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The task of preventing suicide in older adults is an important social burden as older adults aged above 65 are exposed to singular psychological aspects that increase suicide risks. Moreover, when an older adult corpse is found, the medico-legal inspection represents a fundamental tool to identify the exact cause of death, classifying or excluding it as suicide. In this scenario, this review aims to explore the neurobiological factors that could be related to suicidal behavior in older adults. A further goal of this review is the exploration of the medico-legal aspects surrounding older adult suicides, clarifying the importance of forensic investigation. Particularly, this review examines issues such as neurotransmitter imbalances, cognitive impairment, neuroinflammation, psychosocial factors related to geriatric suicide, and neurodegenerative diseases. Additionally, medico-legal aspects such as policy considerations, legal frameworks, mental health assessments, ethical implications and forensic investigation were explored. Considering the importance of this phenomenon, especially in western countries, a need has emerged for focused screening tools on suicidal behavior among older adults, in order to contain it. Therefore, this review makes an exhaustive appraisal of the literature giving insights into the delicate interplay between neurobiology as well as mental health in relation to older adult suicide within a medico-legal context. The comprehension of different aspects about this complex phenomenon is fundamental to propose new and more effective interventions, supporting tailored initiatives such as family support and improving healthcare, specifically towards vulnerable ageing societies to reduce older adult suicide risks.

Background and introduction: Lung cancer is a prevalent and deadly disease globally. Non-small cell lung cancer (NSCLC) is the most common subtype, comprising 85% of cases. Case report: A 65-year-old male ex-smoker presented to our facility with a nocturnal cough. Various investigations revealed that he had metastatic NSCLC, for which he underwent chemotherapy with cisplatin and gemcitabine, followed by immunotherapy with Nivolumab. He achieved a complete response to the therapy and has remained free from recurrence for over 7 years since the initial diagnosis. Discussion and Conclusions: The treatment of metastatic NSCLC remains a significant therapeutic challenge, but the implementation of new therapeutic techniques has expanded the possibilities of achieving complete and durable eradication of the disease.

Given the long-standing debate about the nature of the concept of disease, the objective of this study was to understand how doctors categorize a condition as a disease or not, and what the kind of information they use is. A survey with a set of eighteen clinical vignettes was designed, and nineteen physicians and senior students purposefully selected were asked to interpret those situations as diseases or not and to produce an anonymous short written piece of text providing the motivation of their choice. Realist thematic analysis was used to analyse the answers, and four themes emerged: the temporal dimension of a disease, reification of disease, disease as an existential condition, and disease as a motivation to action. The respondents’ interpretations were very heterogeneous, supporting the idea that physicians do not share a common prototypical concept of disease. The results suggested that the interpretation of a condition as a disease or not is the final outcome of a process, in which information from objective, subjective, and socially mediated elements is taken into consideration. According to a critical realist and systemic approach, we hypothesize that the context of doctor–patient relationship could influence the interpretation of the same condition as being a disease or not.

BackgroundDiabetes mellitus is a prevalent chronic condition that significantly impacts global health. Diabetic foot complications, such as foot ulcers, pose a substantial burden on individuals with diabetes and can lead to serious consequences, including amputation. Platelet-rich plasma (PRP) has emerged as a promising therapeutic approach for enhancing the healing of diabetic foot ulcers.MethodsIn our study, we treated 12 patients with chronic diabetic ulcers using PRP injections administered at three-week intervals. Our objective was to assess the reduction in wound size and the rate of complete healing at 6 months after the start of the treatment. Additionally, we conducted a comprehensive literature review to contextualize our findings.ResultsOut of the 12 patients, 8 achieved complete healing of their diabetic foot ulcers, while the remaining four showed significant improvement with more than 50% reduction in the initial lesion size. 3 patients developed mild irritation at the inoculation site. These outcomes, combined with the evidence from published studies, highlight the effectiveness of PRP in promoting the healing of diabetic foot ulcers.ConclusionIn conclusion, our study demonstrates the potential of platelet-rich plasma (PRP) as a successful therapeutic option for enhancing the healing process of chronic diabetic foot ulcers. The favorable outcomes observed, including a high rate of complete healing and significant wound size reduction, underscore the value of PRP treatment in managing this challenging complication. Further research and larger studies may provide additional insights into the mechanisms and long-term benefits of PRP in diabetic wound healing.

In 2020 André Tiran edited the translation of the Bref traité sur la richesse des royaumes précédé des 1er et 2e discours sur le change by Marc'Antonio de Santis (1605) and published the volume Le Royaume de Naples (1580-1620). Économie, Monnaie et Finance à l’époque d’Antonio Serra, for Classiques Garnier (2020). We present here the dialogue between André Tiran, Simona Pisanelli (both historians of economic thought) and Giovanni Muto (historian of the modern epoch and specialist in the history of the Mezzogiorno), which took place at the University of Turin on 4 October 2021. The authors emphasise the importance of an interdisciplinary approach, both for the faithful translation of classical texts, which must overcome the obstacle made by a vocabulary that has changed, and for the reconstruction of the economic and financial system of the Kingdom of Naples. The three specialists also consider it essential to include the cultural, political, and social dimension in studies of economic issues. English title: Translations and Historical Reconstructions Put to the Test of Time: a Look at the Kingdom of Naples; A Discussion with André Tiran Keywords: Antonio Serra, Marc'Antonio de Santis, Kingdom of Naples, History of Monetary and Banking Systems, Translation Theory and Practices

The recent yellow fever virus (YFV) epidemic in Brazil in 2017 and Zika virus (ZIKV) epidemic in 2015 serve to remind us of the importance of flaviviruses as emerging human pathogens. With the current global flavivirus threat, there is an urgent need for antivirals and vaccines to curb the spread of these viruses. However, the lack of suitable animal models limits the research questions that can be answered. A common trait of all flaviviruses studied thus far is their ability to antagonize interferon (IFN) signaling so as to enhance viral replication and dissemination. Previously, we reported that YFV NS5 requires the presence of type I IFN (IFN-α/β) for its engagement with human signal transducer and activator of transcription 2 (hSTAT2). In this manuscript, we report that like the NS5 proteins of ZIKV and dengue virus (DENV), YFV NS5 protein is able to bind hSTAT2 but not murine STAT2 (mSTAT2). Contrary to what has been demonstrated with ZIKV NS5 and DENV NS5, replacing mSTAT2 with hSTAT2 cannot rescue the YFV NS5-STAT2 interaction, as YFV NS5 is also unable to interact with hSTAT2 in murine cells. We show that the IFN-α/β-dependent ubiquitination of YFV NS5 that is required for STAT2 binding in human cells is absent in murine cells. In addition, we demonstrate that mSTAT2 restricts YFV replication in vivo These data serve as further impetus for the development of an immunocompetent mouse model that can serve as a disease model for multiple flaviviruses.IMPORTANCE Flaviviruses such as yellow fever virus (YFV), Zika virus (ZIKV), and dengue virus (DENV) are important human pathogens. A common flavivirus trait is the antagonism of interferon (IFN) signaling to enhance viral replication and spread. We report that like ZIKV NS5 and DENV NS5, YFV NS5 binds human STAT2 (hSTAT2) but not mouse STAT2 (mSTAT2), a type I IFN (IFN-α/β) pathway component. Additionally, we show that contrary to what has been demonstrated with ZIKV NS5 and DENV NS5, YFV NS5 is unable to interact with hSTAT2 in murine cells. We demonstrate that mSTAT2 restricts YFV replication in mice and that this correlates with a lack of IFN-α/β-induced YFV NS5 ubiquitination in murine cells. The lack of suitable animal models limits flavivirus pathogenesis, vaccine, and drug research. These data serve as further impetus for the development of an immunocompetent mouse model that can serve as a disease model for multiple flaviviruses.

Scientific studies have shown that dysfunctional problems associated with dysmorphisms are the base of malocclusion. The position of the mouth and the head is a component of the general postural arrangement, so any head misalignment creates disharmonies and tensions among the neck muscles. Elastodontics is a treatment based on the use of removable elastomeric devices. These functional appliances are made of elastomeric material, acting tridimensionally on a neuromuscular system with orthopaedic and dental effects. Bioactivators have a vestibular and lingual flange with a free central area that permits them to position teeth without constraints. The flanges are linked by an occlusal plane that maintains the two skeletal bases and teeth in first-class normocclusion with propulsive and retropulsive effects on the maxilla and mandible. Elastomeric devices are generally well tolerated by patients requiring simple collaboration and management. This review aim is to describe the indications and limits of orthodontic therapy with elastomeric devices to provide an overview of elastodontics.

(1) Background: Sentinel lymph node biopsy is important in the search for metastases, especially in patients with malignant breast disease. Our study proposed new techniques to prevent complications such as possible postoperative seroma formation, pain or hypoesthesia of the axillary cord and medial arm surface, as well as motor deficits, to avoid disabling outcomes and presents initial data from our experience with the sentinel lymph node biopsy technique. (2) Methods: We mainly used two radioactive tracer detection techniques and a new technique using a radiotracer called Sentimag-magtrace. The positive lymph node was located and removed to perform histologic analysis. In our study, we evaluate 100 patients who underwent breast cancer surgery. (3) Results: We calculated the identification rates of the different methods of sentinel lymph node detection and found that it was 88.9% using radioactive tracers vs. 89.5% using the magnetic tracer technology (Sentimag). (4) Conclusions: Thus, this technique avoids radiation exposure for both patients and health care providers, and can reduce costs and time.

MiRNAs regulate both physiological and pathological heart functions. Altered expression of miRNAs is associated with cardiovascular diseases (CVDs), making miRNAs attractive therapeutic strategies for the diagnosis and treatment of heart diseases. A recent publication defined, for the first time, the term theranoMiRNA, meaning the miRNAs that may be used both for diagnosis and treatment. The use of in silico tools may be considered fundamental for these purposes, clarifying several molecular aspects, suggesting future directions for in vivo studies. This study aims to explore different bioinformatic tools in order to clarify miRNA interactions with candidate genes, demonstrating the need to use a computational approach when establishing the most probable associations between miRNAs and target genes. This study focused on the functions of miR-133a-3p, miR-21-5p, miR-499a-5p, miR-1-3p, and miR-126-3p, providing an up-to-date overview, and suggests future lines of research in the identification of theranoMiRNAs related to CVDs. Based on the results of the present study, we elucidated the molecular mechanisms that could be linked between miRNAs and CVDs, confirming that these miRNAs play an active role in the genesis and development of heart damage. Given that CVDs are the leading cause of death in the world, the identification of theranoMiRNAs is crucial, hence the need for a definition of in vivo studies in order to obtain further evidence in this challenging field of research.

The ketogenic diet (KD), a diet high in fat and protein but low in carbohydrates, is gaining much interest due to its positive effects, especially in neurodegenerative diseases. Beta-hydroxybutyrate (BHB), the major ketone body produced during the carbohydrate deprivation that occurs in KD, is assumed to have neuroprotective effects, although the molecular mechanisms responsible for these effects are still unclear. Microglial cell activation plays a key role in the development of neurodegenerative diseases, resulting in the production of several proinflammatory secondary metabolites. The following study aimed to investigate the mechanisms by which BHB determines the activation processes of BV2 microglial cells, such as polarization, cell migration and expression of pro- and anti-inflammatory cytokines, in the absence or in the presence of lipopolysaccharide (LPS) as a proinflammatory stimulus. The results showed that BHB has a neuroprotective effect in BV2 cells, inducing both microglial polarization towards an M2 anti-inflammatory phenotype and reducing migratory capacity following LPS stimulation. Furthermore, BHB significantly reduced expression levels of the proinflammatory cytokine IL-17 and increased levels of the anti-inflammatory cytokine IL-10. From this study, it can be concluded that BHB, and consequently the KD, has a fundamental role in neuroprotection and prevention in neurodegenerative diseases, presenting new therapeutic targets.

Recent advances in biomedicine are opening the door to new approaches, and treatment and prevention are being transformed by novel medicines based on genetic engineering, innovative cell-based therapies and tissue-engineered products, and combinations of a medical device with embedded cell or tissue components. These advanced therapy medicinal products (ATMPs) hold one of the keys to making a reality of genuinely personalised medicine. There are an estimated 450 companies across the globe working on the development of gene therapies and more than 1,000 clinical trials underway worldwide, and some 20–30 new ATMPs filings are expected in Europe annually over the next 5 years. But challenges confront the sector, complicating the translation from research into patient access. Scientific, clinical development and regulatory issues are compounded by limited experience with clinical and commercial use, limited manufacturing know-how, high costs, and difficulties in accessing development funding and investment. Pricing and reimbursement and market access issues are an additional challenge, particularly in Europe, where unfamiliarity with the technology and uncertainty over the use of real-world evidence induce caution among clinicians, health technology assessment bodies and payers. There is a need for a review of the suitability of the regulatory and market access framework for these products, focused development of data, public/private partnerships, and fuller collaboration governments, doctors, insurers, patients, and pharmaceutical companies. This paper makes specific recommendations for all stakeholders, ranging from early dialogue on potential products, linking of clinical data and patient registries or standardisation of control frameworks, to a comprehensive approach to evidence generation, assessment, pricing, and payment for ATMPs.

La Piedad Michoacán Mexico Virus (LPMV) is a member of the Rubulavirus genus within the Paramyxoviridae family. LPMV is the etiologic agent of "blue eye disease", causing a significant disease burden in swine in Mexico with long-term implications for the agricultural industry. This virus mainly affects piglets and is characterized by meningoencephalitis and respiratory distress. It also affects adult pigs, causing reduced fertility and abortions in females, and orchitis and epididymitis in males. Viruses of the Paramyxoviridae family evade the innate immune response by targeting components of the interferon (IFN) signaling pathway. The V protein, expressed by most paramyxoviruses, is a well-characterized IFN signaling antagonist. Until now, there were no reports on the role of the LPMV-V protein in inhibiting the IFN response. In this study we demonstrate that LPMV-V protein antagonizes type I but not type II IFN signaling by binding STAT2, a component of the type I IFN cascade. Our results indicate that the last 18 amino acids of LPMV-V protein are required for binding to STAT2 in human and swine cells. While LPMV-V protein does not affect the protein levels of STAT1 or STAT2, it does prevent the IFN-induced phosphorylation and nuclear translocation of STAT1 and STAT2 thereby inhibiting cellular responses to IFN α/β.

In the original article [...]

To successfully establish infection, flaviviruses have to overcome the antiviral state induced by type I interferon (IFN-I). The nonstructural NS5 proteins of several flaviviruses antagonize IFN-I signaling. Here we show that yellow fever virus (YFV) inhibits IFN-I signaling through a unique mechanism that involves binding of YFV NS5 to the IFN-activated transcription factor STAT2 only in cells that have been stimulated with IFN-I. This NS5-STAT2 interaction requires IFN-I-induced tyrosine phosphorylation of STAT1 and the K63-linked polyubiquitination at a lysine in the N-terminal region of YFV NS5. We identified TRIM23 as the E3 ligase that interacts with and polyubiquitinates YFV NS5 to promote its binding to STAT2 and trigger IFN-I signaling inhibition. Our results demonstrate the importance of YFV NS5 in overcoming the antiviral action of IFN-I and offer a unique example of a viral protein that is activated by the same host pathway that it inhibits.

Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds of IFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IκB kinase epsilon (IKKε). However, the mechanism of IKKε activation upon IFN receptor signaling has remained elusive. Here we show that TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family of proteins, interacted with IKKε and promoted induction of IKKε-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKε for subsequent STAT1 phosphorylation. Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response.

Paramyxoviridae is a viral family within the order of Mononegavirales; they are negative single-strand RNA viruses that can cause significant diseases in both humans and animals. In order to replicate, paramyxoviruses–as any other viruses–have to bypass an important protective mechanism developed by the host’s cells: the defensive line driven by interferon. Once the viruses are recognized, the cells start the production of type I and type III interferons, which leads to the activation of hundreds of genes, many of which encode proteins with the specific function to reduce viral replication. Type II interferon is produced by active immune cells through a different signaling pathway, and activates a diverse range of genes with the same objective to block viral replication. As a result of this selective pressure, viruses have evolved different strategies to avoid the defensive function of interferons. The strategies employed by the different viral species to fight the interferon system include a number of sophisticated mechanisms. Here we analyzed the current status of the various strategies used by paramyxoviruses to subvert type I, II, and III interferon responses.

Silvopasture is the deliberate integration of a woody component with grazed pastures as understorey. It is one of the most extended agroforestry practices all over the world. Silvopasture use is key to increase the sustainability of livestock farming systems as silvopasture reduces the use of concentrates since the woody component provides feed for animals. However, it is not an extensively used practice in Europe. This paper aims at evaluating, from Eurostat, LUCAS database and the 118 rural development programs, the current situation of permanent grasslands in the Mediterranean area of Europe as well as the rural development programmes fostering silvopasture to better understand how sustainable land use systems are promoted and provide insights to foster silvopasture across Europe. The results of this study show that most of the policy measures related to silvopasture are adapted to the local necessity. The already existing agroforestry managed land (dehesas/montado) are related to measures supporting regeneration and maintenance while in those areas where agroforestry does not exist the measures are related to forest fire prevention.

Introduction: In Italy, medical simulation is undergoing a phase of intense diffusion, establishing a more decisive and uniform role in medical education. Educators receive many opportunities to train in simulation education, but these provide little room for personal growth and collaboration. This could have a negative impact on education quality and the standardization of processes. Thus, we found a gap in new information technology use, specifically in the informal diffusion of medical simulation content knowledge. Using a blog platform, we identified a space in which people can disseminate information, share their experiences, criticisms, and perspectives. Approach: From March 2016 to November 2019, we implemented a novel pilot project, creating the first Italian blog on simulations, dedicated to simulation educators. It contained the following main sections: communication, debriefing, simulation experiences, instructions for use, journal club, and psychology. Findings: Multidisciplinary personnel contributed to the blog’s content. With over 70 posts, the blog accumulated 25,615 pageviews and 9,056 sessions, without promotional, monetary support or diffusion efforts. The average visitor session was 2.17 minutes long and the average pages viewed in a session was 2.83. Additionally, 30.5% of the users were returning visitors and 58.67% found the website through Google. Insights: Despite the blog’s niche subject, the results were encouraging. The materials were not only meant for personal viewing, but also as a source for announcing public events (meetings and workshops). The project provided educators with an easy tool for continuous education. We believe that it enabled and organized the informal sharing of educational simulation content. As such, it also offered significant insights into formal program consolidation and the standardization of simulation instruction, while we wait for further local scientific literature production. For future developments, we believe that collaborations with other stakeholders, scientific societies, and ethical sponsorship could foster this project’s continuation.

An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation.

BackgroundBreast cancer represents the most frequent neoplasm diagnosed in women of childbearing age. When the tumour is oestrogen receptor-positive, tamoxifen is among the recommended endocrine treatments. Lactating women are advised not to breastfeed while receiving tamoxifen. However, information about tamoxifen transfer into breast milk is lacking.MethodsWe measured the concentration of tamoxifen and its metabolites by liquid chromatography-tandem mass spectrometry in the milk of a nursing mother that was treated for pregnancy-associated breast cancer diagnosed a few months after delivery. She was advised not to breastfeed her child and she collected milk samples for 23 days while the baby was fed with formula.ResultsTamoxifen concentrations in milk increased reaching a maximum of 214 nM. The two active metabolitesZ-4-hydroxy-tamoxifen and Z-endoxifen, could not be quantified in milk the first days after tamoxifen intake, but increased over time and reached clinically significant levels after day 18.ConclusionThis study demonstrates for the first time in human that tamoxifen and its metabolites transfer into milk. Since tamoxifen has a complete oral bioavailability, a long half-life (>7 days) and may interfere with the normal development of the infant, mothers should not breastfeed during tamoxifen treatment.

Reseña del libro de Guido Tortorella Esposito, Juan Hernández Andreu, Realismo crítico y economía civil en España e Italia. Una perspectiva histórica, Ediciones Paraninfo, Madrid, 2019, 215 pp.

Infectious diseases are a common cause of death in young dogs. Several factors are thought to predispose young dogs to microbiological infections. Identifying the cause of death is often a challenge, and broad diagnostic analysis is often needed. Here, we aimed to determine the infectious causes of death in young dogs aged up to 1 year, examining how it relates to age (under and over 6 months), lifestyle (owned versus ownerless), breed (purebred and crossbreed), and gender. A retrospective study was conducted in a 3-year period (2015–2017) on 138 dead dogs that had undergone necropsy and microbiological diagnostics. Enteritis and pneumonia were the most commonly observed lesions. Polymicrobism was more prevalent (62.3%) than single-agent infections and associated with a higher rate of generalised lesions. Ownerless dogs showed over a three-fold higher predisposition to viral coinfections than owned dogs. Above all, canine parvovirus was the most prevalent agent (77.5%), followed by canine coronavirus (31.1%) and canine adenovirus (23.9%); ownerless pups had a higher predisposition to these viruses. Escherichia coli (23.9%), Clostridium perfringens type A (18.1%), and Enterococcus spp. (8.7%) were the most commonly identified bacteria, which mostly involved in coinfections. A lower prevalence of CDV and Clostridium perfringens type A was observed in puppies under 6 months of age. In conclusion, this study is the first comprehensive survey on a wide panel of microbiological agents related to necropsy lesions. It lays the groundwork for future studies attempting to understand the circulation of infectious agents in a determined area.

Abstract Background Modelling and simulation may become clinically applicable tools for detailed evaluation of the cardiovascular system and clinical decision-making to guide therapeutic intervention. Models based on pressure–volume relationship and zero-dimensional representation of the cardiovascular system may be a suitable choice given their simplicity and versatility. This approach has great potential for application in heart failure where the impact of left ventricular assist devices has played a significant role as a bridge to transplant and more recently as a long-term solution for non eligible candidates. Results We sought to investigate the value of simulation in the context of three heart failure patients with a view to predict or guide further management. CARDIOSIM© was the software used for this purpose. The study was based on retrospective analysis of haemodynamic data previously discussed at a multidisciplinary meeting. The outcome of the simulations addressed the value of a more quantitative approach in the clinical decision process. Conclusions Although previous experience, co-morbidities and the risk of potentially fatal complications play a role in clinical decision-making, patient-specific modelling may become a daily approach for selection and optimisation of device-based treatment for heart failure patients. Willingness to adopt this integrated approach may be the key to further progress.

Breast cancer is one of the most frequently diagnosed malignancies during pregnancy. Here, we review the management of women with breast cancer during pregnancy (BCP), focusing on biology, diagnosis and staging, local and systemic treatments, obstetric care and long-term follow-up of children with prenatal exposure to anticancer treatments.

Microglia are the first line of defense at the level of the central nervous system (CNS). Phenotypic change in microglia can be regulated by various factors, including the orexin system. Neuroinflammation is an inflammatory process mediated by cytokines, by the lack of interaction between neurotransmitters and their specific receptors, caused by systemic tissue damage or, more often, associated with direct damage to the CNS. Chronic activation of microglia could lead to long-term neurodegenerative diseases. This review aims to explore how tocopherol (vitamin E) and the orexin system may play a role in the prevention and treatment of microglia inflammation and, consequently, in neurodegenerative diseases thanks to its antioxidant properties. The results of animal and in vitro studies provide evidence to support the use of tocopherol for a reduction in microglia inflammation as well as a greater activation of the orexinergic system. Although there is much in vivo and in vitro evidence of vitamin E antioxidant and protective abilities, there are still conflicting results for its use as a treatment for neurodegenerative diseases that speculate that vitamin E, under certain conditions or genetic predispositions, can be pro-oxidant and harmful.

Antimicrobial peptides (AMPs), α- and β-defensins, possess antiviral properties. These AMPs achieve viral inhibition through different mechanisms of action. For example, they can: (i) bind directly to virions; (ii) bind to and modulate host cell-surface receptors, disrupting intracellular signaling; (iii) function as chemokines to augment and alter adaptive immune responses. Given their antiviral properties and the fact that the development of an effective coronavirus disease 2019 (COVID-19) treatment is an urgent public health priority, they and their derivatives are being explored as potential therapies against COVID-19. These explorations using various strategies, range from their direct interaction with the virus to using them as vaccine adjuvants. However, AMPs do not work in isolation, specifically in their role as potent immune modulators, where they interact with toll-like receptors (TLRs) and chemokine receptors. Both of these receptors have been shown to play roles in COVID-19 pathogenesis. In addition, it is known that a healthy lifestyle accompanied by controlled physical activity can represent a natural weapon against COVID-19. In competitive athletes, an increase in serum defensins has been shown to function as self-protection from the attack of microorganisms, consequently a controlled physical activity could act as a support to any therapies in fighting COVID-19. Therefore, including information on all these players’ interactions would produce a complete picture of AMP-based therapies’ response.

Even if anabolic androgenic steroid (AAS) abuse is clearly associated with a wide spectrum of collateral effects, adolescents and athletes frequently use a large group of synthetic derivatives of testosterone, both for aesthetic uses and for improving performance. Over the last few years, the development of MicroRNA (miRNA) technologies has become an essential part of research projects and their role as potential molecular biomarkers is being investigated by the scientific community. The circulating miRNAs detection as a diagnostic or prognostic tool for the diagnosis and treatment of several diseases is very useful, because with a minimal quantity of sample (peripheral blood), miRNAs are very sensitive. Even more, miRNAs remain stable both at room temperature and during freeze-thaw cycles. These characteristics highlight the important role of miRNAs in the near future as new tools for anti-doping. The article provides a systematic review and meta-analysis on the role of miRNAs as new potential molecular biomarkers of AAS use/abuse. Particularly, this paper analyzed the “miRNA signature” use as biomarkers for health disorders, focusing on the organ damages which are related to ASS use/abuse. Moreover, this review aims to provide a future prospect for less invasive or non-invasive procedures for the detection of circulating miRNA biomarkers as doping assumption signaling.

To overcome the obstacle of antimicrobial resistance, researchers are investigating the use of phage therapy as an alternative and/or supplementation to antibiotics to treat and prevent infections both in humans and in animals. In the first part of this review, we describe the unique biological characteristics of bacteriophages and the crucial aspects influencing the success of phage therapy. However, despite their efficacy and safety, there is still no specific legislation that regulates their use. In the second part of this review, we describe the comprehensive research done in the past and recent years to address the use of phage therapy for the treatment and prevention of bacterial disease affecting domestic animals as an alternative to antibiotic treatments. While in farm animals, phage therapy efficacy perspectives have been widely studied in vitro and in vivo, especially for zoonoses and diseases linked to economic losses (such as mastitis), in pets, studies are still few and rather recent.

At the end of 2019, a new coronavirus (COVID-19) appeared on the world scene, which mainly affects the respiratory system, causing pneumonia and multi-organ failure, and, although it starts with common symptoms such as shortness of breath and fever, in about 2–3% of cases it leads to death. Unfortunately, to date, no specific treatments have been found for the cure of this virus and, therefore, it is advisable to implement all possible strategies in order to prevent infection. In this context, it is important to better define the role of all behaviors, in particular nutrition, in order to establish whether these can both prevent infection and improve the outcome of the disease in patients with COVID-19. In the literature, it is widely shown that states of malnutrition, overweight, and obesity negatively affect the immune system, leading to viral infections, and several studies have shown that nutritional interventions can act as immunostimulators, helping to prevent viral infections. Even if several measures, such as the assumption of a specific diet regimen, the use of dietary supplements, and other similar interventions, are promising for the prevention, management, and recovery of COVID-19 patients, it is important to highlight that strong data from randomized clinical trials are needed to support any such assumption. Considering this particular scenario, we present a literature review addressing several important aspects related to diet and SARS-CoV-2 infection, in order to highlight the importance of diet and supplementation in prevention and management of, as well as recovery from COVID-19.

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues – notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe’s fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear recommendations springing from the convictions of patients, clinicians, academics, medicines authorities, HTA bodies, payers, the diagnostic, pharmaceutical and ICT industries, and national policy makers.

Live visualization of influenza A virus (IAV) structural proteins during viral infection in cells is highly sought objective to study different aspects of the viral replication cycle. To achieve this, we engineered an IAV to express a Tetra Cysteine tag (TC tag) from hemagglutinin (HA), which allows intracellular labeling of the engineered HA protein with biarsenic dyes and subsequent fluorescence detection. Using such constructs, we rescued a recombinant IAV with TC tag inserted in HA, in A/Puerto Rico/8/1934(H1N1) background (HA-TC). This recombinant HA-TC tag reporter IAV was replication-competent; however, as compared to wild type PR8 IAV, it was attenuated in multicycle replication. We confirmed expression of TC tag and biarsenical labeling of HA by immunofluorescence assay in cells infected with an HA-TC tag reporter IAV. Further, we used this reporter virus to visualize HA expression and translocation in IAV infected cells by live confocal imaging. We also tested the utility of the HA-TC IAV in testing chemical inhibitors of the HA translocation. Overall, HA-TC IAV is a versatile tool that will be useful for studying viral life cycle events, virus-host interactions, and anti-viral testing.

Background: On the 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown origin detected in Wuhan City, Hubei Province, China. The infection spread first in China and then in the rest of the world, and on the 11th of March, the WHO declared that COVID-19 was a pandemic. Taking into consideration the mortality rate of COVID-19, about 5–7%, and the percentage of positive patients admitted to intensive care units being 9–11%, it should be mandatory to consider and take all necessary measures to contain the COVID-19 infection. Moreover, given the recent evidence in different hospitals suggesting IL-6 and TNF-α inhibitor drugs as a possible therapy for COVID-19, we aimed to highlight that a dietary intervention could be useful to prevent the infection and/or to ameliorate the outcomes during therapy. Considering that the COVID-19 infection can generate a mild or highly acute respiratory syndrome with a consequent release of pro-inflammatory cytokines, including IL-6 and TNF-α, a dietary regimen modification in order to improve the levels of adiponectin could be very useful both to prevent the infection and to take care of patients, improving their outcomes.

Given the environmental footprints of the conventional agriculture, it is imperative to test and validate alternative production systems, with lower environmental impacts to mitigate and adapt our production systems. In this study, we identified six production systems, four in Italy and two in Denmark, to assess the environmental footprint for comparison among the production systems and additionally with conventional production systems. SimaPro 8.4 software was used to carry out the life cycle impact assessment. Among other indicators, three significantly important indicators, namely global warming potential, acidification, and eutrophication, were used as the proxy for life cycle impact assessment. In Italy, the production systems compared were silvopastoral, organic, traditional, and conventional olive production systems, whereas in Denmark, combined food and energy production system was compared with the conventional wheat production system. Among the six production systems, conventional wheat production system in Denmark accounted for highest global warming potential, acidification, and eutrophication. In Italy, global warming potential was highest in traditional agroforestry and lowest in the silvopastoral system whereas acidification and eutrophication were lowest in the traditional production system with high acidification effects from the silvopastoral system. In Italy, machinery use contributed the highest greenhouse gas emissions in silvopastoral and organic production systems, while the large contribution to greenhouse gas emissions from fertilizer was recorded in the traditional and conventional production systems. In Denmark, the combined food and energy system had lower environmental impacts compared to the conventional wheat production system according to the three indicators. For both systems in Denmark, the main contribution to greenhouse gas emission was due to fertilizer and manure application. The study showed that integrated food and non-food systems are more environmentally friendly and less polluting compared to the conventional wheat production system in Denmark with use of chemical fertilizers and irrigation. The study can contribute to informed decision making by the land managers and policy makers for promotion of environmentally friendly food and non-food production practices, to meet the European Union targets of providing biomass-based materials and energy to contribute to the bio-based economy in Europe and beyond.

Adipose tissue (AT) is strongly associated with development and progression of immune disorders through adipokines secretion, such as adiponectin. This protein has beneficial energetic properties and is involved in inflammation and immunity processes. Three oligomers of circulating adiponectin with different molecular weight are described: High (HMW), Medium (MMW), and Low (LMW). The HMW is the most biologically active oligomers. On binding to its receptors AdipoR1, AdipoR2, and T-cadherin, adiponectin acts on both innate and acquired immunity. The suppression of NF-κB activation and pro-inflammatory cytokine expression in macrophages is mediated by AdipoR1. AdipoR2 mediates polarization of anti-inflammatory M2 macrophages T-cadherin is essential for the M2 macrophage proliferation. Furthermore, adiponectin reduces T cells responsiveness and B cells lymphopoiesis. The immune system is very sensitive to environmental changes and it is not only interconnected with AT but also with the central nervous system (CNS). Cytokines, which are mediators of the immune system, exercise control over mediators of the CNS. Microglia, which are immunity cells belonging to the macrophage family, are present within the CNS. The nervous system is also involved in immunity through the production of neuropeptides such as orexin-A/hypocretin-1. This neuropeptide is involved in metabolic disorders, inflammation and in the immune response. The relationship between adipokines, immunity, and the nervous system is validated by both the role of orexin-A on fat, food intake, and energy expenditure, as well as by role of adiponectin on the CNS. In this review, we focused on the functions of adiponectin and orexin-A as a potential immunity link between AT and CNS.

Enrico Papaleo,1 Carlo Alviggi,2 Giorgio Lorenzo Colombo,3,4 Claudio Pisanelli,5,6 Claudio Ripellino,7 Salvatore Longobardi,8 Pier Luigi Canonico91Centro Scienze della Natalità, Gynecological-Obstetrics Department, San Raffaele Hospital, Vita-Salute San Raffaele, Milan, Italy; 2Department of Neuroscience, Reproductive Sciences and Odontostomatology, University “Federico II” of Naples, Naples, Italy; 3Department of Drug Sciences, University of Pavia, Pavia, Italy; 4SAVE Studi Analisi Valutazioni Economiche, Milan, Italy; 5ACO San Filippo Neri, Rome, Italy; 6Società Italiana Di Farmacia Ospedaliera, Milan, Italy; 7CSD Medical Research Srl, Milan, Italy; 8Medical Department, Merck Serono SpA, Rome, Italy; 9Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy Background: Hypogonadotropic hypogonadal women are characterized by ovarian functionality deficiency, caused by low concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). To recover reproduction functionality, recommended therapies for ovarian induction involve injections of FSH and LH medications. Objective: Since important differences exist between recombinant and urinary gonadotropin therapies in terms of efficacy and cost, the objective of this study was to develop a cost-effectiveness model to compare recombinant FSH (rFSH) + recombinant LH (rLH) and highly purified human menopausal gonadotropin (HP-HMG). Methods: A Markov model was developed, considering three cycles of therapy; probability of pregnancy and miscarriage were considered, and the efficacy was evaluated in terms of pregnancy occurrence. The perspective of the model was that of the Italian Health Service, so only direct cost (drugs, specialist visits, patient examinations, and hospitalizations) were included. Results: rFSH + rLH is associated with a higher total cost (€3,453.50) and higher efficacy (0.87) compared with HP-HMG (€2,719.70 and 0.50). rFSH + rLH generated an incremental cost effectiveness ratio equal to €2,007.30 compared to HP-HMG; the average cost per pregnancy is estimated to be €3,990.00 for recombinant strategy and €5,439.80 for urinary strategy. Results of probabilistic sensitivity analysis were consistent with the abovementioned findings. Conclusion: Despite the higher acquisition cost in comparison to HP-HMG, rFSH + rLH resulted in a higher pregnancy rate, which makes it the recommended choice when considering cost-effectiveness of LH in supporting FSH-induced follicular gonadotropins in hypogonadotropic hypogonadal women. Keywords: HP-HMG, hypogonadotropic hypogonadism, gonadotropin

Definindo-se um “siciliano europeu”, Gesualdo Bufalino, em sua obra literária e poética (especialmente em L’amaro miele e Museo d’ombre) assim como em seus inúmeros artigos jornalísticos e intervenções críticas reunidos em volume (Cere perse, La luce e il lutto), elabora sonoridades e significados que tentam devolver as nuances cromáticas e a imagem em formato de mosaico de uma Sicília que não é apenas “metáfora” - como Leonardo Sciascia escreveu – de uma civilização mediterrânea em contínua transformação, mas também um espaço em que, por meio do dispositivo da memória, é possível revisitar um patrimônio histórico e cultural, material e imaterial, capaz de se afirmar como principio identitário em constante evolução. Nessa perspectiva, o espaço insular siciliano se torna uma fonte inesgotável de representações e autorrepresentações nas quais Bufalino desenvolve uma poética personalíssima e um imaginário que devolvem à Sicília sua vocação natural de “ilha-ponte” e de “ilha-plural” desde sempre influenciada pelo racionalismo europeu e por uma espécie de magismo mítico que sopra com força das margens sulistas do mare nostrum