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From a cohort of 36 patients presenting apperceptive tactile agnosia after first cortical ischemic stroke, 14 showed temporary impairment at admission. A previous multi-voxel analysis of the cortical lesions, using as explanatory variable the course of tactile object recognition performance over the recovery period of 9 months, partitioned the cohort into three subgroups. Of the 14 patients constituting two of the subgroups, 7 recovered from their impairment whereas 7 did not. These two subgroups could not be distinguished at admission. The primary aim of the present study is to present two assessments that can do so.The first assessment comprises a pattern of behavioral measures, determined via principal component analysis, encoded in three tests: picking small objects, macrogeometrical discrimination and tactile object recognition. The receiver operating characteristic curve derived from permutation of the behavioral test scores yielded an 80% probability of correct identification of the patient subgroup and an 8% probability for false identification. As done with the permuted scores, the pattern could predict the persistence of affliction of new stroke patients with tactile agnosia.The second predictive assessment extends our previous evaluation of cortical MRI lesion maps to include subcortical regions. Confirming our previous study, the lesions of the persistently impaired subgroup disrupted significantly the anterior arcuatus fasciculus and associated superior longitudinal fasciculus III in the ipsilesional hemisphere, impeding reciprocal information transfer between supramarginal gyrus and both the ventral premotor cortex and Brodmann area 44. Due to the importance of interhemispheric information transfer in tactile agnosia, we performed a supplementary analysis of tactile object recognition scores. It showed that haptic information transfer from the non-affected to the affected hands in the persistent cases partly restored function during the nine months, possibly following restoration of functional interhemispheric haptic information transfer at the border of posterior corpus callosum and splenium.In conclusion, the combined findings of the cortical lesion at subarea PFt of the inferior parietal lobule and the associated subcortical tract lesions permit almost perfect prediction of persistent impairment of tactile object recognition. The study substantiates the need for combined analysis of both cortical lesions and white matter tract disconnections.

Chemically induced toxicity is the leading cause of recent extinction of honey bees. In this regard, we developed an innovative artificial intelligence-based web app (BeeToxAI) for assessing the acute toxicity of chemicals to Apis mellifera. Initially, we developed and externally validated QSAR models for classification (external set accuracy ∼91%) through the combination of Random Forest and molecular fingerprints to predict the potential for chemicals to cause acute contact toxicity and acute oral toxicity to honey bees. Then, we developed and externally validated regression QSAR models (R2 = 0.75) using Feedforward Neural Networks (FNNs). Afterward, the best models were implemented in the publicly available BeeToxAI web app (http://beetoxai.labmol.com.br/). The outputs of BeeToxAI are: toxicity predictions with estimated confidence, applicability domain estimation, and color-coded maps of relative structure fragment contributions to toxicity. As an additional assessment of BeeToxAI performance, we collected an external set of pesticides with known bee toxicity that were not included in our modeling dataset. BeeToxAI classification models were able to predict four out of five pesticides correctly. The acute contact toxicity model correctly predicted all of the eight pesticides. Here we demonstrate that BeeToxAI can be used as a rapid new approach methodology for predicting acute toxicity of chemicals in honey bees.

Cerebral lesions acquired in the perinatal period can induce cerebral palsy (CP), a multifactorial pathology leading to lifelong motor and cognitive deficits. Several risk factors, including perinatal hypoxia-ischemia (HI), can contribute to the emergence of CP in preterm infants. Currently, there is no international consensus on treatment strategies to reduce the risk of developing CP. A meta-analysis showed that magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery reduces the risk of developing CP (Crowther et al., 2017). However, only a few studies have investigated the long-term effects of MgSO4 and it is not known whether sex would influence MgSO4 efficacy. In addition, the search for potential deleterious effects is essential to enable broad use of MgSO4 in maternity wards. We used a mouse model of perinatal HI to study MgSO4 effects until adolescence, focusing on cognitive and motor functions, and on some apoptosis and inflammation markers. Perinatal HI at postnatal day 5 (P(5)) induced (1) sensorimotor deficits in pups; (2) increase in caspase-3 activity 24 h after injury; (3) production of proinflammatory cytokines from 6 h to 5 days after injury; (4) behavioral and histological alterations in adolescent mice with considerable interindividual variability. MgSO4 prevented sensorimotor alterations in pups, with the same efficacy in males and females. MgSO4 displayed anti-apoptotic and anti-inflammatory effects without deleterious side effects. Perinatal HI led to motor coordination impairments in female adolescent mice and cognitive deficits in both sexes. MgSO4 tended to prevent these motor and cognitive deficits only in females, while it prevented global brain tissue damage in both sexes. Moreover, interindividual and intersexual differences appeared regarding the lesion size and neuroprotection by MgSO4 in a region-specific manner. These differences, the partial prevention of disorders, as well as the mismatch between histological and behavioral observations mimic clinical observations. This underlines that this perinatal HI model is suitable to further analyze the mechanisms of sex-dependent perinatal lesion susceptibility and MgSO4 efficacy.

In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.

In industrialized countries, cerebral palsy affects 2.5‰ of preterm and term infants. At a neurochemical level, the massive release of glutamate constitutes a major process leading to excitotoxicity and neonatal brain lesions. Previous studies, conducted in the laboratory, revealed that, in δ/δVEGFA transgenic mice, glutamate-induced brain lesions are exacerbated suggesting that VEGFA could play a protective action against excitotoxicity. Using a model of cultured cortical brain slices, the aim of the study was to characterize the central effects of VEGF against glutamate-induced excitotoxicity in neonates. Exposure of brain slices to glutamate induced a strong increase of necrotic cell death in the deep cortical layer VI and a decrease of apoptotic death in superficial layers II–IV. When administered alone, a 6-h treatment with VEGFA had no effect on both apoptotic and necrotic deaths. In contrast, VEGFA abolished the glutamate-induced necrosis observed in layer VI. While MEK and PI3-K inhibitors had no effect on the protective action of VEGFA, L-NAME, a pan inhibitor of NOS, abrogated the effect of VEGFA and exacerbated the excitotoxic action of glutamate. Calcimetry experiments performed on brain slices revealed that VEGFA reduced the massive calcium influx induced by glutamate in layer VI and this effect was blocked by L-NAME. Neuroprotective effect of VEGFA was also blocked by LNIO and NPLA, two inhibitors of constitutive NOS, while AGH, an iNOS inhibitor, had no effect. Nitrite measurements, electron paramagnetic resonance spectroscopy and immunohistochemistry indicated that glutamate was a potent inducer of NO production via activation of nNOS in the cortical layer VI. In vivo administration of nNOS siRNA promoted excitotoxicity and mimicked the effects of L-NAME, LNIO and NPLA. A short-term glutamate treatment increased nNOS Ser1412 phosphorylation, while a long-term exposure inhibited nNOS/NR2B protein–protein interactions. Altogether, these findings indicate that, in deep cortical layers of mice neonates, glutamate stimulates nNOS activity. Contrasting with mature brain, NO production induced by high concentrations of glutamate is neuroprotective and is required for the anti-necrotic effect of VEGFA.

Cisplatin is a chemotherapeutic agent whose use is limited by side effects including neuropathies. In proliferating cells, toxic action of cisplatin is based on DNA interactions, while, in quiescent cells, it can induce apoptosis by interacting with proteins. In the present study, we compared cytotoxic mechanisms activated by cisplatin in primate and rodent neurons and in ovary cells in order to determine whether the anti-apoptotic peptide PACAP could selectively reduce neurotoxicity. In quiescent neurons, JNK and sphingomyelinase inhibitors blocked cisplatin-induced cell death. Toxicity was associated with DNA laddering, caspase-3 and -9 activations and Bax induction. These effects were prevented by PACAP. In proliferating cells, cisplatin activated caspase-8 but had no effect on caspase-9. PACAP exerted no protective effect. These data indicate that cisplatin activates distinct apoptotic pathways in quiescent neurons and proliferating cells and that PACAP may reduce neurotoxicity of cisplatin without affecting its chemotherapeutic efficacy.

The aim of the present study was to determine the optimal time to start weaning from Moina minuta to inert diet, assessing its effects on growth performance, stress resistance, feeding cost and intestinal histomorphometry of angelfish and severum during larviculture. Two separate 30-day experiments were conducted with 200 post-larvae each of angelfish (Pterophyllum scalare) and severum (Heros severus). At five days post-hatching, angelfish and severum had an average initial length and weight of 5.58 ± 0.13 mm and 1.72 ± 0.26 mg, and 6.38 ± 0.25 mm and 3.02 ± 0.27 mg, respectively. The larvae were distributed in twenty 1 L aquariums at a density of 10 post-larvae per liter. The experiments included five treatments with four replications, consisting of five supply periods of M. minuta for 0, 5, 10, 15 and 20 days (T0, T5, T10, T15 and T20), followed by a three-day weaning period (50 % M. minuta and inert diet) and then feeding only inert diet. The highest values of final length, length gain, final weight, weight gain, specific growth rate for both length and weight were observed in both species in T15 and T20. Only angelfish post-larvae had a higher value of survival rate when submitted to T15 and T20, and a higher stress resistance to air exposure when submitted to T10, T15 and T20. Both species had the lowest feeding costs in T20. Angelfish and severum post-larvae in T15 and T20 showed the highest value of intestinal villus height and perimeter. Severum post-larvae in T10, T15 and T20 had the best value of villus width. Angelfish post-larvae in T0 and T5 had the highest proportions of goblet cells, while severum post-larvae exhibited this only in T0. It is recommended that angelfish and severum post-larvae be fed with M. minuta for 15 days before weaning.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

The severe drought in California (2012–2016) generated significant public and government concern. State and local watering regulations were enacted to reduce residential and commercial water-use during the droughts. This study presents a comparison of residential runoff volumes before and after local landscape irrigation regulations were enacted during the droughts of 2008 and 2012–2016. Each sampling site (Folsom 1 and Folsom 2) was a storm drain outfall that drained a low-density residential catchment in the City of Folsom. Dry season runoff measured at the sampling sites represents neighborhood outdoor water waste, mainly from landscape irrigation. During the drought of 2012–2016, median runoff flows were significantly reduced after local landscape irrigation regulations were enacted. The daily runoff pattern was also highly influenced by regulation, with reductions of daily peak runoff flows on 4–5 days in a week after watering regulations were enacted. The number of peak flow events in the daily runoff pattern were reduced during this period. In addition, a significant reduction in mean runoff volume occurred. Based on these results, the watering regulations enacted by the City of Folsom had a positive effect on reducing urban runoff from residential neighborhoods during the dry season. As the results are from monitoring sites in a relatively small geographical area, further work should evaluate reductions in irrigation runoff from other California locations to determine if this is a localized phenomenon.

The paper consolidates the role of conventional and stabilized N fertilizers used in coffee crop production in Brazil and their N2O emissions in tropical systems. The experiment consisted of the combination of three fertilizers and five doses with four repetitions, totalling 60 experimental plots. The factors of the experiment were conventional urea (U), ammonium nitrate (AN), and urea + NBPT (UNBPT), while the doses were 0, 150, 275, 400, and 525 kg ha−1 year−1 of N. The municipality is located in a region at 1100 m of altitude, 20°53′26.04″ S and 44°52′04.14″ W. A randomized block design with a 3 × 5 factorial scheme was used. This region, traditional in coffee production, has a tropical humid climate, classified as Cwa according to the Köppen scale, with temperate summer and dry winter. UNBPT and the ammonium nitrate mitigated the N2O emissions by 50.6% and 78.5%, respectively, in comparison to the conventional urea. High C stocks were found in the 1 m soil layer, from 117 to 162 t ha−1 of organic C, indicating the importance of the soil as a C sink in coffee plantations. N stocks varied from 33 to 17 t ha−1 of N but no differences among the treatments were found. Approximately 50% of soil C was in the 0–0.4 m layer as a consequence of the greater amount of plant biomass, nutrients, and biological activity. Soil C:N ratio in the entire layer varied from 4.2 to 9.2. Our results indicate that nitrification is the most predominant process of N2O emissions. The standard EF proposed by the IPCC overestimates the N2O emissions in the Brazilian coffee plantations and the emissions differ according to the N fertilizer technology. These coffee crop systems have an important ability to stock C and N in the soil.

Designing magic shotgun compounds, i.e., compounds hitting multiple targets using artificial intelligence (AI) systems based on machine learning (ML) and deep learning (DL) approaches, has a huge potential to revolutionize drug discovery. Such intelligent systems enable computers to create new chemical structures and predict their multi-target properties at a low cost and in a time-efficient manner. Most examples of AI applied to drug discovery are single-target oriented and there is still a lack of concise information regarding the application of this technology for the discovery of multi-target drugs or drugs with broad-spectrum action. In this review, we focus on current developments in AI systems for the next generation of automated design of multi-target drugs. We discuss how classical ML methods, cutting-edge generative models, and multi-task deep neural networks can help de novo design and hit-to-lead optimization of multi-target drugs. Moreover, we present state-of-the-art workflows and highlight some studies demonstrating encouraging experimental results, which pave the way for de novo drug design and multi-target drug discovery.

Introdução/Objetivo: A paracoccidioidomicose (PCM) é uma infecção fúngica sistêmica grave que causa significativa morte e sofrimento, particularmente na América Latina. O tratamento da PCM é limitado por poucas opções farmacológicas que requerem protocolos de administração de longo prazo. Considerando as poucas classes de drogas disponíveis para o tratamento da PCM e o longo tempo de tratamento, o desenvolvimento de novos compostos anti-PCM é relevante. Nesse contexto, 4-metoxinaftaleno-N-acilhidrazonas surge como um andaime promissor para identificação dos novos compostos. Assim, desenvolvermos novos bioisósteros de 4-metoxinaftaleno-N-acilhidrazona com atividade anti-Paracoccidioides usando um pipeline de otimização in silico. Métodos: Uma série de 4-metoxinaftaleno-N-acilhidrazonas, que já havia sido testada contra Paracoccidioides spp., foi utilizada para desenvolver modelos baseados em forma. Os modelos passaram por validação estatística e foram usados para filtrar uma biblioteca de compostos, que foram ranqueados por meio de funções de pontuação. A análise de docking molecular foi usada para selecionar 6 compostos que foram sintetizados e avaliados biologicamente usando os testes de concentração inibitória mínima (CIM), concentração fungicida mínima (CFM) e citotoxicidade. A similaridade entre o melhor composto identificado com outros compostos testados contra Paracoccidioides spp. e antifúngicos já empregados no tratamento da PCM foi avaliado usando Molecular ACCess System, um sistema de acesso molecular utilizado para realizar pesquisas e análises químicas e biológicas. Resultados: Usando o protocolo aplicado por nós, priorizamos 6 compostos para síntese e avaliação biológica in vitro. Entre eles, dois compostos (AOS2 e AOS3) mostraram atividade nanomolar contra Paracoccidioides spp. com baixa citotoxicidade (índices de seletividade >2048). Esses compostos não são estruturalmente similares aos antifúngicos empregados no tratamento da PCM. Conclusão: A metodologia empregada neste trabalho foi eficiente para projetar 4-metoxinaftaleno-N-acilhidrazonas otimizadas. Os compostos AOS3 e AOS2 são candidatos promissores a antifúngicos para o tratamento da PCM. As estruturas destes compostos ainda podem servir como pontos de partida em perspectiva para o desenvolvimento de novos antifúngicos.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor heavily investigated in infectious and non-infectious diseases. Because of its role in amplifying inflammation, TREM-1 has been explored as a diagnostic/prognostic biomarker. Further, as the receptor has been implicated in the pathophysiology of several diseases, therapies aiming at modulating its activity represent a promising strategy to constrain uncontrolled inflammatory or infectious diseases. Despite this, several aspects concerning its interaction with ligands and activation process, remain unclear. Although many molecules have been suggested as TREM-1 ligands, only five have been confirmed to interact with the receptor: actin, eCIRP, HMGB1, Hsp70 and PGLYRP1. However, the domains involved in the interaction between the receptor and these proteins are not clarified yet. Therefore, here we used in silico approaches to investigate the putative binding domains in the receptor, using hot spots analysis, molecular docking and molecular dynamics simulations between TREM-1 and its five known ligands. Our results indicated the complementarity-determining regions (CDRs) of the receptor as the main mediators of antigen recognition, especially the CDR3 loop. We believe that our study could be used as structural basis for the elucidation of TREM-1′s recognition process, and may be useful for prospective in silico and biological investigations exploring the receptor in different contexts.

The challenges associated to oxygen reduction reaction (ORR) electrocatalysis are undoubtedly the most intricate impediments to solve regarding fuel cell vehicle (FCV) commercialization, mainly due to the complexity of this reaction and the scarcity of the required electrocatalysts. The synthesis of non-precious electrocatalysts with high intrinsic selectivity is indeed crucial in this field, but the methodology utilized to come to selectivity conclusions is undeniably equally important. In this work, we demonstrate how the higher required electrode loadings of a Fe-N-MWCNT catalyst in a rotating ring disc electrode (RRDE) prevent access to all of the peroxide produced by the catalyst during ORR. Via a spraying technique, much smaller amounts of the same catalyst were deposited on a flat boron-doped diamond (BDD) and their loading was determined meticulously by atomic force microscopy (AFM). These ultra-low loadings were investigated using scanning electrochemical microscopy (SECM), which revealed higher peroxide production and lower selectivity. This finding may have crucial implications for future ORR investigations in the laboratory, considering the harmful effect peroxide has on the catalyst.

Background: Human papillomavirus (HPV) vaccination coverage rate (VCR) remains low in France (37.4% in girls in 2021). The French health authority recommended in 2022 to extend vaccination competencies to additional healthcare providers (HCPs), including community pharmacists (CPs). Objectives: To understand the acceptability by general practitioners (GPs), CPs and parents of adolescents of extending vaccination competencies and to identify benefits and barriers of new vaccination pathways. Methods: This cross-sectional research used a qualitative and quantitative approach. For the quantitative survey, GPs, CPs and parents of adolescents eligible to HPV vaccination completed an online questionnaire. Participants were asked to imagine themselves in different pathways and evaluate them. Results: A total of 200 GPs, 201 CPs and 800 parents were included. The level of acceptability of extending vaccination competencies to other HCPs was high in CPs (86% rated ≥7/10), but low in GPs (35%) and intermediate in parents (61%). Parents ranked first (44%) a pathway where GPs prescribed while CPs vaccinated because GPs inspire confidence as vaccine prescribers (80%) and parents prefer to be informed on vaccination by them (80%). CPs ranked first (42%) a scenario where they vaccinated after invitation of adolescents from the French National Health Insurance Fund (NHIS). They emphasized the simplicity of this scenario (94%) and the potential increase of VCR (91%), but asked to be more informed on HPV vaccination (77%) and favored television (83%) for communication campaigns. Conclusions: GPs and parents, in contrast with community pharmacists, were only moderately supportive of the extension the vaccination competencies. Confidence in the HCP remains the primary factor for adherence to a vaccination pathway beyond the simplicity of the pathway. Training of CPs, traceability tool, support from authorities and communication campaigns are levers that will support CPs in their new role and contribute to increase parents' acceptability toward CPs.

One of the most common health risks for senior citizens is a falling event, and to reduces the risk of death, a fall needs to be quickly reported. Thus, automatic fall detection systems were proposed to mitigate the falling problem, most of them relying on image detection. However, identifying a fall from a sequence of images is challenging because the contextual information present in some activities of daily living (ADL) are similar to fall events, and the recognition model has to deal with very high-level information. Furthermore, the publicly available datasets are generally unbalanced, having only synthetic data of fall events. Thus, approaches that do not need explicit labels to train a model are desirable. As falls are rare events, a possible solution is to use a one-class approach, and Generative Adversarial Networks (GAN) have presented competitive results in this context. This paper proposes OneFall-GAN, a One-Class GAN that uses only ADL for training and can identify a fall as an anomaly on the learned representations. We trained our neural network using the data captured by an RGB camera and pre-processed by a pre-trained Mask R-CNN that can segment and binarize a person in a scene. Thus, our model has robust temporal information used in the training phase and once trained, the discriminator is specialized on classifying ADL events. Consequently, when a fall event is presented, it is capable of classifying them as an anomaly. Using this approach, we are turning a binary classification problem into a one-class approach. Our experimental results show that our OneFall-GAN framework is a competitive alternative for fall classification as an anomaly detection task using only visual data, particularly because it achieved the best performance when compared to current state-of-the-art approaches, reaching an accuracy of 99.02%, 0.97 precision, 1.0 recall on PRECIS HAR and 98.75% accuracy, 0.87 precision, 0.99 recall on UP Fall.

Estimating vineyard yield in advance is essential for planning and regulatory purposes at the regional level, with growing importance in a long-term scenario of perceived climate change. With few tools available, the current study aimed to develop a yield estimation model based on remote sensing and climate data with a machine-learning approach. Using a satellite-based time-series of Normalized Difference Vegetation Index (NDVI) calculated from Sentinel 2 images and climate data acquired by local automatic weather stations, a system for yield prediction based on a Long Short-Term Memory (LSTM) neural network was implemented. The study was conducted in the Douro Demarcated Region in Portugal over the period 2016–2021 using yield data from 169 administrative areas that cover 250,000 ha, in which 43,000 ha of the vineyard are in production. The optimal combination of input features, with an Mean Absolute Error (MAE) of 672.55 kg/ha and an Mean Squared Error (MSE) of 81.30 kg/ha, included the NDVI, Temperature, Relative Humidity, Precipitation, and Wind Intensity. The model was tested for each year, using it as the test set, while all other years were used as input to train the model. Two different moments in time, corresponding to FLO (flowering) and VER (veraison), were considered to estimate in advance wine grape yield. The best prediction was made for 2020 at VER, with the model overestimating the yield per hectare by 8 %, with the average absolute error for the entire period being 17 %. The results show that with this approach, it is possible to estimate wine grape yield accurately in advance at different scales.

The potential harmful of 4-Nitrophenol (4-NPh) extensively used in agriculture, pharmaceutics, amongst others industrial applications makes this compound an important organic contaminant. Its removal by heterogeneous catalytic reduction is framed within circular economy purpose the only reaction product, 4-aminophenol (4-APh), is a value-added product and the catalysts can be easily separated and re-used. The most common methods use expensive metals and the search for cheap and easily available material is one of a state of art challenges for the industrial application. Coal fly ash (CFA) are an excellent alternative since contains iron-rich morphotypes in the form of ferrospheresIn this study and, for the first time, the catalytic reduction of 4-nitrophenol (4-NPh) was performed using the original magnetic fraction of CFA or the treated fractions (using water, NaOH or NaBH4) avoiding the incorporation of any metals/oxides nanoparticles. The most promising results were obtained using: 1) the magnetic fraction treated with NaOH, where a complete reduction of 4-NPh was observed in 5 min which is a remarkable catalytic efficiency, comparable with noble metal nanocatalysts in the literature; 2) the magnetic CFA treated under NaBH4 with 100% of 4-NPh reduction in 30 min. These results highlight the potential of the magnetic fractions of CFA to be use as alternative to the precious metal catalysts to successfully convert 4-NPh to 4-APh. Furthermore, these CFA-based catalysts present very good stability with no loss of activity in consecutive 5 cycles showing the ability of these materials to be applied not only in 4-NPh but also in other nitroarenes reduction and potentially in water remediation.

Resumen: Introducción: Son pocas las intervenciones de eSalud dirigidas a padres que analizan sus costes y el ahorro potencial que pueden generar. Los objetivos de este trabajo consistieron en calcular los costes de desarrollo y mantenimiento de una web de pediatría para padres, el coste por visita y por visitante, y el ahorro potencial generado en función de las visitas médicas evitadas como consecuencia de su uso. Métodos: Para los costes de la web se consideraron los costes tecnológicos y del trabajo de los profesionales. El cálculo del coste de los profesionales y de ahorro potencial se basó en los honorarios oficiales y en los precios públicos del Sistema Sanitario Público de Andalucía. Resultados: Durante los 5 años y 6 meses del estudio el coste total de la web fue de 45.201,56€. El coste por visita recibida fue de 0,0155€, y por cada visitante único, de 0,0186€. Entre los 516 usuarios que participaron en el estudio se evitaron visitas presenciales a las consultas de pediatría de atención primaria y a los servicios de urgencias de pediatría por un valor de 22.263,89€. Conclusiones: Los costes de desarrollo de una web de eSalud de pediatría para padres escrita en español, usando tecnología existente y gratuita, son bajos en comparación a otras formas de desarrollo de eSalud. Además, los costes son considerablemente bajos si se dividen entre el número de visitas totales o el número de visitantes. También existe un potencial considerable de ahorro económico al contribuir a evitar visitas presenciales. Abstract: Introduction: There are few studies on e-Health interventions directed at parents that analyse their costs and any potential savings that may occur. The aims of this study consisted of calculating the costs of the development and maintenance of paediatric web site for parents, including the costs per visit and per visitor, and the potentially savings made as regards medical visits avoided as a result of its use. Methods: The technology costs as well as the work of the professionals were considered as costs of the web site. The calculation of the cost of the professionals and the potential savings were based on the official fees and public prices of the Andalusian Public Health Service. Results: During 5 years and 6 months of the study, the total cost of the web site was €45,201.56. The cost per visit received was €0.0155€, and €0.0186 for each single visitor. Among the 516 users that took part in the study, face-to-face visits to Primary Care paediatric clinics were avoided, as well as those to Paediatric Emergency Department, at a savings of €22,263.89. Conclusions: The costs of developing a paediatric e-Health website for parents written in Spanish, using existing and free technologies, are low compared to other forms of e-Health development. Furthermore, the costs are considerably low if they are divided by the total number of visits or the number of visitors. There is also a considerable potential financial saving on contributing to avoid face-to-face visits.

Introduction: There are few studies on e-Health interventions directed at parents that analyse their costs and any potential savings that may occur. The aims of this study consisted of calculating the costs of the development and maintenance of a paediatric web site for parents, including the costs per visit and per visitor, and the potentially savings made as regards medical visits avoided as a result of its use. Methods: The technology costs as well as the work of the professionals were considered as costs of the web site. The calculation of the cost of the professionals and the potential savings were based on the official fees and public prices of the Andalusian Public Health Service. Results: During 5 years and 6 months of the study, the total cost of the web site was €45,201.56. The cost per visit received was €0.0155€, and €0.0186 for each single visitor. Among the 516 users that took part in the study, face-to-face visits to Primary Care paediatric clinics were avoided, as well as those to Paediatric Emergency Department, at a savings of €22,263.89. Conclusions: The costs of developing a paediatric e-Health website for parents written in Spanish, using existing and free technologies, are low compared to other forms of e-Health development. Furthermore, the costs are considerably low if they are divided by the total number of visits or the number of visitors. There is also a considerable potential financial saving on contributing to avoid face-to-face visits. Resumen: Introducción: Son pocas las intervenciones de eSalud dirigidas a padres que analizan sus costes y el ahorro potencial que pueden generar. Los objetivos de este trabajo consistieron en calcular los costes de desarrollo y mantenimiento de una web de pediatría para padres, el coste por visita y por visitante, y el ahorro potencial generado en función de las visitas médicas evitadas como consecuencia de su uso. Métodos: Para los costes de la web se consideraron los costes tecnológicos y del trabajo de los profesionales. El cálculo del coste de los profesionales y de ahorro potencial se basaron en los honorarios oficiales y en los precios públicos del Sistema Sanitario Público de Andalucía. Resultados: Durante los 5 años y 6 meses del estudio el coste total de la web fue de 45.201,56€. El coste por visita recibida fue de 0,0155€, y por cada visitante único, de 0,0186€. Entre los 516 usuarios que participaron en el estudio se evitaron visitas presenciales a las consultas de pediatría de atención primaria y a los servicios de urgencias de pediatría por un valor de 22.263,89€. Conclusiones: Los costes de desarrollo de una web de eSalud de pediatría para padres escrita en español, usando tecnología existente y gratuita, son bajos en comparación a otras formas de desarrollo de eSalud. Además, los costes son considerablemente bajos si se dividen entre el número de visitas totales o el número de visitantes. También existe un potencial considerable de ahorro económico al contribuir a evitar visitas presenciales.

Nowcasting of solar energy considering clouds is important for photovoltaic solar plants and distributed systems. Clouds present a challenge for modeling, due to constant changes in shape and size, and are dependent on local atmospheric conditions. Several methods are being used for the automatic assessment of clouds from the surface to predict solar power generation, assisted by camera, side sensors, etc. During our research we did not find a Systematic Literature Review on this topic. This review is intended to search the related scientific articles to find the state of the art in the area from the period of 2011–2020. We found 65 articles to review after the meta-analysis. We look for the main short-term forecasting methods used. The majority of articles rely on classical statistics approaches based on historical data. Yet recent articles show that this trend might be shifting towards Machine Learning approaches. Our analysis shows that most articles found are based on images captured by fish-eye lenses using a single camera. The most common forecasting techniques are Artificial Neural Networks and Convolutional Neural Networks, with the root mean squared error being the most predominant error metric used for model validation among both classical and Machine Learning approaches.

Introdução: COVID-19 é uma infecção causada pelo SARS-CoV-2, o novo coronavírus detectado em dezembro de 2019 na China. Os sintomas da COVID-19 são semelhantes aos de outras doenças virais respiratórias agudas, prevalecendo como queixas de febre e tosse. Portanto, é imprescindível a realização de exames para diagnóstico. Objetivo: Definir o perfil dos casos suspeitos do COVID-19 em crianças e adolescentes de um hospital terciário do estado de Sergipe, devido à semelhança de sinais e sintomas com outras infecções respiratórias virais prevalentes em pediatria. Métodos: estudo seccional realizado por meio da extração de dados dos prontuários médicos do Hospital e Maternidade Santa Isabel, em Sergipe, entre 24 de março e 28 de setembro de 2020. Para a análise dos dados foram criadas as variantes contínuas e categóricas. Resultados: foram atendidos 302 pacientes, no período analisado, classificados como casos suspeitos de COVID-19, sendo que 54 crianças (17,9%) apresentavam uma ou mais comorbidades subjacentes, sendo a mais prevalente relacionada ao aparelho respiratório, como a asma. A maioria dos casos suspeitos de COVID-19 foram excluídos e apenas 95 (31,5%) foram diagnosticados com a doença. Os sinais e sintomas não mostraram diferença significativa entre os pacientes com e sem SARS-CoV-2, como podemos observar na dispneia (37,9% vs 38,1%. p = 1.000). Comparando os casos suspeitos (descartados) e confirmados, o último teve maior necessidade de ventilação mecânica (18,2% vs 7,8%; p = 0,013), evolução para óbito (11,8% vs 1,7%; p = 0,001) e mais tempo entre a coleta da amostra e a alta hospitalar (p = 0,002). Conclusão: a semelhança na apresentação clínica entre a infecção SARS- Cov-2 e as infecções respiratórias agudas em pediatria torna o diagnóstico diferencial ainda mais difícil, necessitando de exames laboratoriais. Além disso, há um aumento de casos suspeitos de COVID-19, por conta dessa semelhança. Palavras-chave: Infecções por Coronavirus; Infecções Respiratórias; Diagnóstico.