Search

Yoshiya Tanaka,1 Mark C Genovese,2,3 Hironori Matsushima4 1The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan; 2Division of Immunology and Rheumatology, Stanford University, Stanford, CA, USA; 3Gilead Sciences, Inc, Foster City, CA, USA; 4Gilead Sciences, Inc, Tokyo, JapanCorrespondence: Yoshiya Tanaka, The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, 807-8555, Japan, Tel +81-93-603-1611, Fax +81-93-691-7580, Email tanaka@med.uoeh-u.ac.jpAbstract: Filgotinib is an orally administered, preferential Janus kinase (JAK) inhibitor indicated for the treatment of moderate-to-severe rheumatoid arthritis (RA). The short-term safety, efficacy, and patient-reported outcomes (PROs) with filgotinib from Phase 2b/3 clinical trials (DARWIN 1 and 2; FINCH 1, 2, and 3) are described in patients who inadequately responded to methotrexate (MTX) and biologic disease-modifying antirheumatic drugs or who were naïve to MTX. This article reviews the safety and efficacy from the long-term extension (LTE) trials, DARWIN 3 (N=739) and FINCH 4 (N=2731), and PROs across the filgotinib development program in RA. Overall, in the DARWIN clinical trials (conducted from 2013– 2023), patients received their LTE treatment for ≤ 8 years, while in the FINCH trials (ongoing from 2016– 2025), patients received filgotinib treatment for ≤ 6 years in the LTE. The longer-term safety profile and consistent, sustained efficacy (American College of Rheumatology 20/50/70, Clinical Disease Activity Index, and Disease Activity Scale in 28 joints with C-reactive protein response rates) of filgotinib were largely similar to those observed in the shorter-term parent trials ≤ 52 weeks. PRO results from the parent trials showed improvements in patients’ quality of life with filgotinib treatment, which compared to or exceeded improvements seen with placebo and active comparators (adalimumab, MTX). Filgotinib has a higher specificity for JAK1 compared with other therapeutic treatments, leading to reduced inhibition of JAK2/3–dependent pathways, potentially providing a distinct safety profile. Filgotinib is approved in Europe and Japan for treatment of people with moderate-to-severe RA, though it has not been approved by the US Food and Drug Administration, due to concerns around the benefit/risk profile of the filgotinib 200-mg dosage and the potential impact on semen parameters.Keywords: Janus kinase inhibitors, selectivity, JAKi, disease-modifying antirheumatic drug, DMARD, RA

This work deals with the analysis of the energy performance and the environmental impact of a Heating, Ventilation and Air Conditioning (HVAC) system based on an innovative Air-to-Water electrical Heat Pump (AWHP) using propane (R290) as the refrigerant. A building of the University of Bologna located in Forlì (North of Italy) is considered for replacing a condensing gas boiler and a conventional chiller with an AWHP using R290. To evaluate the efficiency of the existing heating system and the potential savings linked to the adoption of the propane AWHP, the building energy model was created and calibrated by collecting monthly thermal and electrical consumptions as a function of the actual climate data. In this paper, the main features of the R290-based AWHP are described in detail by emphasising the device performance as a function of the operating conditions (i.e., air and water temperature and speed of the scroll compressor). A series of scenarios have been studied to evaluate the energy performance of the propane AWHP with respect to the reference scenario under various operating conditions. The results show that while the total primary energy demand increases adopting the propane AWHP with respect to the case of a gas boiler, the non-renewable primary energy fraction decreases significantly, with a dramatic increase in the renewable quote. From an economic point of view, lower annual costs are obtained by adopting a propane AWHP coupled to fan coils, mainly when the electrical heat pump is used in a thermally insulated building in which a photovoltaic system is installed.

Schools are critical settings in our nation's public health response to the youth mental health crisis. There is strong empirical support that comprehensive, universal programs promote students' social and emotional development and academic success. However, schools, particularly Title I schools, often lack the capacity to implement entire programs as intended, due in part to limited resources that necessitate adapted program content and implementation supports. Use of core components (i.e., kernels) across evidence-based social-emotional learning programs provides opportunities for low-resource schools to select a targeted set of classroom strategies best suited to their needs, values, resources, and goals. This paper describes the collaborative kernel selection and implementation process we used in the context of a community-university partnership with seven Title I elementary schools across two school districts in the Southeastern USA. Partners consisted of district and school leadership, educators as implementers, local school mental health professionals as implementation champions, and university partners and an independent capacity building consultation firm as external consultants. The team used a phased approach via the Exploration, Preparation, Implementation, Sustainment framework to (1) identify kernels based on each school's needs; (2) adapt kernels to align with existing programming and resources; (3) tailor kernels to each educator and their classroom; and (4) support ongoing implementation via multi-tiered supports. Examples of this approach, including examples of data feedback to inform decisions, are featured to promote replication in other community-university partnerships.

Christina Jensen,1,2 Signe Holm Nielsen,1,3 Mohammed Eslam,4 Federica Genovese,1 Mette Juul Nielsen,1 Roslyn Vongsuvanh,4 Raj Uchila,4 David van der Poorten,4 Jacob George,4 Morten Asser Karsdal,1 Diana Julie Leeming,1 Nicholas Willumsen1 1Biomarkers & Research, Nordic Bioscience, Herlev, Denmark; 2Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark; 3Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark; 4Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, AustraliaCorrespondence: Christina JensenNordic Bioscience, Herlev Hovedgade 205-207, Herlev 2730, DenmarkTel: +4544525252Fax: +4544525251Email chj@nordicbio.comPurpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80– 90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We evaluated circulating cross-linked pro-peptides of type III collagen (PC3X) as a diagnostic and prognostic biomarker for HCC.Patients and Methods: PC3X was measured by ELISA in plasma from patients with HCC (n=79), cirrhosis (n=86), non-cirrhotic hepatitis-B infection (n=74) and from healthy controls (n=44). PC3X was compared to the liver fibrosis marker PRO-C3 and the HCC tumor-cell derived marker alpha-fetoprotein (AFP). Diagnostic and prognostic potential was evaluated by AUROC and by calculating hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS).Results: PC3X, PRO-C3 and AFP were significantly elevated in patients with HCC compared to other liver diseases and healthy controls (p=0.0002, p< 0.0001). In patients with normal AFP (< 20 IU/mL), PC3X and PRO-C3 separated HCC from cirrhosis with an AUROC of 0.72 and 0.68, respectively. High PC3X and AFP predicted for poor PFS (HRPC3X=1.80, p=0.032; HRAFP=1.70, p=0.031) and OS (HRPC3X=2.12, p=0.024; HRAFP=2.55; p=0.003), whereas PRO-C3 did not (PFS: HR=1.19, p=0.059 and OS: HR=1.12, p=0.324). PC3X was independent of AFP (PFS: HR=1.74, p=0.045 and OS: HR=2.21, p=0.018) and combining the two improved prognostic value (PFS: HR=2.66, p=0.004 and OS: HR=5.86, p< 0.0001).Conclusion: PC3X is associated with HCC independent of AFP and provides diagnostic and prognostic value for HCC patients. If validated, this suggests that PC3X has biomarker potential for HCC.Keywords: tumor microenvironment, extracellular matrix, fibrosis, liver cancer

Recently the European Commission presented the REPowerEU plan to rapidly reduce dependence on fossil fuels, accelerate the green transition and tackle the climate crisis through greater and better use of renewable energy sources. In Europe from 2035 with the “Fit for 55” climate package, pure electric or hybrid fuel cell electric vehicles will replace new pure or hybrid ICE vehicles fed by gasoline or diesel to reduce pollution and the generation of climate-altering gas emissions. Based on this context, in this article a poly-generative energy system for the hydrogen, electric and thermal powers production is defined to satisfy the needs of pure electric or hybrid fuel cell electric mobility and/or the electric/thermal loads of a residential building located in Rende (Italy) on two typical winter and summer days. It consists mainly of an SOFC system fed by biogas or bio-methane in cogenerative arrangement, a photovoltaic system and a PEM electrolyzer. Technical feasibility study results of the system show that for the mixed fleet of 30 vehicles the output electrical and thermal powers and hydrogen production are respectively 60 kW, 19 kW, 3.1 kg (biogas) and 60 kW, 33 kW, 3.1 kg (bio-methane). Furthermore, the system covers totally the electric load in summer day and at 80% (biogas) or totally (bio-methane) the thermal load for hot water production in summer and winter days.

The present paper reports the case of a 3 years old, female Bearded Dragon (Pogona vitticeps) presenting lethargy, anorexia, weight loss, and anemia and marked leukocytosis at CBC. The majority of leukocytes were lymphocytic/lymphoblastic cells (97%). Immunocytochemical staining of blood smears marked for CD3 (neg) and CD79a (pos) suggested immunophenotype B. The patient died after one month from diagnosis. Histology evidenced lymphoid infiltration in the heart, spleen, liver, kidneys and gut. In addition, in the bone marrow a massive infiltration of lymphoid cells confirmed the diagnosis of leukemia. Immunohistochemistry confirmed the CD79a positivity of a large part of infiltrating lymphoid cells indicating a B cells immunophenotype of the neoplastic population. The presence of lymphocytosis and multiorgan infiltration supported the diagnosis of lymphocytic leukemia. Finally, a revision of the literature has also been made.

The purpose of this paper is to give a strategic overview of the existing standards governing the construction and operation of hydrogen refueling stations. A succinct and comprehensive study of hydrogen refueling station standards globally, in Europe, and in Italy is conducted and discussed in light of the new European Hydrogen Strategy and Roadmap. Among the numerous topics examined, a particular emphasis is placed on the standards in force for on-site hydrogen production via water electrolysis, hydrogen storage, both liquid and gaseous, and refueling protocols for light-duty and heavy-duty vehicles, on an international level through the provision of ISO, IEC, and SAE standards; on a European level through the examination of the CEN/CENELEC database; and on an Italian national level through the analysis of the UNI database.

Abstract: This Roadmap article provides a succinct, comprehensive overview of the state of electronic structure methods and software for molecular and materials simulations. Seventeen distinct sections collect insights by 51 leading scientists in the field. Each contribution addresses the status of a particular area, as well as current challenges and anticipated future advances, with a particular eye towards software related aspects and providing key references for further reading. Foundational sections cover density functional theory and its implementation in real-world simulation frameworks, Green's function based many-body perturbation theory, wave-function based and stochastic electronic structure approaches, relativistic effects and semiempirical electronic structure theory approaches. Subsequent sections cover nuclear quantum effects, real-time propagation of the electronic structure, challenges for computational spectroscopy simulations, and exploration of complex potential energy surfaces. The final sections summarize practical aspects, including computational workflows for complex simulation tasks, the impact of current and future high-performance computing architectures, software engineering practices, education and training to maintain and broaden the community, as well as the status of and needs for electronic structure based modeling from the vantage point of industry environments. Overall, the field of electronic structure software and method development continues to unlock immense opportunities for future scientific discovery, based on the growing ability of computations to reveal complex phenomena, processes and properties that are determined by the make-up of matter at the atomic scale, with high precision.

Valentina Lorenzoni,1 Fabio Baccetti,2 Stefano Genovese,3 Enrico Torre,4 Giuseppe Turchetti1 1Institute of Management, Scuola Superiore Sant’Anna, Pisa, Italy; 2SD Diabetology, ASL Toscana Nordovest, Massa Carrara, Italy; 3Cardiovascular and Metabolic Department, IRCCS Multimedica Sesto San Giovanni, Milan, Italy; 4SSD Endocrinologia, Diabetologia e Malattie metaboliche, ASL 3 Genovese, Genoa, Italy Objective: Diabetes mellitus is a chronic disease related to a significant impact in both epidemiologic and economic terms. In Italy, around 3.6 million people are affected by diabetes and this number is expected to increase significantly in the next few years. As recommended by current national and international guidelines, metformin (Met) is prescribed as first-line pharmacological treatment, and many pharmacological alternatives are available for patients uncontrolled with Met monotherapy. Despite the availability of many innovative oral antidiabetic drugs (OADs), such as dipeptidyl peptidase 4 inhibitors (DPP4-i) and its first-in-class sitagliptin (SITA), which entered the Italian market in the last 10 years, their usage is consistently lower than traditional drugs such as sulfonylureas (SUs). In fact, due to higher acquisition costs, the prescription of innovative OADs in Italy is restricted to specialist, resulting in a prominent usage of traditional OAD that can be prescribed also by general practitioners (GPs). A cost consequence analysis (CCA) was performed in order to compare SITA with SU, as second-line therapy in add-on to Met, in terms of costs and related clinical events over 36 months.Methods: A CCA was conducted on a hypothetical cohort of 100,000 type 2 diabetes mellitus (T2DM) patients uncontrolled with Met monotherapy, from both the Italian National Health Service (INHS) and societal perspective. Therefore, both direct (drugs, self-monitoring, hypoglycemia, major cardiovascular events [MACEs], and switch to insulin) and indirect costs (expressed in terms of productivity losses) were evaluated. Clinical and economic data were collected through Italian national tariffs, literature, and experts’ opinions. Three expert clinicians finally validated data inputs. To assess robustness of base case results, a one-way sensitivity analysis (OWSA) and a conservative scenario analysis – excluding MACEs – were carried out.Results: In the base case analysis, the higher drug costs related to SITA were offset by other management costs (ie, lower use of devices for glycemia self-monitoring, lower incidence of hypoglycemia and MACE, and delay to insulin switch). As a result, the economic evaluation showed that, compared to SU, SITA was cost saving from both societal (–€61,217,723) and INHS (–€51,846,442) perspectives over 3 years as add-on to Met. The base case results were also confirmed by the scenario analysis and by the OWSA performed on the key parameters. The adoption of SITA, in a cohort of 100,000 diabetes patients, would avoid 26,882 non-severe hypoglycemic events, 6,528 severe hypoglycemic events, and 1,562 MACEs.Conclusion: This analysis suggests that, compared to SU, SITA could be a sustainable and cost-saving alternative for the management of T2DM patients uncontrolled with Met monotherapy from both clinical and economic perspectives. Keywords: diabetes, dipeptidyl peptidase 4 inhibitors, sitagliptin, sulfonylurea, cost-­consequence analysis

S Riva,1 S Del Sordo,2,3 U Genovese,1,3 G Pravettoni1 1Department of Oncology and Hemato-oncology, University of Milan, Italy; 2FOLSATEC (Foundations & Ethics of the Life Sciences) PhD School, University of Milan, Milan, Italy; 3Healthcare Accountability Lab, University of Milan, Milan, Italy Aims: The overall goal of this article is to make a scientific comment about the psycho-social consequences of hemophilia patients affected by human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) and to point out the related medicolegal issues. Methods: This commentary takes into account some published evidences about the current scenario of hemophilia patients infected by HIV and/or HCV who received contaminated blood products in the late 1970s through 1985. Results: Several psychological and medicolegal consequences are related with HIV and HCV contamination of blood products. A multidisciplinary approach is needed to treat all the difficulties experienced by these patients and to ensure good clinical decisions in medical practice. Conclusion: The literature on the psychosocial functioning of hemophilia patients with human HIV and HCV infection offers a number of implications, including medicolegal issues, that can be discussed for guaranteeing a good level of care and safeguard of this group of patients. Keywords: hemophilia, viral contaminated blood products, monetary compensation, medico-legal issues, medical decision making

The present paper illustrates the results of the second set of measurements carried out in the BiomethER project (EU-LIFE). BiomethER aimed to design and build two innovative bio-methane production plants, located in the Emilia Romagna region (Italy), so it aims to demonstrate that bio‑methane could replace traditional methane in several applications. One of these applications is road transport where bio-methane can fuel a compressed natural gas (CNG) vehicle. So, three passenger cars have been tested with two gases: conventional natural gas and bio-methane coming from a BiomethER plant. For each vehicle have been measured the emissions and performances on the chassis dynamometer, while an inspection of combustion chambers of the engines was carried out to evaluate their wear condition. This campaign confirms results achieved in the first one, there are no appreciable deviations for fuel consumption and CO2 emissions between the two fuels, acceleration and maximum power were almost the same for the three vehicles tested. Indeed, the vehicle fuelled by methane has significant carbon deposits on the piston crown while the bio-methane fuelled do not have the same.

The focus of the study is the analysis and sizing of the air conditioning system on board the vehicle which operates in thermal transient for the duration of the typical mission, using “fan coil” type air conditioning devices powered by a hot or cold heat vector fluid loaded into “electro-thermal” charging station and the related ground cogeneration plant (at the BUS terminus). For winter air conditioning, it was assumed that a heat transfer fluid at a temperature of 90 ° C could be stored on board. This value allows the use of water as a heat transfer fluid without pressurizing the systems, minimizing costs and supply problems, and is compatible with the characteristics of ICE cogeneration systems. For summer air conditioning, it was assumed that ice or fluid at a temperature of -20 ° C could be loaded. Also in this case it was decided to operate with a common fluid, such as a solution of water and salt (e.g. calcium chloride CaCl2). A comparative analysis of two solutions was carried out: the first involves the standard solution with BUS air conditioning system with heat pump powered by traction batteries charged by the grid and the second one analyzes the use of a high temperature Fuel Cell in a trigenerative configuration with refrigeration unit absorption fueled by the fumes of the FC. The trigeneration plant produces 100 kW of electricity via SOFC (Solid Oxide Fuel Cell) and, through an exchanger, water at 95 ° C which is stored on board the BUS for winter heating and feeds an absorption refrigeration machine that produces fluid at a temperature of -20 ° C for summer conditioning. For the two solutions, the savings of non-renewable primary energy and the reduction of GHG emissions compared to the standard solution (recharging the electric BUS from the network with on-board air conditioning powered by the traction batteries) are calculated through a WTW analysis. Consumption and emissions of electric powertrains, potentially for consumption and zero emissions, are closely linked to the methods of production and distribution of electricity.

This article reviews and summarizes current reproduction and replication practices in political science. We first provide definitions for reproducibility and replicability. We then review data availability policies for 28 leading political science journals and present the results from a survey of editors about their willingness to publish comments and replications. We discuss new initiatives that seek to promote and generate high-quality reproductions and replications. Finally, we make the case for standards and practices that may help increase data availability, reproducibility, and replicability in political science.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKƴ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Bio-methane as fuel in a natural gas engine is a viable solution to reduce greenhouse gas emissions. The present paper illustrates the results of the first set of measurements carried out in the BiomethER project (EULIFE). BiomethER aimed to design and build two innovative bio-methane production plants, located in Emilia Romagna region (Italy), fed by different feedstock: the first one with sewage sludge and the other with landfill waste. Biogas extracted by the anaerobic digester was cleaned and upgraded to biomethane for road vehicles application. To verify the compatibility of biomethane in conventional compressed natural gas engine (CNG) vehicles, three passenger cars have been tested with two gases: conventional natural gas and bio-methane coming by BiomethER sewage sludge plant. Test concerned dynamic performances and exhaust emissions and was operated on the chassis dynamometer facility, in ENEA Casaccia Research Centre. Preliminary results showed no appreciable deviation was noticeable for fuel consumption and CO2 emissions between the two fuels, acceleration and maximum power were almost the same for the three vehicles tested. The WTW evaluation of GHG emissions for the biomethane resulted in up to 79% lower in comparison with natural gas provided by the Italian pipeline.

Fuel cell technologies and hydrogen can represent a potential and powerful enabler for replacing traditional diesel vehicles, especially in railways. In this train of thought, the present paper aims to investigate a fuel cell hybrid powertrain for a regional route. The main powertrain components are numerically modeled and the railway operations are simulated. The results achieved, in terms of power demand, efficiency and hydrogen consumption, are discussed and they are useful for properly sizing the refueling system. As a matter of fact, the train will be fueled with compressed hydrogen, produced on-site at a hydrogen central depot, where a hydrogen refueling station is thought to be installed. The hydrogen generation unit is considered to be a PEM unit, operating at 353 K and 20 bar. The produced hydrogen is then compressed by mean of a volumetric compressor and then stored in hydrogen tank type II, at 350 bar. The dispensing scheduling is based on the daily hydrogen demand required by the fuel cell-based train route, according to the railway timetable. The system is indeed investigated from a technical point of view, proving the integration of such systems to represent a clean, sustainable, and flexible option.