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In this paper a general methodology is proposed for reducing computing times in procedures for solving road network design problems. Extensively studied in the literature, such problems concern the design of road networks, in terms of flow directions, capacity expansion and signal settings in urban contexts, and in terms of link addition and capacity expansion in rural contexts. The solution is almost always formulated as a bi-level model, where the upper level operates on the network design decision variables, while the lower level estimates the equilibrium traffic flows, which must be known in order to determine objective function values. Computing times required for calculating equilibrium traffic flows at each iteration of the network design procedure significantly affect the total solution time. Hence, any reduction in computing times of the lower level, which has to be implemented numerous times at any step of the upper-level algorithm, allows the global computing time to be considerably reduced. In this context, the methodology proposed herein seeks to reduce computing times of the traffic assignment problem and hence of the whole network design procedure, acting on the traffic flows adopted in the initialisation phase of the assignment algorithm. Obviously, this approach is feasible only if the topology of the network configuration remains unchanged and therefore only if the network design decision variables are limited to capacity expansion, in rural contexts, or signal settings and capacity expansion, in urban contexts. The proposed approach is tested on a real-scale case study: the rural road network of Vilnius County (Lithuania). Preliminary results underline the feasibility of the proposal and a significant reduction in computing times of up to 80% compared to traditional approaches.

Evidence on the efficacy of phythotherapic remedies for the treatment of menopausal symptoms were reviewed. Evidence of the literature were graded and level of reccomandation defined. A strenght A recommendation was given for isaproponol extract of Cimicifuga recemosa (systematic review and metanalysis). Strength B recommendation, due to some inconsistent findings or lower quality studies, was given to the use of soy isoflavones, genistein above 30 mg/day, equol containing product and pollen extract. Strength C reccomendation for very weak evidence of efficacy was given to resveratrol, hops, dioscorea, enotera. No evidence of efficacy on vasomotor symptoms was found for Hyperycum perforatum, matcha, ginseng, that find no place in the treatment of vasomotor symptoms.

The Covid-19 pandemic hastened the use of technologies that replaced some urban activities, normally based on people interactions, thus significant changes occurred in mobility demand. Recently, also in Italy, for urban short-distance travels, “non-conventional” ways of moving spread, encouraged by governmental measures addressed to sustainable mobility, too. Defined as “urban micro-mobility” including e-scooters, these modalities of moving had a significant success, producing impacts on mobility and urban safety. This study focuses on the analysis of the spread of e-scooters use in Italy, relating both to the pandemic event and to the post-emergency phase. Specifically, this study is articulated into three parts: 1) the overview on urban micro-mobility particularly referred to the use of e-scooters in Italy; 2) the results of direct surveys (questionnaires) addressed to the undergraduate students, considered as a significant age range; 3) the effectiveness of these “alternative mobility” to improve urban sustainability.

The recent SARS-CoV-2 outbreak has challenged companies, from both service and industry sectors, to reorganize how their business are operated in order to guarantee continuity to their operations while maintaining proper and safe conditions for workers and customers as well. In fact, a recognized preventive measure against the coronavirus spread, that has been adopted by many governments all over world, is to limit as much as possible and to make safer social interactions in the workplace. The effect of such measures is very impactful on those activities that require physical presence or a direct interaction with physical resources such as shop floors. For example, on an assembly line, it could be more difficult for operators to maintain appropriate distances if the new workplace and the new working conditions have been attentively conceived and deployed. This paper has the objective of showing how computer simulation can support companies in this complex task and, at the same time, of providing an operational tool and a case study application. Particularly, it uses a computer simulation tool (i.e., AnyLogic), to model and evaluate alternative design solutions with the aim of making the considered shop floor more resilient from the coronavirus spread perspective. We focused on the automotive sector and considered the case of a two-sided single model assembly line and the related surrounding areas. Various reconfigurations of the assembly line were considered with the aim of reducing contagion likelihood during production. In order to increase the distance between operators, we compared different solutions involving centralized and decentralized warehouses as well as collaborative robots (i.e., cobots). Each configuration was also tested with respect to the individual protection parameter, i.e., we explicitly considered the type of protection the operators use while performing their activities (no mask, surgical or FFP2 mask).

Background and objective: Consumer interests in probiotic foods have increased in recent decades. Food industries respond to these growing interests by developing innovative products and guaranteeing high production efficiency. Cereals, due to their prebiotic nature, are good fermentable substrates; from which, potentially functional foods could be achieved. The aim of this study was to verify effects of D-glucose addition on fermentation of rice, oat and wheat flours. Material and methods: Suspensions of 15% of cereals flours (rice, oat and wheat) in distilled water added with increasing glucose concentrations (2, 5, 7 and 10% w v-1) were fermented by Lactobacillus paracasei CBA L74 for 24 h. Then, pH, microbial growth and lactic acid production were assessed. Results and conclusion: Rice fermentation was not affected by glucose addition. For oat and wheat, addition of D-glucose increased bacterial concentration, as well as lactic acid production. In particular, the best growth was achieved by the addition of 2 and 5% of glucose. Furthermore, lactic acid concentration increased with increased glucose concentration. In conclusion, D-glucose addition seems to be unnecessary for the improvement of rice fermentation. On the contrary, oat and wheat fermentations need further available carbon sources for a better Lactobacillus growth and a higher lactic acid production. Conflict of interest: The authors declare no conflict of interest.

The recent recognition that grade 3 (G3) neuroendocrine neoplasms (NENs) can be divided into two different categories according to the histopathological differentiation, that is G3 neuroendocrine tumors (NETs) and G3 neuroendocrine carcinomas (NECs) has generated a lot of interest concerning not only the diagnosis, but also the differential management of such new group of NENs. However, several issues need to be fully clarified in order to put G3 NETs and G3 NECs in the right place. The aim of this review is to focus on those issues that are still undetermined starting from the current knowledge, evaluating the available evidence and the possible clinical implications.

Discovery of disease age-of-onset modifiers is important for clinical trials and drug design. Zhang et al. perform a genome-wide analysis of epigenetic functional polymorphisms and identify an association between the C6orf10/LOC101929163 locus and age of FTD/ALS onset. The risk allele may be associated with a pro-inflammatory state in the brain., The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Accepting and sharing about oneself as a sexual and gender minority (SGM) individual is complex. This is even more complex for individuals who identify as both SGM and Latino because they possess more than one minoritized identity. As a result, SGM Latino youth are more susceptible to higher levels of stress, which if not effectively managed, can lead to homelessness, anxiety and depression, and substance abuse. Latino family members find it difficult to learn how to positively interact with their SGM family member (e.g., in the early phases of coming out). In this quantitative survey study, researchers examined survey data collected from 1,877 Latino youth concerning home experiences, health, identity, and parental nativity. Data were drawn from the LGBTQ National Teen Survey, an online, anonymous comprehensive survey designed to advance understanding of the experiences of SGM adolescents (13-17 years of age). The survey, developed and distributed by the Human Rights Campaign, examined perceptions of familial acceptance regarding SGM identity during youth. Significant relationships were found between family acceptance, sexual orientation, and parental nativity (birthplace of parents in- or outside of the United States). The findings provide for a rich discussion about the implications for helping Latino SGM youth and educating Latino family members.

SUMMARYThe gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines. However, it is unknown whether this effect involves IgA, a mucosal antibody that coats intestinal microbes. Here we found that gut IgA increased peripheral IgG responses to pneumococcal vaccines, as these responses were profoundly impaired in mice with global or mucosa-restricted IgA deficiency. The positive effect of IgA on vaccine-induced IgG production implicated gut bacteria. Indeed, IgG responses to pneumococcal vaccines were also defective in ex-germ free mice recolonized with gut microbes from mouse or human IgA-deficient donors. IgA exerted this IgG-enhancing effect by constraining the systemic translocation of intestinal commensal antigens, which caused chronic immune activation, including T cell overexpression of programmed death-1. This immune inhibitory receptor hindered vaccine-specific IgG production by eliciting functional B cell unresponsiveness, which was reverted by anti-programmed death-1 treatment. Thus, gut IgA is functionally interconnected with systemic IgG via intestinal microbes.

Background Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock. Methods This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization. Results Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points. Conclusion Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time. Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.

Accurate state-of-health (SoH) monitoring is considered a key element in avoiding faulty operation of fuel cell stacks. Such faulty operation could relate to problems in the balanceof-plant, having a global effect on the stack performance, or to problems in the stack itself, where the effect could initially be very local. This research topic was addressed in the European project INSIGHT, with the final aim to demonstrate advanced SoH monitoring in a real environment by implementing newly developed hardware equipped with novel perturbation routines and data fitting routines in a µ-CHP system from SOLIDpower. The results of the test that followed, including validation of the routines and hardware as well as simulation of different kinds of faulty operation, are reported here.

One of the most striking properties of Kinetic Alfv��n Waves (KAW) is that, unlike the also Alfv��nic Electromagnetic Ion Cyclotron (EMIC) waves, these waves are right-hand polarized in the plasma frame. In particular, this signature property is key for the identification of KAW from in situ measurements of plasma waves. From the theoretical point of view, both the dispersion relation and the polarization of KAW has been mostly studied in proton-electron plasmas. However, most astrophysical and space plasmas are multi-species, and therefore in these systems the dispersion properties of the KAW may not depend only on the macroscopic parameters of proton and electron distributions, but also on the parameters of heavier ions. Here, using Vlasov linear theory we study the dispersion properties of Alfv��nic modes in multi-species plasmas composed by electrons, protons, and O$^+$ ions, with macroscopic plasma parameters relevant to the inner magnetosphere. In consistency with recent observations, our numerical results show that the presence of O$^+$ ions allows the existence of KAW in a wider wave-number range and at smaller wave-normal angles compared to the electron-proton case, but at the same time isotropic O$^+$ ions tend to reduce (or even inhibiting) the growth rates of unstable KAW triggered by anisotropic protons. These results suggest that magnetospheric ions may play an important role on the energy transfer from large macroscopic scales to sub-ionic and electronic scales, especially during intense geomagnetic storms in which O$^+$ ions can dominate the plasma composition in the inner magnetosphere., 16 pages, 4 figures, in press

Background Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low-density lipoprotein receptor re-uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. Methods Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman's coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28- and 90-day mortality. Results Median plasma PCSK9 levels were 278 [182-452] ng mL-1 on day 1. PCSK9 correlated positively with PTX3 at the three time-points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28- and 90-day mortality rate as compared to other quartiles. Conclusion In our sub-analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

Annotated corpora, provided that they adopt international standards and expose data in open format, have many more chances to be easily exploited and reused for different objectives than traditional, analogue corpora. This paper aims at presenting the results of the early adhesion to best practices and principles afterward codified as Open Science and FAIR principles in the frame of projects concerned with digital textual corpora, in a niche area of research such as the pre-Islamic Arabian epigraphy. The case study analysed in this paper is the Digital Archive for the Study of pre-Islamic Arabian inscriptions - DASI, an online annotated corpus of the textual sources from Ancient Arabia, which also exposes its records in standard formats (oai_dc, EpiDoc, EDM) in an OAI-PMH repository. The initiatives of reuse of DASI open data in the frame of the recently ANR-funded project Maparabia (CNRS-CNR) are discussed in the paper, focusing on the exploitation of DASI's onomastic and geographic data in a new reference tool, the Gazetteer of Ancient Arabia. After introducing DASI and Maparabia projects and highlighting the objectives of the Gazetteer, the paper describes the conceptual model of its database and the module importing data from DASI. The population of the Gazetteer, implying also a data entry and manipulation phase, is exemplified by the case-study of the Ancient South Arabian place 'Bar?qish/Yathill'. Based on the above experience, limitations and opportunities of data reuse and synchronisation issues between systems are discussed.

As the COVID-19 outbreak traveled through various Italian regions, all national and local administrations issued measures to counter the spread of the contagion and organize healthcare. The Italian healthcare system is, indeed, a decentralized system with 21 regional health systems (RHSs), with different models of healthcare service delivery and organization. This study investigates whether a different organization of RHSs would have led to different management of the COVID-19 epidemic, and evaluates the effect of different approaches in epidemic management on the COVID-19 epidemiological trend. A set of indicators is identified by conducting an online synchronous Focus Group, involving an experts panel. A Pearson’s correlation test was performed on the values assumed by the historical series of indicators investigate correlations among the trends represented by the indicators or between them and external factors. The comparison between the experiences of the different Italian regions, regarding the management of the epidemic, has helped to confirm and emphasize the importance of a community-based approach in health care—integrated with the hospital’s functions for the care of complex conditions and the need for specialized assistance.