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Background & aims Pancreatic cystic lesions (PCLs) are frequent incidental findings. As most PCLs require costly diagnostic evaluation and active surveillance, it is important to clarify their prevalence in asymptomatic individuals. We therefore aimed at performing a systematic review and meta-analysis to determine it. Methods: a systematic search was conducted and studies meeting inclusion criteria were included. The prevalence of PCLs was pooled across studies. A random effect model was used with assessment of heterogeneity. Results 17 studies, with 48,860 patients, were included. Only 3 were prospective; 5 studies were conducted in the US, 7 in Europe, 4 in Asia and 1 in Brazil. The pooled prevalence of PCLs was 8% (95% CI 4–14) with considerable heterogeneity (I2 = 99.5%). This prevalence was higher in studies of higher quality, examining older subjects, smaller cohorts, and employing MRCP (24.8% vs 2.7% with CT-scan). The pooled rate of PCLs was four times higher in studies conducted in the US than in Asia (12.6% vs 3.1%). 7 studies reported the prevalence of mucinous lesions, with a pooled rate of 4.3% (95% CI 2–10; I2 = 99.2%), but of 0.7% only for worrisome features or high risk stigmata. Conclusion The rate of incidentally detected PCLs is of 8%. Mucinous lesions are the most common incidentally detected PCLs, although they rarely present with potential indication for surgery. The observed different rates in the US and other geographic Areas suggest that different protocols might be necessary to help balancing costs and effectiveness of follow-up investigations in asymptomatic subjects.

The onset of the Acheulean, marked by the emergence of large cutting tools (LCTs), is considered a major technological advance in the Early Stone Age and a key turning point in human evolution. The Acheulean originated in East Africa at ~ 1.8–1.6 Ma and is reported in South Africa between ~ 1.6 and > 1.0 Ma. The timing of its appearance and development in North Africa have been poorly known due to the near-absence of well-dated sites in reliable contexts. The ~ 1 Ma stone artefacts of Tighennif (Algeria) and Thomas Quarry I-Unit L (ThI-L) at Casablanca (Morocco) are thus far regarded as documenting the oldest Acheulean in North Africa but whatever the precision of their stratigraphical position, both deserve a better chronology. Here we provide a chronology for ThI-L, based on new magnetostratigraphic and geochemical data. Added to the existing lithostratigraphy of the Casablanca sequence, these results provide the first robust chronostratigraphic framework for the early North African Acheulean and firmly establish its emergence in this part of the continent back at least to ~ 1.3 Ma.

The megalithic jar sites of Laos (often referred to as the Plain of Jars) remain one of Southeast Asia’s most mysterious and least understood archaeological cultures. The sites, recently inscribed as UNESCO World Heritage, host hollowed stone jars, up to three metres in height, which appear scattered across the landscape, alone or clustered in groups of up to more than 400. Until now, it has not been possible to estimate when the jars were first placed on the landscape or from where the stone was sourced. Geochronological analysis using the age of detrital zircons demonstrates a likely quarry source for one of the largest megalithic jar sites. Optically Stimulated Luminescence (OSL) dating suggests the jars were positioned at the sites potentially as early as the late second millennium BC. Radiocarbon dating of skeletal remains and charcoal samples places mortuary activity around the jars from the 9-13th century AD, suggesting the sites have maintained ritual significance from the period of their initial placement until historic times.

Introduction Spondyloarthrits (SpA) share clinical, genetic and immunological features with Inflammatory Bowel Diseases (IBD), and enteropathic SpA (eSpA) represent the clinical evidence of the association between gut and joint diseases. This cross-sectional study aimed to report data of eSpA patients collected from the first Italian database. Patients and methods A specific web-based interface has been created to insert and collect the main clinical, serologic and imaging data from patients with eSpA, as well as disease activity, comorbidities and treatment, in a real-life scenario. Results Data were collected in 14 Italian centers (7 rheumatology and 7 gastroenterology units). A total of 347 eSpA patients were enrolled in the study. Type 1 peripheral eSpA was the most frequent form. Crohn’ Disease (CD) was the most represented IBD. CD activity was similar among eSpA, whereas UC activity was slightly higher in the axial and mixed form than in the peripheral eSpA. The disease was active in less than half of axial eSpA patients and in only 18% of patients with peripheral eSpA. Furthermore, most of the patients had an inactive IBD. Nineteen percent of the total eSpA patients were free of therapy at the time of the enrollment and 61% of the patients were receiving biotechnological agents. Conclusions The multidisciplinary management of eSpA patients, favored by this ad hoc created web-based platform, allowed to obtain data from the largest eSpA cohort. The information coming of this database might advance knowledge of eSpA and improve their standard of care.

Purpose To investigate the imaging features of emerging COVID-19 pneumonia on chest ultrasound (US), radiographs (CXR) and computed tomography (CT) examinations performed at admission and to provide a comprehensive radiological literature review on ongoing radiological data from recent publications. Materials and methods In this retrospective single-center study, we enrolled consecutive patients from February 15, 2020, to March 15, 2020, with laboratory-confirmed SARS-CoV-2 hospitalized in Valduce Hospital (Como, Italy). Multi-modality imaging findings were evaluated and compared. Literature research was conducted through a methodical search on Pubmed and Embase databases. Results Fifty-eight patients (36 men, 22 women; age range, 18–98 years) were included in the study. Among these, chest US, CXR, and CT were performed respectively in twenty-two, thirty-two and forty-two patients. Lung US findings were consistent with diffuse B lines (100%) and subpleural consolidations (27.3%). CXR showed prevalent manifestations of consolidations (46.9%) and hazy increased opacities (37.5%). Typical CT features included bilateral and multilobar ground-glass opacities (GGO) with (59.5%) and without (35.7%) consolidations having a predominantly peripheral distribution (64.3%). Other imaging features included crazy paving pattern (57.1%), fibrous stripes (50%), subpleural lines (35.7%), architectural distortion (28.6%), air bronchogram sign (26.2%), vascular thickening (23.8%) and nodules (2.4%). Also, enlarged lymph nodes (14.3 %) and pleural effusion (7.1%) were observed. The literature review identified twenty-six original studies supporting our imaging chest findings. Conclusion The spectrum of chest imaging manifestations of COVID-19 pneumonia upon admission includes B-lines and consolidations on US, consolidations and hazy increased opacities on CXR, and multifocal GGO with consolidations on CT.

Background The term sepsis is used to designate a systemic condition of infection and inflammation associated with hemodynamic changes that result in organic dysfunction. Gestational sepsis can impair the development of the central nervous system and may promote permanent behavior alterations in the offspring. The aim of our work was to evaluate the effects of maternal sepsis on inflammatory cytokine levels and synaptic proteins in the hippocampus, neocortex, frontal cortex, and cerebellum of neonatal, young, and adult mice. Additionally, we analyzed the motor development, behavioral features, and cognitive impairments in neonatal, young and adult offspring. Methods Pregnant mice at the 14th embryonic day (E14) were intratracheally instilled with saline 0.9% solution (control group) or Klebsiella spp. (3 × 108 CFU) (sepsis group) and started on meropenem after 5 h. The offspring was sacrificed at postnatal day (P) 2, P8, P30, and P60 and samples of liver, lung, and brain were collected for TNF-α, IL-1β, and IL-6 measurements by ELISA. Synaptophysin, PSD95, and β-tubulin levels were analyzed by Western blot. Motor tests were performed at all analyzed ages and behavioral assessments were performed in offspring at P30 and P60. Results Gestational sepsis induces a systemic pro-inflammatory response in neonates at P2 and P8 characterized by an increase in cytokine levels. Maternal sepsis induced systemic downregulation of pro-inflammatory cytokines, while in the hippocampus, neocortex, frontal cortex, and cerebellum an inflammatory response was detected. These changes in the brain immunity were accompanied by a reduction of synaptophysin and PSD95 levels in the hippocampus, neocortex, frontal cortex, and cerebellum, in all ages. Behavioral tests demonstrated motor impairment in neonates, and depressive-like behavior, fear-conditioned memory, and learning impairments in animals at P30 and P60, while spatial memory abilities were affected only at P60, indicating that gestational sepsis not only induces an inflammatory response in neonatal mouse brains, but also affects neurodevelopment, and leads to a plethora of behavioral alterations and cognitive impairments in the offspring. Conclusion These data suggest that maternal sepsis may be causatively related to the development of depression, learning, and memory impairments in the litter.

Funerary landscapes are eminent results of the relationship between environments and superstructural human behavior, spanning over wide territories and growing over centuries. The comprehension of such cultural palimpsests needs substantial research efforts in the field of human ecology. The funerary landscape of the semi-arid region of Kassala (Eastern Sudan) represents a solid example. Therein, geoarchaeological surveys and the creation of a desk-based dataset of thousands of diachronic funerary monuments (from early tumuli up to modern Beja people islamic tombs) were achieved by means of fieldwork and remote sensing over an area of ∼4100 km2. The wealth of generated information was employed to decipher the spatial arrangement of sites and monuments using Point Pattern Analysis. The enormous number of monuments and their spatial distribution are here successfully explained using, for the first time in archaeology, the Neyman-Scott Cluster Process, hitherto designed for cosmology. Our study highlights the existence of a built funerary landscape with galaxy-like aggregations of monuments driven by multiple layers of societal behavior. We suggest that the distribution of monuments was controlled by a synthesis of opportunistic geological constraints and cultural superstructure, conditioned by the social memory of the Beja people who have inhabited the region for two thousand years and still cherish the ancient tombs as their own kin's.

Herpes simplex virus 1 (HSV-1) infects skin and mucosal epithelial cells and then travels along axons to establish latency in the neurones of sensory ganglia. Although viral gene expression is restricted during latency, the latency-associated transcript (LAT) locus encodes many RNAs, including a 2 kb intron known as the hallmark of HSV-1 latency. Here, we studied HSV-1 infection and the role of the LAT locus in human skin xenografts in vivo and in cultured explants. We sequenced the genomes of our stock of HSV-1 strain 17syn+ and seven derived viruses and found nonsynonymous mutations in many viral proteins that had no impact on skin infection. In contrast, deletions in the LAT locus severely impaired HSV-1 replication and lesion formation in skin. However, skin replication was not affected by impaired intron splicing. Moreover, although the LAT locus has been implicated in regulating gene expression in neurones, we observed only small changes in transcript levels that were unrelated to the growth defect in skin, suggesting that its functions in skin may be different from those in neurones. Thus, although the LAT locus was previously thought to be dispensable for lytic infection, we show that it is a determinant of HSV-1 virulence during lytic infection of human skin., Author summary Herpes simplex virus type 1 (HSV-1) infects and destroys the outer layer of skin cells, producing lesions known as cold sores. Although these lesions heal, the virus persists in the host for the lifetime and can reactivate to cause new lesions. This is possible because the virus enters the axons of neurones in the skin and moves to their cell bodies located in spinal or cranial nerve bundles called ganglia, where the virus becomes dormant (latent). The most abundant viral RNAs expressed during this state are the latency associated transcripts (LATs), which have been considered a hallmark of HSV-1 latency. Here, we studied HSV-1 infection and spread in human skin. Unexpectedly, we found that the LAT locus is necessary for lesion formation in skin. HSV-1 viruses that were genetically mutated to delete the start of the locus could not spread in skin, whereas viruses with many other genetic mutations had this capacity. Our results suggest that an antiviral drug that inhibits transcripts from this region of the viral genome could block viral spread in skin, or a vaccine could possibly be produced by genetically modifying the virus at the LAT locus and by doing so, limit the virus’ ability become latent in neurones.

Background and objectives: Electrocardiograph abnormalities (i.e., QT interval prolongation) have been described in inflammatory bowel diseases (IBD). We aimed to measure the QT interval in a cohort of patients with IBD and to analyze its relationship with clinical and inflammatory activity. Materials and Methods: We performed a cross-sectional study that included 38 IBD outpatients and 38 &ldquo, age- and sex-matched&rdquo, healthy controls. Nine patients had active IBD, and 29 were in clinical remission. Among the latter, 10 patients had sustained (lasting &gt, 1 year) and 19 had short-term remission (&le, 1 year). Corrected QT (QTc) interval was measured on standard 12-lead electrocardiograph. A systematic review of the literature on studies investigating the QT interval in patients with IBD was also performed. Results: QTc interval values were similar between IBD patients and healthy controls (417.58 &plusmn, 22.05 ms vs. 409.13 &plusmn, 19.61 ms, respectively, p: 0.479). Patients with active IBD had significantly higher QTc values (435.11 &plusmn, 27.31 ms) than both controls (409.13 &plusmn, 19.61 ms) and patients in remission (412.14 &plusmn, 17.33 ms) (p: 0.031). Post hoc analysis showed that the difference in QTc values between active IBD and remission was attributable to the group of patients with sustained remission (p &lt, 0.05). Lastly, a significant correlation between QTc interval and C-reactive protein (CRP) values was observed (Spearman test: r = 0.563, p: 0.0005). Conclusions: Our study demonstrates an association between QTc duration and both clinical and inflammatory activity in patients with IBD. The higher the CRP value, the longer is the QTc duration. For practical purposes, all patients with active IBD should undergo a standard ECG. Prescription of drugs able to modify the QT interval should be avoided in patients with active IBD. The systematic review of the literature indicated that this is the first published study demonstrating an association between the QTc duration and CRP values in patients with IBD.

Knowledge about the function of varicella-zoster virus glycoprotein M is limited; the requirement of gM for skin and neural tropism are unknown. VZV gM contains two predicted YXXΦ trafficking motifs and a dileucine motif in the carboxyl-terminus. We constructed a recombinant VZV with gM truncated from the first YXXΦ and five additional viruses with YXXΦ tyrosine substitutions, alone and in combination with dileucine substitution. All recombinant viruses grew to high titer but mutation of the membrane-proximal YXXΦ motif reduced plaque size in cultured cells and altered gM localization. C-terminus truncation had a pronounced effect on virion morphogenesis and plaque size, but not on overall replication kinetics in vitro. Mutation of gM trafficking motifs and truncation attenuated replication in human skin xenografts in vivo; gM truncation did not alter neurotropism. Our results demonstrate that the gM C-terminus is dispensable for virus replication in cultured cells but is important for skin pathogenesis.

Diesel exhaust particles (DEPs) and non-exhaust particles from abrasion are two main representative sources of air pollution to which humans are exposed daily, together with emerging nanomaterials, whose emission is increasing considerably. In the present work, we aimed to investigate whether DEPs, metal oxide nanoparticles (MeO-NPs), and their mixtures could affect alveolar cells. The research was focused on whether NPs induced different types of death in cells, and on their effects on cell motility and migration. Autophagy and cell cycles were investigated via cytofluorimetric analyses, through the quantification of the autophagic biomarker LC3B and PI staining, respectively. Cellular ultrastructures were then observed via TEM. Changes in cell motility and migration were assessed via transwell migration assay, and by the cytofluorimetric analysis of E-cadherin expression. A colony-forming efficiency (CFE) assay was performed in order to investigate the interactions between cells inside the colonies, and to see how these interactions change after exposure to the single particles or their mixtures. The results obtained suggest that NPs can either reduce the toxicity of DEPs (CuO) or enhance it (ZnO), through a mechanism that may involve autophagy as cells’ response to stressors and as a consequence of particles’ cellular uptake. Moreover, NPs can induce modification of E-cadherin expression and, consequentially, of colonies’ phenotypes.

Background Neuroendocrine Neoplasms (NENs) are a heterogeneous group of tumours deriving from the diffuse endocrine system. NENs may occur almost everywhere in the body but are most common in the gastrointestinal tract, the pancreas, and the lungs, with gastroenteropancreatic (GEP) tumours representing 70% of all NENs. GEP-NENs have rarely been reported in association with inflammatory bowel diseases (IBDs) but no definitive relationship between these tumours and IBD has been established Methods This was an ECCO COllaborative Network For Exceptionally Rare case reports project (ECCO-CONFER). We included cases of GEP-NENs diagnosed in patients with IBD that met the diagnostic criteria for NEN according to the European Neuroendocrine Tumour Society. Data were retrospectively collected in a standardized case report form and analysed for event association with patient’s and IBD-related factors Results GEP-NEN was diagnosed in 100 patients with IBD [61% female, 55% Crohn’s disease, median age 48 years (IQR 37–59)]. Overall the most common location was the appendix (39/100) followed by the colon (22/100). Complete IBD-related data was available for 50 individuals with a median follow-up of 30.5 months (IQR 11.2–70) following NEN diagnosis. At the last follow-up data, 47/50 patients were alive. Three deaths occurred, of which 2 were related to NEN. Median duration of IBD at NEN diagnosis was 84 months (IQR 10–151), and in 18% of cases NEN and IBD were diagnosed concomitantly. 20/50 of NENs were at stage I (T1N0M0) and 28/50 graded G1 (ki 67 ≤2 %) at diagnosis. Incidental diagnosis of NEN either during follow-up or during surgery as well as receiving diagnosis of NEN concomitantly with IBD was significantly associated with an earlier NEN stage (p< 0.01 and p Conclusion In the largest case series to date, prognosis of patients with concomitant GEP-NEN and IBD seems favorable. Incidental NEN diagnosis correlates with an earlier NEN stage and IBD-related therapies are independent of NEN stage and grade. The association of GEP-NEN location and the segment affected by IBD may suggest a possible role of inflammation in NEN tumorigenesis

Key Points Question Can factors that are readily available at diagnosis be used to estimate the risk of progression of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs)? Findings In this cohort study that included 540 patients under surveillance for a median of 51.5 months, initial cyst size greater than 15 mm, body mass index greater than 26.4, and heavy smoking were associated with progression risk of BD-IPMNs. The AA blood genotype was also associated with progression risk. Meaning Results of this study suggest that cyst size alone is not a reliable factor to estimate progression risk, but along with other readily available data, size is helpful for planning personalized surveillance of BD-IPMNs., Importance Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are common pancreatic preneoplastic lesions, but their surveillance is not personalized. Objective To investigate patient- and cyst-related factors associated with progression into worrisome features (WFs) or high-risk stigmata (HRS) categories of BD-IPMNs. Design, Setting, and Participants Cyst- and patient-related factors of consecutive BD-IPMNs without WFs or HRS in 540 patients diagnosed from 2009 to 2018 with at least 12 months’ surveillance until February 28, 2020, were registered in a 2-center ambispective cohort study in Italy. In a subgroup, the ABO blood group was studied for the first time in this setting. Exposure Cyst-related and patients-related factors and ABO blood group. Main Outcomes and Measures The study outcome was the appearance of WFs or HRS according to the 2017 International Association of Pancreatology guidelines. Survival probability was calculated using Kaplan-Meier curve and risk factors identified by Cox proportional hazards regression. ABO blood group was inferred through genotypes with DNA extraction. Results Of 540 patients with BD-IPMNs (median age, 66 years [interquartile range, 58.5-72.0 years]; 337 women [62.4%]) undergoing surveillance for a median of 51.5 months (interquartile range, 28-84 months) for 2758 person-years, 130 patients (24.1%) experienced progression. Probability of progression was 3.7% at 1 year, 23.4% at 5 years, and 43.3% at 10 years; 15 patients (2.8%) underwent surgery, 7 patients (1.3%) had malignant histologic findings, and 3 patients (0.56%) died of pancreatic-associated disease. Initial cyst size greater than 15 mm (hazard ratio [HR], 2.05; 95% CI, 1.44-2.91), body mass index greater than 26.4 (HR, 1.72; 95% CI, 1.19-2.50), and heavy smoking (HR, 1.81; 95% CI, 1.14-2.86) were significant independent factors associated with progression risk. The AA blood genotype was also associated with progression risk (HR, 3.49; 95% CI, 1.04-11.71) compared with the OO genotype in the investigated subgroup. Conclusions and Relevance This analysis of factors associated with progression of BD-IPMNs according to recent guidelines suggests that cyst size alone is not a reliable factor for estimation of progression risk; however, along with other readily available data, size is helpful for planning personalized surveillance of BD-IPMNs., This cohort study examines the use of patient- and cyst-related factors available at baseline for estimation of the risk of progression in patients with branch-duct intraductal papillary mucinous neoplasms.

Diesel exhaust particles (DEP) are responsible for both respiratory and cardiovascular effects. However many questions are still unravelled and the mechanisms behind the health effects induced by the exposure to ultrafine particles (UFP) need further investigations. Furthermore, different emission sources can lead to diverse biological responses. In this perspective, here we have compared the effects of three DEPs, two standard reference materials (SRM 1650b and 2975) and one DEP directly sampled from a EuroIV vehicle without Diesel Particulate Filter (DPF). For the biological investigations, different in vitro lung models involving both epithelial and vascular endothelial cells, were used. Cell viability, oxidative stress, inflammation, DNA damage and endothelial activation markers were investigated at sub-cytotoxic DEP doses. The data obtained have shown that only DEP EuroIV, which had the major content of polycyclic aromatic hydrocarbons (PAHs) and metals, was able to induce oxidative stress, inflammation and consequent endothelial activation, as demonstrated by the expression of adhesion molecules (ICAM-1 and VCAM-1) and the release of inflammatory markers (IL-8) from endothelial cells. Standard reference materials were not effective under our experimental conditions. These data suggest that oxidative stress, endothelial activation and systemic inflammatory cytokines release are crucial events after DEP exposure and that the source of DEP emission, responsible of the particle chemical fingerprint, may have a key role in the resulting adverse biological outcomes.

Background Hospitalization and death in patients with chronic pancreatitis (CP) are often due to extra-pancreatic events. Recent guidelines recommend the use of the MUST score to assess CP patients’ nutritional status, but its association with clinical outcomes has been poorly investigated. The aims of this study are to evaluate the incidence of extra-pancreatic events in patients with CP during follow-up and their association with the nutritional status. Methods Retrospective analysis of single-centre cohort of CP patients prospectively enrolled and followed-up. Exocrine pancreatic insufficiency (EPI) was assessed by fecal elastase, MUST score calculated at diagnosis. The occurrence of hospitalizations or death were recorded. Differences between subgroups were analysed by Fisher’s and T-test and hospitalization-free survival with Kaplan-Meier curves and Cox regression analysis. Results Of 111 enrolled patients (64% male; mean age 57); 52% had alcoholic aetiology, 53% EPI, 10% severe CP and 26% a MUST score≥2 at diagnosis. During a median follow-up of 37 months, 3.6% of patients died and 34.2% needed hospitalization, in 50% of cases for extrapancreatic events (2% cardiovascular events, 8% infections and 3% cancer). There was no significant association between EPI, BMI Conclusions A sizeable portion of CP patients are at high risk of malnutrition and are hospitalized during the follow-up, often for extra-pancreatic events. The nutritional status evaluated with the MUST score lacks accuracy in predicting the risk of these events.

Varicella-zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian varicella virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.

Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms for which very little is known about either environmental or genetic risk factors. Only a handful of association studies have been performed so far, suggesting a small number of risk loci. Methods: To replicate the best findings, we have selected 16 SNPs suggested in previous studies to be relevant in PNET etiogenesis. We genotyped the selected SNPs (rs16944, rs1052536, rs1059293, rs1136410, rs1143634, rs2069762, rs2236302, rs2387632, rs3212961, rs3734299, rs3803258, rs4962081, rs7234941, rs7243091, rs12957119, and rs1800629) in 344 PNET sporadic cases and 2,721 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium. Results: After correction for multiple testing, we did not observe any statistically significant association between the SNPs and PNET risk. We also used three online bioinformatic tools (HaploReg, RegulomeDB, and GTEx) to predict a possible functional role of the SNPs, but we did not observe any clear indication. Conclusions: None of the selected SNPs were convincingly associated with PNET risk in the PANDoRA consortium. Impact: We can exclude a major role of the selected polymorphisms in PNET etiology, and this highlights the need for replication of epidemiologic findings in independent populations, especially in rare diseases such as PNETs. Cancer Epidemiol Biomarkers Prev; 26(8); 1349–51. ©2017 AACR.

Varicella-zoster virus (VZV) is the skin-tropic human alphaherpesvirus responsible for both varicella-zoster and herpes zoster. Varicella-zoster and herpes zoster skin lesions have similar morphologies, but herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. We hypothesized that skin aging could also influence the outcome of the anterograde axonal transport of VZV to skin. We utilized human skin xenografts maintained in immunodeficient (SCID) mice to study VZV-induced skin pathology in vivo in fetal and adult skin xenografts. Here we found that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations. In addition to measures of VZV infection, we examined the expression of type I interferon (IFN) pathway components in adult skin and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection in vivo . Our results demonstrated that VZV infection of adult skin triggers intrinsic IFN-mediated responses such as we have described in VZV-infected fetal skin xenografts, including MxA as well as promyelocytic leukemia protein (PML), in skin cells surrounding lesions. Further, we observed that VZV elicited altered cell signaling and proliferative and inflammatory responses that are involved in wound healing, driven by follicular stem cells. These cellular changes are consistent with VZV-induced activation of STAT3 and suggest that VZV exploits the wound healing process to ensure efficient delivery of the virus to keratinocytes. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies in vivo . IMPORTANCE Varicella-zoster virus (VZV) is the agent responsible for both varicella-zoster and herpes zoster. Herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. To examine the effect of skin aging on VZV skin lesions, we utilized fetal and adult human skin xenografts maintained in immunodeficient (SCID) mice. We measured VZV-induced skin pathology, examined the expression of type I interferon (IFN) pathway components in adult skin, and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection in vivo . Our results demonstrate that characteristics of aging skin are preserved in xenografts; that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations; and that VZV infection elicits altered cell signaling and inflammatory responses. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies in vivo .

Purpose: Deformation analysis from 3D echocardiography results in a considerable amount of parameters, for which the conventional statistical approach is cumbersome. We investigate local motion and deformation patterns to determine the parameters of relevance for the study of LV myocardial deformation in the presence of LAD infarct. Methods: The study included 46 patients acquired at max. 5 days after LAD infarct (37 sequences) and at 1-year follow-up (33 sequences), and 46 controls. Patients were selected if they had a LVEF

Cardiac CT (CCT) is an imaging modality that is becoming a standard in clinical cardiology. We evaluated indications, safety, and impact on patient management of routine CCT in a multicenter national registry. MATERIALS AND METHODS: During a period of 6 months, 47 centers in Italy enrolled 3,455 patients. RESULTS: CCT was performed mainly with 64-slice CT scanners (73.02 %). Contrast agents were administrated in 3,185 patients (92.5 %). Mean DLP changes with type of scanner and was lower in >64 row detector scanner. The most frequent indication for CCT was suspected CAD (44.8 %), followed by calcium scoring (9.6 %), post-angioplasty/stenting (8.3 %), post-CABGs (7.5 %), study of cardiac anatomy (4.22 %) and assessment in patients with known CAD (4.1 %) and acute chest pain (1.99 %). Most of the CCTs were performed in outpatient settings (2,549; 74 %) and a minority in inpatient settings (719, 20.8 %). Adverse clinical events (mild-moderate) occurred in 26 examinations (0.75 %). None of them was severe. In 45.3 % of the cases CCT findings impacted patient management. CONCLUSION: CCT is performed with different workloads in participating centers. It is a safe procedure and its results have a strong impact on patient management.

Arterial distensibility can be measured either by echotracking or by nuclear magnetic resonance (MRI). Little information, however, is available on the comparison between the two methods and on the relationships between the results obtained with the two approaches and the arterial stiffness gold standard measurement, i.e., pulse wave velocity (PWV). In 28 normotensive subjects (age 33.0 ± 10.4 years, mean ± SD) we measured aortic diameter 1cm above iliac bifurcation, aortic pulse pressure by tonometry and calculated arterial distensibility via the Reneman formulae for both methods. Aortic diameter and aortic distensibility were not superimposable and higher values were systematically detected with the MRI approach than with the ultrasound one. However, PWV showed a significant correlation with aortic distensibility values obtained by both methods (r= 0.50 and r= 0.49, p&nbsp

Background Herbal remedies and other complementary and alternative medicine (CAM) are used by 30% of the patients with liver and inflammatory bowel diseases. However, there are no data regarding CAM use in patients with pancreatic disorders, including potential pancreatotoxicity. Aim of the study The aim of the study was to assess the prevalence of CAM use in patients with pancreatic disorders and screen for pancreatotoxicity. Materials and methods This was a cross-sectional survey of consecutive outpatients seen at a Pancreas Center. Data were collected in a specific questionnaire. Descriptive statistics were used to analyze the prevalence and the patterns of CAM use. Characteristics associated with CAM use were analyzed by appropriate statistics. Results Of 108 patients (52% male; mean age, 65±13 years), 47 (43.5%) used CAM. The use of CAM was more frequent among patients with previous acute pancreatitis (47%). Reported reasons for the use of CAM were to help standard therapies and for an overall better feeling. About 61% of the patients reported advantages with treatment. As compared with nonusers, CAM users were more often female (55% vs. 42%), with a higher school degree (43% vs. 36%), more frequently performing physical activity (51% vs. 41%), and reporting anxiety (45% vs. 31%). However, none of these differences were statistically significant. Three patients with previous acute pancreatitis reported the use of Serenoa repens that is potentially pancreatotoxic. Discussion The rate of CAM use in patients with pancreatic disorders is similar to those reported for other digestive diseases. CAM use seems to be more frequent in women with a higher education level and a "healthier lifestyle." Patients might not be aware of the potential pancreatotoxicity of CAM, which should be carefully considered by physicians.

INTRODUCTION Budesonide belongs to low-bioavailability steroids class. A novel oral formulation of budesonide, which uses the Multi-Matrix System (MMX) for delivering drugs to the colon, is now available as a possible treatment of ulcerative colitis patients intolerant or not-responding to first-line therapy with 5-ASA. Areas covered: in this review we present information about the development and the use of budesonide MMX and we provide data about its mechanism of action as well as, pharmacodynamics and pharmacokynetics. Moreover, we present the available literature data about the efficacy and, mainly, the safety of budesonide-MMX. Expert opinion: budesonide-MMX is a new therapeutic option in mild-to-moderate UC patients. Its good safety profile in clinical trials undoubtedly represents a strength for a possible wide use in clinical practice, mainly if it will be confirmed by post-marketing data. Other indications, such as treatment of colonic Crohn's disease, could theoretically be considered, if sustained by reliable scientific data.

Data on surveillance for pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs) with "familial pancreatic cancer" (FPC) and specific syndromes are limited and heterogeneous.We conducted a systematic review and meta-analysis of PDAC surveillance studies in HRIs.Prevalence of solid/cystic pancreatic lesions and of lesions considered a successful target of surveillance (proven resectable PDAC and high-grade precursors) was pooled across studies. The rate of lesions diagnosed by endoscopic ultrasonography (EUS)/magnetic resonance imaging (MRI) and across different HRI groups was calculated.Sixteen studies incorporating 1588 HRIs were included. The pooled prevalence of pancreatic solid and cystic lesions was 5.8% and 20.2%, respectively. The pooled prevalence of patients with lesions considered a successful target of surveillance was 3.3%, being similar to EUS or MRI and varying across subgroups, being 3% in FPC, 4% in hereditary pancreatitis, 5% in familial melanoma, 6.3% in hereditary breast/ovarian cancer, and 12.2% in Peutz-Jeghers syndrome. The pooled estimated rate of lesions considered a successful target of surveillance during follow-up was 5/1000 person-years.Surveillance programs identify successful target lesions in 3.3% of HRIs with a similar yield of EUS and MRI and an annual risk of 0.5%. A higher rate of target lesions was reported in HRIs with specific DNA mutations.

Different inflammation-based scores such as the neutrophil/lymphocyte ratio (NLR), the Odonera Prognostic Nutritional Index (PNI), the Glasgow Prognostic Score, the platelet/lymphocyte ratio, and the C-reactive protein/albumin ratio have been found to be significantly associated with pancreatic cancer (PDAC) prognosis. However, most studies have investigated patients undergoing surgery, and few of them have compared these scores. We aimed at evaluating the association between inflammatory-based scores and PDAC prognosis. In a single center cohort study, inflammatory-based scores were assessed at diagnosis and their prognostic relevance as well as that of clinic-pathological variables were evaluated through multiple logistic regression and survival probability analysis. In 206 patients, age, male sex, tumor size, presence of distant metastasis, access to chemotherapy, and an NLR > 5 but not other scores were associated with overall survival (OS) at multivariate analysis. Patients with an NLR < 5 had a median survival of 12 months compared to 4 months in those with an NLR > 5. In the 81 patients with distant metastasis at diagnosis, an NLR > 5 resulted in the only variable significantly associated with survival. Among patients with metastatic disease who received chemotherapy, the median survival was 3 months in patients with an NLR > 5 and 7 months in those with an NLR < 5. The NLR might drive therapeutic options in PDAC patients, especially in the setting of metastatic disease.

Background Inflammatory bowel disease (IBD) patient’s knowledge is a key factor for shared treatment decision making. Some studies have already investigated IBD knowledge but never focused on patient’s awareness about the major disease outcomes nor clinical course nor therapeutic aspects. The aim of the present study is to assess disease knowledge in IBD patients using a novel 11 items questionnaire. Methods An 11 items questionnaire was developed. The questionnaire explored different aspects of IBD course and prognosis: pattern of symptoms, disease complications, need for surgery, risk and prevention of colon-rectal cancer (CRC), extra-intestinal manifestations (EIMs), predictors of poor prognosis, benefit/risk of immunosuppressive and biological therapy and IBD in pregnancy. The questionnaire was handed out to consecutive Crohn’s disease (CD) and ulcerative colitis (UC) patients in regular follow-up at a referral centre. Clinical and socio-demographic characteristics were collected in a dedicate database. Descriptive analysis of quantitative variables was presented as mean or median. Fisher test and Student’s t-test were used for categorical and continuous variables. A p < 0.05 was considered statistically significant. Results Three hundred and four patients were enrolled and 290 completed the questionnaire (95%). Of these 53% UC and 47% CD. The mean age was 51 years (range 18–83); 56% were male. Most of the patients were in clinical remission (85%). The mean number of appropriate answer was 4 upon 11. Overall only 26% answered successfully more than half of the items. Looking at the single items, two third of patients were aware of current strategies of CRC prevention, chance of EIMs and woman capability to become pregnant. The questions about immunosuppression and biologic therapy were more correctly answered by those patients who had experienced them (p = 0.000001), whereas those about the risk of surgery were not influenced by the patient’s previous clinical history (UC p = 1; CD p = 0.067). Only about one third of women were aware of the most relevant risk factor of worst pregnancy outcome. Age Conclusion These results suggest that the overall disease knowledge in IBD patients is low and should be improved. Young age, education and biologic exposure are associated with an adequate awareness of disease course. This questionnaire should be validated and correlated to other patient-related measures such as health engagement and health literacy in prospective studies.

Objectives Transabdominal ultrasonography (US) usually reveals diagnosis of biliary acute pancreatitis (AP). Guidelines suggest repeating US in AP patients without cause at first examination. This approach has been poorly investigated, as well as the accuracy of repeated US as compared with that of magnetic resonance cholangiopancreatography. This study aims at evaluating the diagnostic accuracy of repeated US for biliary AP. Methods The accuracy of each test for diagnosis of biliary AP was evaluated according to the final diagnosis. Comparison between tests was obtained by examining the areas under the receiver operating characteristic curves. Results Among 155 patients, the etiology was biliary in 52% and alcoholic in 20%. The accuracy of the first US alone and of the 2 combined examinations for a biliary etiology were 66% and 83%, respectively. Comparison of receiver operating characteristic curves showed a better performance of repeated US (difference between areas under the curve, 0.135; 95% confidence interval, 0.02–0.24; P = 0.021). Magnetic resonance cholangiopancreatography had high specificity (93%) but low sensitivity (62%), with 76% accuracy. The accuracy of the combination of the 2 US examinations and of elevated alanine transferase was 87%. Conclusions Repeated US is effective for biliary AP diagnosis. The combination of repeated US examinations and biochemical tests seems an effective approach, whereas magnetic resonance cholangiopancreatography might be restricted to selected cases.

Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV-host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.

The varicella-zoster virus (VZV) ORF61 protein is necessary for normal replication in vitro and virulence in human skin xenografts in the severe combined immunodeficiency mouse model in vivo . These experiments identify a hydrophobic domain that mediates ORF61 self-interaction. While not needed to inhibit host cell defenses, disruption of this domain (residues 250 to 320) severely impairs VZV growth, transactivation of the immediate early 63 and glycoprotein E genes, and the pathogenesis of VZV skin infection in vivo .

The tropism of herpes simplex virus (HSV-1) for human sensory neurons infected in vivo was examined using dorsal root ganglion (DRG) xenografts maintained in mice with severe combined immunodeficiency (SCID). In contrast to the HSV-1 lytic infectious cycle in vitro , replication of the HSV-1 F strain was restricted in human DRG neurons despite the absence of adaptive immune responses in SCID mice, allowing the establishment of neuronal latency. At 12 days after DRG inoculation, 26.2% of human neurons expressed HSV-1 protein and 13.1% expressed latency-associated transcripts (LAT). Some infected neurons showed cytopathic changes, but HSV-1, unlike varicella-zoster virus (VZV), only rarely infected satellite cells and did not induce fusion of neuronal and satellite cell plasma membranes. Cell-free enveloped HSV-1 virions were observed, indicating productive infection. A recombinant HSV-1-expressing luciferase exhibited less virulence than HSV-1 F in the SCID mouse host, enabling analysis of infection in human DRG xenografts for a 61-day interval. At 12 days after inoculation, 4.2% of neurons expressed HSV-1 proteins; frequencies increased to 32.1% at 33 days but declined to 20.8% by 61 days. Frequencies of LAT-positive neurons were 1.2% at 12 days and increased to 40.2% at 33 days. LAT expression remained at 37% at 61 days, in contrast to the decline in neurons expressing viral proteins. These observations show that the progression of HSV-1 infection is highly restricted in human DRG, and HSV-1 genome silencing occurs in human neurons infected in vivo as a consequence of virus-host cell interactions and does not require adaptive immune control.