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Abstract Neuroendocrine carcinoma of the urinary bladder is a rare entity, accounting less then 1% of urinary bladder malignancies. The vast majority of the neuroendocrine carcinoma of the urinary bladder is represented by small cell neuroendocrine carcinoma while just few cases of large cell neuroendocrine carcinoma (LCNEC) have been reported. In this cases report we describe a rare case of primary bladder LCNEC. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2474700528951562.

Background: Popillia japonica Newman is a scarab beetle native to Japan that is considered a serious pest outside its native range. It can feed on more than 400 host plants and spread about 10 km per year in invaded territories, therefore it is considered the second most important quarantine pest in Europe. Both chemical and biological insecticides have been used for control, with variable results. Despite ongoing efforts, P. japonica remains a threat in invaded countries, and it is necessary to test more effective and sustainable solutions in the context of integrated pest management. Here we present a study on long-lasting insecticide-treated nets (LLINs) assembled in semiochemical-baited attract-and-kill devices (A&Ks) as a means to control adults of P. japonica with low environmental impact. This study complements previous ones in which we first evaluated the effectiveness of the LLINs in the laboratory and then tested both effectiveness and duration in field-exposed A&Ks against P. japonica. In the present work we compared the effectiveness of three different densities of A&Ks per hectare in areas where the population of P. japonica was numerically homogeneous., Results: The different densities of A&K (1, 2, 4 A&Ks per ha) resulted in an overall reduction of the population of P. japonica by about two thirds in comparison to the control area., Conclusions: This study suggests that the use of one A&K per hectare, requiring minimal management effort, is an effective ratio for reducing local populations of P. japonica. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Europe faces regular introductions and reintroductions of bluetongue virus (BTV) serotypes, most recently exemplified by the incursion of serotype 3 in the Netherlands. Although the long-distance wind dispersal of the disease vector, Culicoides spp., is recognized as a virus introduction pathway, it remains understudied in risk assessments. A Quantitative Risk Assessment framework was developed to estimate the risk of BTV-3 incursion into mainland Europe from Sardinia, where the virus has been present since 2018. We used an atmospheric transport model (HYbrid Single-Particle Lagrangian Integrated Trajectory) to infer the probability of airborne dispersion of the insect vector. Epidemiological disease parameters quantified the virus prevalence in vector population in Sardinia and its potential first transmission after introduction in a new area. When assuming a 24h maximal flight duration, the risk of BTV introduction from Sardinia is limited to the Mediterranean Basin, mainly affecting the southwestern area of the Italian Peninsula, Sicily, Malta, and Corsica. The risk extends to the northern and central parts of Italy, Balearic archipelago, and mainland France and Spain, mostly when maximal flight duration is longer than 24h. Additional knowledge on vector flight conditions and Obsoletus complex-specific parameters could improve the robustness of the model. Providing both spatial and temporal insights into BTV introduction risks, our framework is a key tool to guide global surveillance and preparedness against epizootics., (© 2024 The Author(s). Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Bridging the gap between the micro and the macro scale in modelling food security to inform context-specific regionalised policies remains a major scientific challenge. A better understanding of the relations between global and local drivers impacting local food self-sufficiency (LFSS) is essential. We applied to the whole Mediterranean environmental area (Southern and Northern) a modelling framework for structural estimates (PLS-PM) using qualitative and quantitative methods to combine local-level information from field surveys and participatory workshops with global-level data. Our findings show that farmland expansion and intensification spatially disconnected from urban consumption areas do not appear to foster LFSS. On the other hand, public policies appear key to enhancing LFSS in the Mediterranean area if appropriate to the particular regional context. We outline how this multi-level modelling methodology can contribute to a place-based approach by informing context-specific regionalised policies aimed at food security., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Large GWAS indicated that genetic factors influence the response to SARS-CoV-2. However, sex, age, concomitant diseases, differences in ancestry, and uneven exposure to the virus impacted the interpretation of data. We aimed to perform a GWAS of COVID-19 outcome in a homogeneous population who experienced a high exposure to the virus and with a known infection status. We recruited inhabitants of Bergamo province-that in spring 2020 was the epicenter of the SARS-Cov-2 pandemic in Europe-via an online questionnaire followed by personal interviews. Cases and controls were matched by age, sex and risk factors. We genotyped 1195 individuals and replicated the association at the 3p21.31 locus with severity, but with a stronger effect size that further increased in gravely ill patients. Transcriptome-wide association study highlighted eQTLs for LZTFL1 and CCR9 . We also identified 17 loci not previously reported, suggestive for an association with either COVID-19 severity or susceptibility., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Tolvaptan and octreotide-long-acting release (LAR) have renoprotective effects in autosomal dominant polycystic kidney disease (ADPKD) that are partially mediated by amelioration of compensatory glomerular hyperfiltration. We compared the effects of tolvaptan and octreotide-LAR combination therapy versus those of tolvaptan monotherapy in patients with ADPKD., Methods: This pilot, randomized, placebo-controlled, cross-over trial primarily compared the effects of 1- and 4-week treatments with octreotide-LAR (two 20-mg i.m. injections) or placebo (two i.m. 0.9% saline solution injections) added-on tolvaptan (up to 90 and 30 mg/d) on GFR (iohexol plasma clearance) in 19 consenting patients with ADPKD referred to a clinical research center in Italy. Analyses were intention-to-treat. The local ethical committee approved the study., Results: At 4 weeks, GFR significantly decreased by a median (interquartile range) of 3 (-1 to 5) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.01) and by 7 (3-14) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR (P=0.03). GFR changes during the two treatment periods differed by 2 (-5 to 14) ml/min per 1.73 m2 (P=0.28). At 1 week, GFR significantly decreased by 3 (0-7) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.006) and by 10 (-6 to 16) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR add-on therapy (P<0.001). GFR changes during the two treatment periods significantly differed by 3 (0-12) ml/min per 1.73 m2 (P=0.012). Total kidney volume nonsignificantly changed by 4 (-48 to 23) ml with tolvaptan and placebo (P=0.74), whereas it decreased significantly by 41 (25-77) ml with tolvaptan and octreotide-LAR (P=0.001). Changes during the two treatment periods differed by 36 (0-65) ml (P=0.01). Octreotide-LAR also attenuated (P=0.02) the aquaretic effect of tolvaptan. Treatments were well tolerated., Conclusions: In patients with ADPKD, octreotide-LAR added-on tolvaptan reduced GFR more effectively than octreotide-LAR and placebo. Octreotide-LAR also reduced total and cystic kidney volumes and attenuated the acquaretic effect of tolvaptan., Clinical Trial Registry Name and Registration Number: Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447., (Copyright © 2023 by the American Society of Nephrology.)

Brown rot in stored stone fruits, caused by Monilinia spp., may be due to preharvest and storage factors, but the combined effect of these factors has yet to be investigated. We set up two experiments to monitor the progression of brown rot during the storage of nectarines subjected to various preharvest and storage conditions. We assessed the effects of different agricultural practices (irrigation regimen × fruit load) and harvest dates on brown rot progress during storage in 2018 and the effect of different storage temperatures in 2019. We found that the cumulative incidence of brown rot during storage increased with individual fruit mass, which was influenced by agricultural practices, and for later harvest dates. It also increased with storage temperature. We observed that during storage no secondary infections developed in nectarines not in direct contact with fruits infected with Monilinia laxa . These findings led to the identification of candidate variables describing the brown rot risk on nectarines during storage, such as individual fruit mass, meteorological conditions before fruit harvest, prevalence of brown rot at harvest, and storage temperature. We used these variables to build a mathematical model for estimating the time-to-appearance of brown rot symptoms in stored nectarines. This model fitted the experimental data well, highlighting the need to pay greater attention to the interaction between preharvest and storage conditions. This model could be used to evaluate management strategies for reducing the impact of brown rot in nectarines during storage.

Aims: In type 2 diabetic patients with obesity, hyperfiltration is a risk factor for accelerated glomerular filtration rate (GFR) decline and is ameliorated by calorie restriction (CR). We assessed whether CR-induced amelioration of hyperfiltration could translate into slower long-term GFR decline in this population., Methods: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded endpoint trial, consenting >40-year-old patients with type 2 diabetes, BMI ≥27 kg/m 2 , creatinine <1.2 mg/dL and albuminuria ≤300 mg/24 h were randomized (1:1) to two-year 25% CR (n = 53) or standard diet (SD, n = 50). Primary outcome was 6-month measured GFR. Analyses were by modified intention-to-treat., Results: At 6 months GFR decreased by 5.16 ± 10.03 mL/min (P = 0.001) with CR, and by 0.98 ± 9.71 mL/min (P = 0.497) with SD. Between-group difference was significant (P = 0.044). GFR decline from 6 to 24 months was significant with SD (P < 0.01), but not with CR (P = 0.075). Between-group difference, however, was not significant (P = 0.414). Body weight, BMI, waist circumference, systolic blood pressure, HbA1c, blood glucose, serum triglycerides decreased and ApoA-I concentration increased with CR. No changes were observed with SD. Between-group differences were significant. CR was tolerated well., Conclusions: In obese type 2 diabetic patients, CR ameliorated glomerular hyperfiltration and several cardiovascular risk factors, and blunted long-term GFR decline., Trial Registration: NCT01930136., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Previous studies have identified regions where the occurrence of rainfall significantly increases or decreases the probability for subsequent rainfall over periods that range from a few days to several weeks. These observable phenomena are termed "rainfall feedback" (RF). To better understand the land-atmosphere interactions involved in RF, the behavior of RF patterns was analyzed using data from 1849 to 2016 at ~3000 sites in the contiguous United States. We also considered changes in major land-use types and applied a geographically weighted regression model technique for analyzing the predictors of RF. This approach identified non-linear and spatially non-stationary relationships between RF, climate, land use, and land type. RF patterns in certain regions of the United States are predictable by modeling variables associated with climate, season, and land use. The model outputs also demonstrate the extent to which the effect of precipitation, temperature, and land use on RF depend on season and location. Specifically, major changes were observed for land use associated with agriculture in the western United States, which had negative and positive influences on RF in summer and winter, respectively. In contrast, developed land in the eastern United States correlated with positive RF values in summer but with negative ones in winter. We discuss how changes in climate and land use would be expected to affect land-atmosphere interactions, as well as the possible role that physical mechanisms and rain-enhanced bioaerosol emissions may play in the spatiotemporal changes observed for historical patterns of rainfall frequency in the United States., (© 2021 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Background: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy., Methods and Findings: VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion., Conclusions: Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients., Trial Registration: EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: GR is a member of PLOS Medicine’s Editorial Board. All other authors declare no competing interests.

Background: We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression., Methods and Findings: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design., Conclusions: In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression., Trial Registration: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14., Competing Interests: The authors have declared that no competing interests exist.

The collection and analysis of air samples for the study of microbial airborne communities or the detection of airborne pathogens is one of the few insights that we can grasp of a continuously moving flux of microorganisms from their sources to their sinks through the atmosphere. For large-scale studies, a comprehensive sampling of the atmosphere is beyond the scopes of any reasonable experimental setting, making the choice of the sampling locations and dates a key factor for the representativeness of the collected data. In this work we present a new method for revealing the main patterns of air-mass connectivity over a large geographical area using the formalism of spatio-temporal networks, that are particularly suitable for representing complex patterns of connection. We use the coastline of the Mediterranean basin as an example. We reveal a temporal pattern of connectivity over the study area with regions that act as strong sources or strong receptors according to the season of the year. The comparison of the two seasonal networks has also allowed us to propose a new methodology for comparing spatial weighted networks that is inspired from the small-world property of non-spatial networks.

Background and Objectives: Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis., Design, Setting, Participants, & Measurements: In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization., Results: At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P =0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m 2 ; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls., Conclusions: Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis., Clinical Trial Registry Name and Registration Number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17., (Copyright © 2021 by the American Society of Nephrology.)

Agronomic practices can alter plant susceptibility to diseases and represent a promising alternative to the use of pesticides. Yet, they also alter crop quality and quantity so that the evaluation of their efficacy is not straightforward. Here we couple a compartmental epidemiological model for brown rot diffusion in fruit orchards with a fruit-tree growth model explicitly considering the role of agronomic practices over fruit quality. The new modelling framework permits us to evaluate, in terms of quantity and quality of the fruit production, management scenarios characterized by different levels of regulated deficit irrigation and crop load. Our results suggest that a moderate water stress in the final weeks of fruit development and a moderate fruit load provide effective control on the brown rot spreading, and eventually guarantee monetary returns similar to those that would be obtained in the absence of the disease.

Aims: To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy., Materials and Methods: In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin-creatinine ratio > 1000 mg/g (or > 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed., Results: Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18-54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25-10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07-10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50-17.75, P = 0.009 and HR 4.75, 95% CI 1.01-22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups., Conclusions: In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications., (© 2019 John Wiley & Sons Ltd.)

Recent detections of Xylella fastidiosa in Corsica Island, France, has raised concerns on its possible spread to mainland France and the rest of the Mediterranean Basin. Early detection of infected plants is paramount to prevent the spread of the bacteria, but little is known about this pathosystem in European environments, hence standard surveillance strategies may be ineffective. We present a new methodological approach for the design of risk-based surveillance strategies, adapted to the emerging risk caused by X. fastidiosa. Our proposal is based on a combination of machine learning techniques and network analysis that aims at understanding the main abiotic drivers of the infection, produce risk maps and identify lookouts for the design of future surveillance plans. The identified drivers coincide with known results in laboratory studies about the correlation between environmental variables, such as water stress and temperature, and the presence of the bacterium in plants. Furthermore, the produced risk maps overlap nicely with detected foci of infection, while they also highlight other susceptible regions where X. fastidiosa has not been found yet. We conclude the paper presenting a list of recommended regions for a risk-based surveillance campaign based on the predicted spread and probability of early detection of the disease.

MicroRNA (miRNA) expression is dysregulated in many human malignancies, and a growing number of studies are focused on their potential use as tumor biomarkers. To identify a miRNA signature for papillary thyroid carcinomas (PTC), we investigated miRNA expression profiles in two independent cohorts of PTCs, which included major histological subtypes [classical-type (PTC‑CT), follicular-variant (PTC‑FV), and tall-cell variant (PTC‑TCV)] and cases with low or intermediate risk of recurrence. Using TaqMan® Array Human MicroRNA A+B Cards v3.0, we first performed microRNA profiling of normal and neoplastic thyroid tissues from 29 PTC patients. Promising candidates were then investigated in a second, independent cohort of 76 PTCs using Custom TaqMan® Array MicroRNA Cards. We identified a molecular signature of 11 miRNAs that were significantly upregulated (miR‑146b-5p, miR‑146b-3p, miR‑221-3p, miR‑222‑5p, miR‑222‑3p) or downregulated (miR‑1179, miR‑486‑5p, miR‑204-5p, miR‑7-2-3p, miR‑144-5p, miR‑140-3p) in PTC tissues vs. normal thyroid tissue. Upregulation of miR‑146b-5p and miR‑222‑3p was also significantly associated with an increased risk of recurrence. Higher than normal expression of miR‑146b-5p and miR‑146b-3p characterized PTC‑CT and PTC‑TCV but not PTC‑FV, whereas miR‑21-5p was significantly upregulated only in PTC‑TCV. When PTC‑FV were subclassified as encapsulated (PTC‑EFV) or infiltrative (PTC‑IFV), miR‑204-5p was downregulated in all histological subtypes except PTC‑EFV, which displayed expression levels similar to those of normal thyroid tissues. These findings provide new insights into the molecular classification of PTC, showing that different miRNA expression profiles are associated with different histological types of PTC and different risks of recurrence.