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Francesca Giordano,1 Giuseppina Daniela Naimo,1 Alessandra Nigro,1 Francesco Romeo,2 Alessandro Paolì,1 Francesca De Amicis,1 Adele Vivacqua,1 Catia Morelli,1 Loredana Mauro,1 Maria Luisa Panno1 1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza 87036, Italy; 2Pathologic Anatomy Unit, Annunziata Hospital, Cosenza, ItalyCorrespondence: Maria Luisa PannoDepartment of Pharmacy and Health and Nutrition Sciences, University of Calabria, Rende, Cosenza 87036, ItalyTel +39 984 492927Email mamissina@yahoo.itPurpose: Neuroendocrine differentiation of prostate cancer, induced by androgen deprivation therapy, is mainly related to advanced disease and poor clinical outcome. Genetic and epigenetic alterations are the key elements of the prostate carcinogenesis. A group of compounds able to induce changes in this sense is inhibitors of histone deacetylase, to which it belongs valproic acid (VPA). In the present paper, we evaluated the role of this molecule on the neuroendocrine differentiation of LNCaP cells together with the effect on proliferation and survival signals.Methods: Cell growth was analyzed by MTT and flow cytometry, while expression of proteins through Western blot analysis.Results: Our results have documented that VPA in LNCaP cells reduces cell proliferation, decreases the S phase and Cyclin A, and up-regulates the cyclin-dependent kinase inhibitors p21waf and p27. The acquisition of androgen-independent condition is consistent with an induction of β-III Tubulin and gamma Enolase, both markers of neuroendocrine phenotype. However, all these features cease with the removal of valproate from the culture medium, demonstrating the transitory nature of the epigenetic event. The VPA treatment does not compromise the survival phosphorylated signals of Akt, ERK1/2 and mTOR/p70S6K that remain up-regulated. Consistently, there is an increase of phospho-FOXO3a, to which corresponds the decreased expression of the corresponding oncosuppressor protein.Conclusion: Overall, our findings indicate that VPA in LNCaP prostate tumor cells, although it reduces cell proliferation, is able to drive neuroendocrine phenotype and to maintain the survival of these cells. Keeping in mind that neuroendocrine differentiation of prostate cancer appears to be associated with a poor prognosis, it is necessary to develop new treatments that do not induce neurodifferentiation but able to counteract cell survival.Keywords: prostate cancer, cell proliferation, cell cycle, neuroendocrine tumor

Coronary-pulmonary artery fistulas (CPAFs) are rare entities that can cause significant left-to-right shunting and complicate routine coronary artery bypass grafting. There are no best practice guidelines and a scarcity of reports regarding concomitant treatment of CPAF with coronary artery disease. We present a case of bilateral CPAFs in a 60-year-old man with symptomatic coronary artery disease treated successfully with coronary artery bypass, epicardial ligation, and transpulmonary closure of CPAF with patch reconstruction. This case highlights the importance of optimal myocardial protection and complete closure of the fistula to prevent risk of coronary steal.

Abstract Oligomeric species arising during the aggregation of α-synuclein are implicated as a major source of toxicity in Parkinson’s disease, and thus a major potential drug target. However, both their mechanism of formation and role in aggregation are largely unresolved. Here we show that, at physiological pH and in the absence of lipid membranes, α-synuclein aggregates form by secondary nucleation, rather than simple primary nucleation, and that this process is enhanced by agitation. Moreover, using a combination of single molecule and bulk level techniques, we identify secondary nucleation on the surfaces of existing fibrils, rather than formation directly from monomers, as the dominant source of oligomers. Our results highlight secondary nucleation as not only the key source of oligomers, but also the main mechanism of aggregate formation, and show that these processes take place under conditions which recapitulate the neutral pH and ionic strength of the cytosol.

Os satélites de geonavegação são o exemplo mais comum de aplicação da relatividade no cotidiano. Como exatamente a deformação do espaço-tempo afeta os relógios embarcados nos veículos espaciais não é de conhecimento comum. A dedução das equações utilizadas hoje pelas constelações satelitais para compensar esse efeitos é um trabalho interdisciplinar que não está presente na literatura. Por isso, este trabalho aborda de forma didática a questão. Partimos da equação de campo de Einstein e obtivemos todas as equações que possibilitam medições de precisão da ordem de milímetros. Primeiramente com uma abordagem clássica que representa a maior parte do atraso dos relógios. Atraso este associado a um incerteza de dezenas de quilômetros por dia. Em seguida observamos como as órbitas excêntricas dos satélites de navegação geram variações periódicas com amplitudes que chegaram a 217 ns, gerando incertezas de até 65 m. Por fim utilizamos um termo de perturbação do potencial terrestre para deduzir uma equação ainda mais precisa, da ordem de centímetros. Esta leva em conta o achatamento do planeta e a inclinação das órbitas.

Classes de Recomendação Classe I: Condições para as quais há evidências conclusivas e, na sua falta, consenso geral de que o procedimento é seguro e útil/eficaz. Classe II: Condições para as quais há evidências conflitantes e/ou divergência de opinião sobre a segurança e utilidade/eficácia do procedimento. Classe IIa: Peso ou evidência/opinião a favor do procedimento. A maioria aprova. Classe IIb: Segurança e utilidade/eficácia menos estabelecidas, havendo opiniões divergentes. Classe III: Condições para as quais há evidências e/ou consenso de que o procedimento não é útil/eficaz e, em alguns casos, pode ser prejudicial. Níveis de Evidência Nível A: Dados obtidos a partir de múltiplos estudos randomizados de bom porte, concordantes e/ou de metanálise robusta de estudos randomizados. Nível B: Dados obtidos a partir de metanálise menos robusta, a partir de um único estudo randomizado e/ou de estudos observacionais. Nível C: Dados obtidos de opiniões consensuais de especialistas.

Error metrics are useful for evaluating model performance and have been used extensively in climate change studies. Despite the abundance of error metrics in the literature, most studies use only one or two metrics. Since each metric evaluates a specific aspect of the relationship between the reference data and model data, restricting the comparison to just one or two metrics limits the range of insights derived from the analysis. This study proposes a new framework and composite error metrics called Bergen metrics to summarize the overall performance of climate models and to ease interpretation of results from multiple error metrics. The framework of Bergen metrics are based on the p norm, and the first norm is selected to evaluate the climate models. The framework includes the application of a non-parametric clustering technique to multiple error metrics to reduce the number of error metrics with minimum information loss. An example of Bergen metrics is provided through its application to the large ensemble of regional climate simulations available from the EURO-CORDEX initiative. This study calculates 38 different error metrics to assess the performance of 89 regional climate simulations of precipitation and temperature over Europe. The non-parametric clustering technique is applied to these 38 metrics to reduce the number of metrics to be used in Bergen metrics for eight different sub-regions in Europe. These provide useful information about the performance of the error metrics in different regions. Results show it is possible to observe contradictory behaviour among error metrics when examining a single model. Therefore, the study also underscores the significance of employing multiple error metrics depending on the specific use case to achieve a thorough understanding of the model behaviour.

Objective: To report on suicide plans and attempts among Brazilian physicians and to investigate the associated risk factors. Methods: From January 2018 to January 2019, a nationwide online survey was conducted among Brazilian physicians using the Tool for Assessment of Suicide Risk and the Satisfaction with Life Scale. Multivariate exploratory associations of demographic, psychological, and work-related factors were performed on reports of suicide plans and attempts. Results: Of the 4,148 participants, 1,946 (53.5%) were male, 2,527 (60.9%) were 30 to 60 years old, 2,675 (64.5%) had two to four jobs, and 1,725 (41.6%) worked 40 to 60 hours a week. The overall prevalence of suicide plans was 8.8% (n=364), and suicide attempts were reported by 3.2% (n=133) of participants. Daily emotional exhaustion (ORadj = 7.857; 95%CI 2.282-27.051, p = 0.002), weekly emotional exhaustion (ORadj = 7.953; 95%CI 2.403-26.324, p = 0.001), daily frustration at work (ORadj = 3.093; 95%CI 1.711-5.588, p < 0.001), and bisexuality (ORadj = 5.083; 95%CI 2.544-10.158, p < 0.001) were significantly associated with higher odds of suicide. Extremely dissatisfied physicians reported suicide plans and attempts in 38.3% of cases, whereas extremely satisfied physicians reported suicide plans and attempts in only 2.8% of cases (p < 0.001). Conclusion: Brazilian physicians with a history of suicide plans and attempts express emotional exhaustion and frustration at work. There is an urgent need for actions to promote professional safeguards and resilience.

The search for reliable and easily accessible biomarkers in Parkinson’s disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson’s disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson’s disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson’s disease, has been the most investigated Parkinson’s disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson’s disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson’s disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson’s disease patients: total tau, phosphorylated tau, amyloid-β1–42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson’s disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson’s disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.

Abstract This analytical cross-sectional study aimed to analyze the access of patients with special needs (PSN) in Brazilian municipalities to hospital dental care of the Unified Health System (Sistema Único de Saúde - SUS), based on data from the Hospital Information System of the Unified Health System (Sistema de Informações Hospitalares do SUS- SIH/SUS - SIH), from 2010 to 2018. The Kolmogorov-Smirnov normality test was performed; the Poisson regression was used to verify factors associated with the variable total number of hospitalization authorizations with the main procedure of dental treatment for PSN (“Total de Autorizações de Internação Hospitalar” – AIH), the Spearman correlation test with a significance level of 5% was used to characterize the relationships between the Municipal Human Development Index per municipality - (Índice de Desenvolvimento Humano Municipal - HDI) and the Oral Health Coverage in the Family Health Strategy by municipality (Cobertura de saúde bucal na estratégia saúde da família por município - SBSF Coverage), and the relationship of the AIH with SBSF Coverage. A total of 127,691 procedures were performed, of which 71,517 (56%) were clinical procedures, such as restorations, endodontic treatments, supra and subgingival scaling, among others. Municipalities in the Midwest (PR=5.117) and Southeast (RP = 4.443) regions had more precedures than the others. A weak correlation was found between AIH and SBSF Coverage (r = -0.2, p < 0.001) and HDI and SBSF Coverage (r = -0.074, p < 0.001). Population size, region, health coverage, oral hygiene, and number of dentists in hospitals affected the availability of dental procedures in PSN.

The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases.

Resumo O campo da Odontologia do Trabalho tem considerado lastro teórico-científico. Esta revisão de escopo objetiva desvelar o estado da arte acerca do tema em sete bases de pesquisas indexadas, considerando quase 100 anos de publicações (1921-2020). Das 337 produções inicialmente identificadas, realizou-se recorte para os últimos seis anos (2015-2021/janeiro), aplicando-se metodologia proposta pela extensão do Prisma para revisões de escopo (Prisma-ScR). Contudo, plataformas de revisões rápidas usadas para tomada de decisões em formulações de políticas públicas ou em aperfeiçoamentos de sistemas de saúde responderam por apenas 20 publicações, enquanto a amostra de 34 produções revelou peculiaridades: pesquisas privilegiam regimes de trabalho; associam o campo de estudo e prática ao modelo stricto sensu da saúde ocupacional; desconsideram concepções amplas e humanizantes do campo da Saúde do Trabalhador; tendem a priorizar a própria saúde ocupacional odontológica e parecem reduzir o conceito do acidente de trabalho a doenças. Tais questões precisam ser superadas se a perspectiva for manter-se em vanguarda, promovendo saúd e e segurança em contextos contemporâneos de trabalho, pois, embora seja evidente a transversalidade desse campo de saberes e práticas, é necessário mais, é preciso ousar para retirá-la da invisibilidade, seja em organizações privadas ou públicas de trabalho.

Oligomeric alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin have emerged as promising diagnostic biomarkers for Parkinson’s disease (PD). This study aimed to assess and compare the diagnostic value of these biomarkers in discriminating between 38 PD patients and 24 healthy subjects (HSs) using easily accessible biological samples. Additionally, the study sought to determine the diagnostic potential of combining these biomarkers and to explore their correlations with clinical features. Salivary oligomeric α-syn levels were quantified using competitive ELISA, while skin biopsies were analyzed through immunofluorescence to detect phosphorylated α-syn at Ser129 (p-S129). Both biomarkers individually were accurate in discriminating PD patients from HSs, with a modest agreement between them. The combined positivity of salivary α-syn oligomers and skin p-S129 aggregates differentiated PD patients from HSs with an excellent discriminative ability with an AUC of 0.9095. The modest agreement observed between salivary and skin biomarkers individually suggests that they may reflect different aspects of PD pathology, thus providing complementary information when combined. This study’s results highlight the potential of utilizing a multimodal biomarker approach to enhance diagnostic accuracy in PD.

Cholangiocytes, the epithelial cells that line the biliary tree, can proliferate under the stimulation of several factors through both autocrine and paracrine pathways. The cocaine-amphetamine-regulated-transcript (CART) peptide has several physiological functions, and it is widely expressed in several organs. CART increases the survival of hippocampal neurons by upregulating brain-derived neurotrophic factor (BDNF), whose expression has been correlated to the proliferation rate of cholangiocytes. In the present study, we aimed to evaluate the expression of CART and its role in modulating cholangiocyte proliferation in healthy and bile duct ligated (BDL) rats in vivo, as well as in cultured normal rat cholangiocytes (NRC) in vitro. Liver samples from both healthy and BDL (1 week) rats, were analyzed by immunohistochemistry and immunofluorescence for CART, CK19, TrkB and p75NTR BDNF receptors. PCNA staining was used to evaluate the proliferation of the cholangiocytes, whereas TUNEL assay was used to evaluate biliary apoptosis. NRC treated or not with CART were used to confirm the role of CART on cholangiocytes proliferation and the secretion of BDNF. Cholangiocytes proliferation, apoptosis, CART and TrkB expression were increased in BDL rats, compared to control rats. We found a higher expression of TrkB and p75NTR, which could be correlated with the proliferation rate of biliary tree during BDL. The in vitro study demonstrated increased BDNF secretion by NRC after treatment with CART compared with control cells. As previously reported, proliferating cholangiocytes acquire a neuroendocrine phenotype, modulated by several factors, including neurotrophins. Accordingly, CART may play a key role in the remodeling of biliary epithelium during cholestasis by modulating the secretion of BDNF.

Extreme weather events, such as windstorms, hurricanes, and heat waves, exert a significant impact on global natural catastrophes and pose substantial challenges for weather forecasting systems. To enhance the accuracy and preparedness for extreme weather events, this study explores the potential of using expert crowdsourcing in storm forecasting research through the application of stigmergic collaboration. We present the development and implementation of an expert Crowdsourcing for Semantic Annotation of Atmospheric Phenomena (eCSAAP) system, designed to leverage the collective knowledge and experience of meteorological experts. Through a participatory co-creation process, we iteratively developed a web-based annotation tool capable of capturing multi-faceted insights from weather data and generating visualizations for expert crowdsourcing campaigns. In this context, this article investigates the intrinsic coordination among experts engaged in crowdsourcing tasks focused on the semantic annotation of extreme weather events. The study brings insights about the behavior of expert crowds by considering the cognitive biases and highlighting the impact of existing annotations on the quality of data gathered from the crowd and the collective knowledge generated. The insights regarding the crowdsourcing dynamics, particularly stigmergy, offer a promising starting point for utilizing stigmergic collaboration as an effective coordination mechanism for weather experts in crowdsourcing platforms but also in other domains requiring expertise-driven collective intelligence.

This paper provides experimental data on the temperature rise during granular flows in a small-scale rotating drum due to heat generation. All heat is believed to be generated by conversion of some mechanical energy, through mechanisms such as friction and collisions between particles and between particles and walls. Particles of different material types were used, while multiple rotation speeds were considered, and the drum was filled with different amounts of particles. The temperature of the granular materials inside the rotating drum was monitored using a thermal camera. The temperature increases at specific times of each experiment are presented in form of tables, along with the average and standard deviation of the repetitions of each setup configuration. The data can be used as a reference to set the operating conditions of rotating drums, in addition to calibrating numerical models and validating computer simulations.

Abstract Emerging infectious diseases are a growing threat in sub-Saharan African countries, but the human and technical capacity to quickly respond to outbreaks remains limited. Here, we describe the experience and lessons learned from a joint project with the WHO Regional Office for Africa (WHO AFRO) to support the sub-Saharan African COVID-19 response. In June 2020, WHO AFRO contracted a number of consultants to reinforce the COVID-19 response in member states by providing actionable epidemiological analysis. Given the urgency of the situation and the magnitude of work required, we recruited a worldwide network of field experts, academics and students in the areas of public health, data science and social science to support the effort. Most analyses were performed on a merged line list of COVID-19 cases using a reverse engineering model (line listing built using data extracted from national situation reports shared by countries with the Regional Office for Africa as per the IHR (2005) obligations). The data analysis platform The Renku Project ( https://renkulab.io ) provided secure data storage and permitted collaborative coding. Over a period of 6 months, 63 contributors from 32 nations (including 17 African countries) participated in the project. A total of 45 in-depth country-specific epidemiological reports and data quality reports were prepared for 28 countries. Spatial transmission and mortality risk indices were developed for 23 countries. Text and video-based training modules were developed to integrate and mentor new members. The team also began to develop EpiGraph Hub, a web application that automates the generation of reports similar to those we created, and includes more advanced data analyses features (e.g. mathematical models, geospatial analyses) to deliver real-time, actionable results to decision-makers. Within a short period, we implemented a global collaborative approach to health data management and analyses to advance national responses to health emergencies and outbreaks. The interdisciplinary team, the hands-on training and mentoring, and the participation of local researchers were key to the success of this initiative.

Understanding the biomechanical impact of injuries and reconstruction of the anterior cruciate ligament (ACL) is vital for improving surgical treatments that restore normal knee function. The purpose of this study was to develop a technique that enables parametric analysis of the effect of the ACL reconstruction (ACLR) in cadaver knees, by replacing its contributions with that of a specimen-specific virtual ACLR that can be enabled, disabled, or modified. Twelve ACLR reconstructed knees were mounted onto a motion simulator. In situ ACLR graft forces were measured using superposition, and these data were used to design specimen-specific virtual ACLRs that would yield the same ligament force-elongation behaviors. Tests were then repeated using the virtual ACLR in place of the real ACLR and following that in ACL deficient knee by disabling the virtual ACLR. In comparison to the ACL deficient state, the virtual ACLRs were able to restore knee stability to the same extent as real ACLRs. The average differences between the anterior tibial translation (ATT) of the virtual ACLR versus the real ACLR were +1.6 ± 0.9 mm (p = 0.4), +2.1 ± 0.4 mm (p = 0.4), and +1.0 ± 0.9 mm (p = 0.4) during Anterior drawer, Lachman and Pivot-shift tests, respectively, which is small in comparison to the full ATT range of motion (ROM) of these knees. Therefore, we conclude that a virtual ACLR can be used in place of real ACLR during biomechanical testing of cadaveric knees. This capability opens the door for future studies that can leverage parameterization of the ACLR for surgical design optimization. [ABSTRACT FROM AUTHOR]

Background: Transcranial magnetic stimulation‐electroencephalography (TMS‐EEG) has demonstrated decreased excitability in the primary motor cortex (M1) and increased excitability in the pre‐supplementary motor area (pre‐SMA) in moderate‐advanced Parkinson's disease (PD). Objectives: The aim was to investigate whether these abnormalities are evident from the early stages of the disease, their behavioral correlates, and relationship to cortico‐subcortical connections. Methods: Twenty‐eight early, drug‐naive (de novo) PD patients and 28 healthy controls (HCs) underwent TMS‐EEG to record TMS‐evoked potentials (TEPs) from the primary motor cortex (M1) and the pre‐SMA, kinematic recording of finger‐tapping movements, and a 3T‐MRI (magnetic resonance imaging) scan to obtain diffusion tensor imaging (DTI) reconstruction of white matter (WM) tracts connecting M1 to the ventral lateral anterior thalamic nucleus and pre‐SMA to the anterior putamen. Results: We found reduced M1 TEP P30 amplitude in de novo PD patients compared to HCs and similar pre‐SMA TEP N40 amplitude between groups. PD patients exhibited smaller amplitude and slower velocity in finger‐tapping movements and altered structural integrity in WM tracts of interest, although these changes did not correlate with TEPs. Conclusions: M1 hypoexcitability is a characteristic of PD from early phases and may be a marker of the parkinsonian state. Pre‐SMA hyperexcitability is not evident in early PD and possibly emerges at later stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]