symptomatic patients with anti-tTG titer <10 times ULN should undergo upper endoscopy with duodenal biopsies to confirm diagnosis. The aim of this study was to assess the accuracy of serological tests to diagnose CD in asymptomatic patients., Methods: We retrospectively reviewed data of 286 patients (age range: 10 months to 17 years) with CD diagnosis based on elevated titer of anti-tTG, EMA positivity, and histology. All patients were distinguished between symptomatic and asymptomatic; histological lesions were graded according to the Marsh-Oberhuber (MO) criteria. Fisher exact test was applied to analyze both groups in terms of diagnostic reliability of serological markers., Results: A total of 196 patients (68.53%) had anti-tTG titers ≥10 times ULN. Among them, a group of 156 patients (79.59%) also had symptoms suggestive of CD ("high-titer" symptomatic); of these, 142 patients (91.02%) showed severe lesion degree (3a, 3b, 3c MO). Conversely, 40 out of 196 patients (20.40%) were asymptomatic ("high-titer" asymptomatic) and 37 patients (92.5%) of them showed severe lesion degree (3a, 3b, 3c MO). No difference in histological damage was found between "high-titer" symptomatic and "high-titer" asymptomatic children (Fisher exact test, P=1.000)., Conclusions: If confirmed in large multicenter prospective studies, the "biopsy-sparing" protocol seems to be applicable to both symptomatic and asymptomatic patients with anti-tTG titer ≥10 times ULN, positive EMA, and HLA-DQ2/DQ8.

CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

Background: The rising interest towards minimally invasive surgery has led to the introduction of laparo-endoscopic single site (LESS) surgery as the natural evolution of conventional multiport laparoscopy. However, this new surgical approach is hampered with peculiar technical difficulties. The SPIDER surgical system has been developed in the attempt to overcome some of these challenges. Our study aimed to compare standard laparoscopy and SPIDER technical performance on a surgical simulator, using standardized tasks from the Fundamentals of Laparoscopic Surgery (FLS)., Methods: Twenty participants were divided into two groups based on their surgical laparoscopic experience: 10 PGY1 residents were included in the inexperienced group and 10 laparoscopists in the experienced group. Participants performed the FLS pegboard transfers task and pattern cutting task on a laparoscopic box trainer. Objective task scores and subjective questionnaire rating scales were used to compare conventional laparoscopy and SPIDER surgical system., Results: Both groups performed significantly better in the FLS scores on the standard laparoscopic simulator compared to the SPIDER. Inexperienced group: Task 1 scores (median 252.5 vs. 228.5; p = 0.007); Task 2 scores (median 270.5 vs. 219.0; p = 0.005). Experienced group: Task 1 scores (median 411.5 vs. 309.5; p = 0.005); Task 2 scores (median 418.0 vs. 331.5; p = 0.007). Same aspects were highlighted for the subjective evaluations, except for the inexperienced surgeons who found both devices equivalent in terms of ease of use only in the peg transfer task., Conclusions: Even though the SPIDER is an innovative and promising device, our study proved that it is more challenging than conventional laparoscopy in a population with different degrees of surgical experience. We presume that a possible way to overcome such challenges could be the development of tailored training programs through simulation methods. This may represent an effective way to deliver training, achieve mastery and skills and prepare surgeons for their future clinical experience.

Objective: The aim of this study was to assess pre- and postoperative taste ability in patients undergoing middle ear surgery for otosclerosis or chronic otitis media. Olfactory function was also evaluated to rule out taste deficits due to concomitant nasal pathology., Methods: All patients underwent ear, nose, and throat examination, otomicroscopy, nasal endoscopy, anterior rhinomanometry, taste testing, and olfactory testing. Patients were evaluated at 1 to 5 days preoperatively (T0), and at 1 (T1), 6 (T6), and 12 (T12) months postoperatively., Results: Both groups of patients experienced worsening of the mean taste threshold postoperatively. This phenomenon was more serious in poststapedotomy patients. Follow-up showed progressive improvement in both groups. All values of olfactory testing were within the normal range for otosclerosis patients. Patients with chronic otitis media showed variable postoperative findings., Conclusion: Chorda tympani function can be negatively affected by middle ear surgery. Deficits may be more marked in stapedotomy patients than in those undergoing tympanoplasty. Postoperative recovery of taste is satisfactory, although with different timelines for the 2 types of pathology., (© The Author(s) 2014.)

The occurrence of heart failure during the whole pre-discharge course of coronary revascularization, as far as its influence on subsequent prognosis, is poorly understood. The present study examined the effect of transient heart failure (THF) developing in the acute and rehabilitative phase on survival after coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI). Patients in the Italian survey on cardiac rehabilitation and secondary prevention after cardiac revascularization (ICAROS) were analyzed for THF, the latter being defined either as signs and symptoms consistent with decompensation or cardiogenic shock. ICAROS was a prospective, multicenter registry of 1,262 consecutive patients discharged from 62 cardiac rehabilitation (CR) facilities, providing data on risk factors, lifestyle habits, drug treatments, and major cardiovascular events (MACE) during a 1-year follow-up. Records were linked to the official website of the Italian Association of Cardiovascular Prevention and Rehabilitation (GICR-IACPR). The overall prevalence of pre-discharge THF was 7.6%, with 69.8% of cases in acute wards, 22.9% during CR, and 7.3% in both settings. THF affected more frequently patients with chronic cardiac condition (42.7 vs. 30.6%; p < 0.05), age ≥75 years (33.3 vs. 23.1%; p < 0.005), COPD (19.8 vs. 12.3%; p < 0.05), and chronic kidney disease (17.7 vs. 7%; p < 0.001). After discharge, THF patients showed good maintenance rates of RAAS modulators (90.6%) and beta-blockers (83.3%), while statin therapy significantly decreased from 81.3 to 64.6% (p < 0.05). The pursuit of secondary prevention targets, as far as self-reported drug adherence, was not different among groups. Patients with THF had increased 1-year mortality (8.3 vs. 1.6%, p < 0.001). Moreover, THF independently predicted adverse outcome with OR for recurrent events (mainly further episodes of decompensation) of 2.4 (CI 1.4-4.3). Patients who experienced THF after coronary revascularization had increased post-discharge mortality and cardiovascular events. Hemodynamic instability, rather than recurrent myocardial ischemia, seems to be linked with worse prognosis.

Background & Aims: We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome., Methods: We studied noncholestatic cirrhotics submitted to primary deceased-donor liver transplantation in a prospective group (n=140) from Rome and in a validation retrospective cohort (n=157) from Udine, Italy. Pre-ischaemia and post-reperfusion cholesterol metabolism gene mRNA was measured by RT-PCR in 74 grafts of the study group., Results: At Cox regression analysis, independently from confounders including recipient MELD score, the recipient pre-operative sTC pooled quintiles 2-5, compared with the lowest quintile showed HR (95% CI) and significances for overall graft loss (GL) of 0.215 (0.104-0.444) P<0.001 in the study group and 0.319 (0.167-0.610) P=0.001 in the validation cohort. Analysing sTC as a continuous variable, the risk of overall GL for every 10-mg/dl decrease in pre-operative sTC increased by 13% and by 9% in the study group and in the validation cohort respectively. In the study group, independent associations at multivariate analyses were: (a) high graft pre-ischaemia expression of INSIG-1, which indicates hepatocellular cholesterol depletion, with post-reperfusion graft necrosis; (b) GL with inadequate graft post-reperfusion response to cholesterol depletion, shown by a failure to reduce the PCSK9 to LDLR expression ratio; (c) GL with a relative increase of sTC on post-operative day-7, selectively because of the LDL fraction, which indirectly suggests poor cholesterol uptake from blood., Conclusions: Low recipient pre-transplant sTC concentration, its post-operative day-7 increase and a genetically determined low graft cholesterol availability predict poor liver transplant outcome., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Construct validity of virtual laparoscopic simulators for basic laparoscopic skills has been proposed; however, it is not yet clear whether the simulators can identify the actual experience of surgeons in more complex procedures such as laparoscopic Roux-en-Y gastric bypass. This study tested the ability of the Lap Mentor simulator to recognize the experience in advanced laparoscopic procedures and to assess its role in the certification of bariatric surgeons., Methods: Twenty surgeons were divided into two groups according to their experience in laparoscopic and bariatric surgery. The general group included 10 general surgeons performing between 75 and 100 nonbariatric laparoscopic procedures. The bariatric group included 10 bariatric surgeons performing between 50 and 100 laparoscopic bariatric procedures. Participants were tested on the simulator in one basic task (task 1: eye-hand coordination) and in two tasks of the gastric bypass module (task 2: creation of the gastric pouch; task 3: gastrojejunal anastomosis)., Results: Comparing the groups, no significant differences were found in task 1. Analyzing the results from the gastric bypass module (bariatric vs. general), in task 2, significant differences (p < 0.05) were found in the median volume of the gastric pouch (21 vs. 48 cm(3)), in the percentage of fundus included in the pouch (8.4 vs. 29.4 %), in the complete dissection at the angle of His (10 vs. 3), and in safety parameters. In task 3, significant differences were found in the size and position of enterotomies., Conclusions: The Lap Mentor may be proposed as a certification tool for bariatric surgeons because it also recognizes their specific skills in the technical details of the procedure that affect long-term results. Furthermore, the possibility of analyzing the performance in detail can help define areas where the surgeon is lacking. These findings indicate a potential role of the Lap Mentor in tailoring the training to maximize improvement.

Background: Better knowledge of the suprascapular notch anatomy may help to prevent and to assess more accurately suprascapular nerve entrapment syndrome. Our purposes were to verify the reliability of the existing data, to assess the differences between the two genders, to verify the correlation between the dimensions of the scapula and the suprascapular notch, and to investigate the relationship between the suprascapular notch and the postero-superior limit of the safe zone for the suprascapular nerve., Methods: We examined 500 dried scapulae, measuring seven distances related to the scapular body and suprascapular notch; they were also catalogued according to gender, age and side. Suprascapular notch was classified in accordance with Rengachary's method. For each class, we also took into consideration the width/depth ratio. Furthermore, Pearson's correlation was calculated., Results: The frequencies were: Type I 12.4%, Type II 19.8%, Type III 22.8%, Type IV 31.1%, Type V 10.2%, Type VI 3.6%. Width and depth did not demonstrate a statistical significant difference when analyzed according to gender and side; however, a significant difference was found between the depth means elaborated according to median age (73 y.o.). Correlation indexes were weak or not statistically significant. The differences among the postero-superior limits of the safe zone in the six types of notches was not statistically significant., Conclusions: Patient's characteristics (gender, age and scapular dimensions) are not related to the characteristics of the suprascapular notch (dimensions and Type); our data suggest that the entrapment syndrome is more likely to be associated with a Type III notch because of its specific features.