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Introdução e Objetivos: As perturbações ansiosas e depressivas são hoje prevalentes, com impacto significativo nas populações. Nas últimas décadas, assistimos ao aparecimento de inúmeros dispositivos com ecrã que se incorporaram na nossa rotina diária, o que levou a uma exposição crescente dos indivíduos a estes. Pretendemos caracterizar uma amostra da população portuguesa e estudar a relação entre o tempo de ecrã e a psicopatologia e perceber se estão diretamente associados, como postulado por estudos internacionais. Métodos: Usando questionários de autopreenchimento no contexto da consulta, avaliamos a história de hábitos de contacto com os diferentes tipos de ecrã em adultos jovens (18-45 anos) com seguimento em consulta de Psiquiatria por perturbações afetivas e/ou ansiosas, em comparação com adultos jovens sem psicopatologia conhecida, a partir de uma amostra de conveniência nos Cuidados de Saúde Primários. Resultados e Conclusões: Não foi encontrada uma associação entre o tempo de ecrã e a presença de psicopatologia. Ainda assim, concluímos que a grande maioria dos adultos (72,4%) está exposta a ecrãs mais de quatro horas por dia. Também constatámos que, entre os controlos, aqueles que fazem um uso excessivo de ecrã, usam-no frequentemente para adormecer e apresentam mais dificuldades para iniciar o sono. Este trabalho reforça a necessidade de mais investigação sobre o real impacto do tempo de ecrã na saúde mental dos indivíduos, no sentido de promover o uso racional destas tecnologias.

Background: The connection between corticotherapy and neuropsychiatric symptoms is widely known, being one of the first questions we need to assess when presenting with first episode psychiatric symptoms or confusional state. Aims: To date, data on cases related to inhaled corticotherapy and neuropsychiatric effects is scarce. In this paper we describe a rare case in a young woman. Methods: The clinical case presented led us to try to understand the data published on the subject in order to discuss it in greater length. Results and Conclusions: We present and discuss a 27-year-old patient’s case, with no previous psychiatric disease, who was admitted to our Psychiatric ward after the onset of severe acute behavioural disturbance characterized by aggressiveness, visual and auditory hallucinatory activity, misidentification and altered conscience status. It was later found that seven days earlier she had been prescribed inhaled corticotherapy for a minor respiratory infection. A few days after corticotherapy withdrawal, the clinical symptoms improved significantly.

As perturbações do uso do álcool constituem, pela sua prevalência e transversalidade, um problema de saúde pública grave, com um impacto social e económico significativo, motivos pelos quais importa discutir a necessidade de uma mudança de paradigma na abordagem e tratamento da Perturbação do Uso do Álcool (PUA). A 5ª edição do «Diagnostic and Statistical Manual of Mental Disorders» (DSM-V) abandonou a distinção entre consumo nocivo e dependência de álcool, procedendo à sua integração numa designação - PUA. Esta é definida como um padrão de consumo de álcool prejudicial, que conduz a uma debilitação do estado de saúde e a sofrimento clinicamente significativo. O consumo excessivo de álcool representa uma ameaça à saúde pública mundial, constituindo uma das principais causas de mortalidade e morbilidade. Segundo o relatório da OMS, no ano de 2011, o consumo excessivo de álcool foi responsável por 5.9% de todas as mortes globais (cerca de 3.3 milhões de mortes) e por 5.1% da carga global de doença (avaliada em disability-adjusted life years). Na Europa regista-se um dos maiores consumos anuais de álcool per capita (10,9L de álcool puro) em relação à média mundial (6,2L de álcool puro), com Portugal a apresentar um consumo anual de 12,9L. A prevalência de PUA em Portugal no ano de 2010 foi de 5,8%, sendo inferior à média da Região Europeia da OMS (7,5%). Importa salientar que na Europa o consumo de álcool representa o terceiro principal fator de risco de doença e de morte prematura, superado apenas pelo tabagismo e hipertensão arterial. A nível nacional, um estudo realizado com dados de 2005 demonstrou que cerca de 3.8% da mortalidade é atribuível ao consumo de álcool, com maior incidência nos homens (5,6%) do que nas mulheres (1,8%). O álcool é responsável pela ocorrência de um elevado número de patologias e problemas de saúde, verificando-se também uma elevada incidência de anos de vida perdidos em idades mais jovens por acidentes rodoviários. O consumo de álcool encontra-se igualmente associado a danos que afetam tanto o indivíduo que consome como terceiros, havendo evidência de associação entre o consumo de álcool e a prevalência da criminalidade nos diferentes contextos sociais: laboral, viação e familiar. A PUA é uma patologia associada a elevados custos em saúde, tendo sido estimado em Portugal um total de 1916 milhões de euros no âmbito de cuidados de saúde em ambulatório e internamento, por doenças relacionadas com o álcool, no ano de 2005. Não obstante, a percentagem de indivíduos com esta doença que recebe tratamento permanece ainda reduzida, estimando-se que apenas 8% dos doentes com dependência de álcool na Europa são tratados. Uma das principais barreiras ao tratamento é a relutância de muitos doentes se comprometerem com a abstinência, além de que os programas de abstinência apresentam uma reduzida efetividade, com 70% a 80% de recaídas no decurso do primeiro ano após o tratamento. As recomendações recentes sugerem estratégias de intervenção com maior enfoque na redução de consumos de risco e minimização dos problemas relacionados com o uso e abuso de álcool, podendo constituir uma opção válida enquanto alternativa adicional aos programas orientados sobretudo para a abstinência, especialmente quando o prosseguimento do acompanhamento do doente está dependente da continuação do consumo de álcool. Globalmente, a intervenção no consumo nocivo de álcool permitirá melhorar os indicadores nacionais no que diz respeito ao número de anos de vida com saúde, tendo também um impacto social positivo significativo, nomeadamente na diminuição das situações de crime de violência, homicídios, acidentes rodoviários e ferimentos causados sob o efeito do álcool. Importa reforçar que o combate efetivo aos efeitos negativos do consumo excessivo do álcool na sociedade apenas poderá ser feito mediante uma forte aposta na prevenção, nomeadamente junto dos jovens. Por forma a fazer face a este desafio, é necessário capacitar os cuidados de saúde primários para a deteção precoce da PUA e resposta adequada às necessidades dos doentes. Reveste-se de especial importância a implementação de estratégias e políticas abrangentes, com envolvimento do estado, sociedade, profissionais de saúde e doentes. Por outro lado, deve assegurar-se que a disponibilização, venda, acesso e consumo de álcool no mercado seja feita de forma segura e não indutora de consumo de risco e nocivo, através de educação, regulação, regulamentação e fiscalização adequadas. A reunião de reflexão permitiu evidenciar a necessidade de colocar a problemática da PUA na agenda política como um dos principais problemas de saúde pública em Portugal.

PURPOSE: To improve the measurement system, during a research for the prevention of adhesions, we explored the feasibility of introducing three continuous numeric variables to quantify the intensity of pericardial adhesions. METHODS: To validate these three new numeric variables - time spent to dissect the adhesions (Δt), the amount of sharp dissection (ShpD) and the adhesion's collagen area (ACA) - as useful tools in measuring the severity of pericardial adhesions, data from a randomized study on adhesion prevention enrolling twenty-four swine, were analysed. A statistical Spearman's test and regressions models were applied to verify the correlation and the relationship between the results of a standard severity score (SS) and Δt, between SS and ShpD used in adhesiolysis and, also, between SS and ACA. RESULTS: There was a statistically significant correlation between SS and Δt, between SS and ShpD, as well as between SS and ACA, all measured by the Spearman's test (r=0.897, r=0.932, r=0.66; pOBJETIVO: A fim de melhorar a metodologia de mensuração das aderências pericárdicas, avaliamos, durante um estudo de prevenção de aderências pericárdicas, a possibilidade da utilização de três de novas variáveis contínuas e numéricas. MÉTODOS: Para validar estas novas variáveis numéricas - tempo de dissecção (Δt), quantidade de dissecção cruenta (ShpD) e a área de colágeno na aderência (ACA) como instrumentos precisos na quantificação das aderências pericárdicas, foram analisados os dados de um estudo para prevenção de aderências que envolveu 24 porcos. Foram aplicados modelos de regressão e o teste de Spearman para avaliar a força e os tipos correlações entre os resultados do escore padrão de classificação de aderências (SS) e o Δt, entre o SS e o ShpD, e, também, entre o SS e a ACA. RESULTADOS: Foram evidenciadas correlações, estatisticamente significativas, entre o SS e o Δt, entre o SS e o ShpD, também como entre o SS e a ACA avaliadas através do teste de Spearman (r=0,897, r=0,932 , r=0,66; p

PURPOSE: To compare the biocompatibility of ethyl-cyanoacrylate (ECA) and octylcyanoacrylate (OCA) wound closures to sutures in rat skin. METHODS: Twenty-four male Wistar rats were subjected to three incisions which were closed using ECA, OCA or sutures . Rats were divided into four groups which received biopsies on the 3rd, 7th, 14th or 21st post-operative days. Necrosis, inflammation, dermatitis, infection, dehiscence, cicatricial enlargement and costs were examined; the histopathology evaluated was epithelialization, deep openings, foreign substance reaction, residues of synthesis material, fibrosis, inflammation, dehiscence and necrosis. RESULTS: The tissue adhesives presented the largest dehiscence levels, and ECA the lowest cost while the other measures were similar. Regarding histopathology, deep openings were more common with OCA and granulomas were most frequently obtained with ECA. The two tissue adhesives produces less inflammation than the inicial suture from post-operative day 7, while ECA and OCA cause similar inflammatory reactions. ECA did not differ significantly from OCA and sutures on other measures. CONCLUSION: ECA was well tolerated in this study and did not induce necrosis, allergic reactions or infections, presenting several advantages in relation to OCA and sutures, including lower costs and fewer complications.OBJETIVO: Investigar a biocompatibilidade do etil-cianoacrilato (ECA) em fechamento de pele em ratos comparativamente ao octil-cianoacrilato (OCA) e à sutura. MÉTODOS: Rattus norvegicus albinus (n=24) foram submetidos a três incisões, cada uma fechada por um dos métodos de síntese estudados. Quatro grupos (n=6) foram feitos, conforme o dia pós-operatório (DPO) em que foram eutanasiados: 3DPO, 7DPO,14DPO e 21DPO. Necrose, edema, eritema, dermatite, infecção, deiscência, alargamento cicatricial e custos foram os itens examinados; histopatologicamente avaliou-se epitelização, abertura profunda, reação de corpo estranho, resíduos de material de síntese, fibrose, reação inflamatória, deiscência e necrose. RESULTADOS: Os adesivos apresentaram os maiores níveis de deiscências, e o ECA o custo mais baixo; nos demais itens, não houve diferenças. Histopatologia: A abertura profunda foi mais comum com o OCA; ECA foi o material mais encontrado em granulomas; os adesivos foram mais brandos que a sutura a partir do 7º DPO no quesito inflamação, enquanto que o ECA causou uma reação similar ao OCA; nos outros itens, ECA não apresentou diferença importante em relação ao OCA e à sutura. CONCLUSÃO: O ECA foi bem tolerado neste grupo de estudo, sem induzir necrose, reações alérgicas e infecção, apresentando diversas vantagens de uso em relação ao OCA e à sutura.

OBJETIVO: desenvolver um modelo experimental de isquemia global normotérmica transitória capaz de demonstrar os tempos de isquemia e reperfusão necessários para desenvolvimento de lesão de isquemia/reperfusão em intestinos delgados de ratos Wistar através clampeamento de aorta abdominal suprarrenal. MÉTODOS: Vinte ratos Wistar adultos machos, pesando entre 250 e 350g, foram distribuídos aleatoriamente em cinco grupos, com quatro ratos cada, e submetidos a tempos crescentes de isquemia (0 - 30 - 45 - 60 - 90 minutos). Dentro de cada grupo, à exceção do grupo controle, dois ratos foram submetidos à 60 minutos de reperfusão e dois à 90 minutos. Após os procedimentos, procedeu-se análise histológica através de medição de áreas de necrose. RESULTADOS: O grau de necrose intestinal variou de 15 a 54% (p=0,0004). Houve tendência de aumento progressivo no grau de lesão relacionado ao aumento no tempo de isquemia, contudo, os maiores graus de lesão foram observados nos menores tempos de reperfusão. A análise do coeficiente de variação de necrose entre os dez grupos de isquemia/reperfusão demonstrou diferença estatisticamente significante em 15 postos, sendo 13 relacionados ao grupo controle. CONCLUSÃO: O modelo foi capaz de demonstrar os tempos necessários para que ocorra lesão de isquemia/reperfusão intestinal através de clampeamento aórtico e poderá servir como base para facilitar o desenvolvimento de estudos voltados para a compreensão deste tipo de lesão.

Abstract Electronic inhalers provide information about patterns of routine inhaler use. During a 12-week study, 360 asthma patients using albuterol Digihaler generated 53,083 inhaler events that were retrospectively analyzed. A total of 41,528 (78%) of the recorded inhalation events were suitable for flow analysis (having a PIF ≥ 18 L/min and

Abstract Division and differentiation events by which cell populations with specific functions are generated often take place as part of a developmental programme, which can be represented by a sequence of compartments. A compartment is the set of cells with common characteristics; sharing, for instance, a spatial location or a phenotype. Differentiation events are transitions from one compartment to the next. Cells may also die or divide. We consider three different types of division events: (i) where both daughter cells inherit the mother’s phenotype (self-renewal), (ii) where only one of the daughters changes phenotype (asymmetric division), and (iii) where both daughters change phenotype (symmetric division). The self-renewal probability in each compartment determines whether the progeny of a single cell, moving through the sequence of compartments, is finite or grows without bound. We analyse the progeny stochastic dynamics with probability generating functions. In the case of self-renewal, by following one of the daughters after any division event, we may construct lifelines containing only one cell at any time. We analyse the number of divisions along such lines, and the compartment where lines terminate with a death event. Analysis and numerical simulations are applied to a five-compartment model of the gradual differentiation of hematopoietic stem cells and to a model of thymocyte development: from pre-double positive to single positive (SP) cells with a bifurcation to either SP4 or SP8 in the last compartment of the sequence.

Abstract We introduce a two-dimensional dimerized lattice model that reveals a remarkable feature: the emergence of a complex, non-trivial topological multiferroic phase marked by zero Berry curvature and a significant Berry connection that influences the model’s bulk topology. This model extends the one-dimensional Rice-Mele Hamiltonian model to explore polarization-dependent topological properties in a 2D Su-Schrieffer-Heeger lattice, providing a detailed framework for studying the impact of symmetry-breaking and spatially varying potentials on electronic and spin properties. The findings are particularly relevant for spintronics, offering a foundation for topologically robust and electrically controlled spin-conducting edge states, with implications for developing advanced spin-dependent transport devices.

Abstract By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Summary: Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53–0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Background: The individualized PREdiction of DIsease Control using digital sensor Technology (iPREDICT) program was developed for asthma management using digital technology. Devices were integrated into daily lives of patients to establish a predictive model of asthma control by measuring changes from baseline health status with minimal device burden. Objectives: To establish baseline disease characteristics of the study participants, detect changes from baseline associated with asthma events, and evaluate algorithms capable of identifying triggers and predicting asthma control changes from baseline data. Patient experience and compliance with the devices were also explored. Design: This was a multicenter, observational, 24-week, proof-of-concept study conducted in the United States. Methods: Patients (⩾12 years) with severe, uncontrolled asthma engaged with a spirometer, vital sign monitor, sleep monitor, connected inhaler devices, and two mobile applications with embedded patient-reported outcome (PRO) questionnaires. Prospective data were linked to data from electronic health records and transmitted to a secure platform to develop predictive algorithms. The primary endpoint was an asthma event: symptom worsening logged by patients (PRO); peak expiratory flow (PEF) 8 puffs/24 h or >4 puffs/day/48 h). For each endpoint, predictive models were constructed at population, subgroup, and individual levels. Results: Overall, 108 patients were selected: 66 (61.1%) completed and 42 (38.9%) were excluded for failure to respond/missing data. Predictive accuracy depended on endpoint selection. Population-level models achieved low accuracy in predicting endpoints such as PEF 4 SABA puffs/day/48 h. Individual models, constructed for patients with high endpoint overlap, exhibited significant predictive accuracy, especially for PEF 4 SABA puffs/day/48 h. Conclusion: This multidimensional dataset enabled population-, subgroup-, and individual-level analyses, providing proof-of-concept evidence for development of predictive models of fluctuating asthma control.

Drinking water utilities and commercial vendors are developing battery-powered autonomous robots for the internal inspection of pipelines. However, these robots require nearby charging stations next to the pipelines of the water distribution networks (WDN). This prompts practical questions about the minimal number of charging stations and robots required. To address the questions, an integer linear programming optimization is formulated, akin to set covering, based on the shortest path of the charging stations to each node along a pipeline. The optimization decisions revolve around designating nodes as charging stations, considering the maximum distance (δmax) at which a robot can cover a hard constraint. For optimal placement, two objective formulations are proposed: (i) minimize the total number of stations, representing total cost; and (ii) maximize the total redundancy of the system. The methodology is applied to three WDN topologies (i.e. Modena, FiveReservoirs, and E-Town). Results show the influence of topology on the total number of stations, the number of robots, and the redundancy of the charging stations network. A trade-off between δmax and total number of stations emphasizes robot battery capacity's significance mariocastrogama. HIGHLIGHTS A new method for the selection of locations of optimal charging locations for monitoring robots.; Application of two different formulations for solving the problem, each with its advantages and disadvantages.; It allows utilities to solve business-related questions on the subject.;

The growth of high-quality in vitro potato plants (Solanum stenotomum subsp. stenotomum, Solanum stenotomum subsp. goniocalyx, and Solanum tuberosum subsp. andigena) is affected by multiple biological, operational, and environmental factors. Research on in vitro culture is frequently focused on the species, explant, composition of the culture medium, and incubation conditions, but only limited information is available on the effect of the gas exchange rate and volume of in vitro culture vessels under variable planting densities. In the present study, these factors were evaluated with a set of seven diverse potato landraces. The results were compared to the plants’ responses in routinely used in vitro culture vessels, i.e., 13 × 100 mm and 25 × 150 mm test tubes, and GA7® magenta vessels. In vitro potato plants grown in plastic vessels equipped with a HEPA filter delivering a high gas exchange rate developed thicker stems (0.95 mm), a higher total average leaf area (2.51 cm2), increased chlorophyll content in leaves (32.2 ppm), and lower moisture content in their tissues (90.1%) compared to filter systems with lower gas exchange rates. A high planting density of 10 × 10 plants per vessel (360 and 870 mL) negatively affected the average stem width and root length but increased the plant height (3.4 cm). High fluctuations of ion-uptake of NO3−, Ca++, K+, and Na+ were observed between genotypes, with some accessions having a 4.6-times higher Ca++-ion concentration in their tissues (190–234 ppm). The in vitro plants developed more robust stems, longer roots, and larger leaves within in vitro culture vessels equipped with a HEPA filter (high gas exchange rate) compared to the control vessels, in contrast to the chlorophyll content in leaves, which was higher in plants grown in narrow test tubes. Depending on the purpose of the subculture of in vitro plants, their growth and development can be molded using different gas exchange rates, planting densities, and vessel volumes.

Modeling wildfire dynamics is complex and challenging due to the multiple scales involved in fire propagation, from physical–chemical processes to the interaction with topography and meteorological conditions. To provide reliable indicators of the risk of an ongoing wildfire, models aimed at informing policy-making should quantify the primary sources of uncertainty in their predictions. In this paper, we introduce a novel methodology built on top of Cellular Automata to assess the impact of uncertainty by implementing wildfire ensemble modeling using data from the Spanish National Forestry Data Repositories. Uncertainty is embedded in the model considering the ±2σ deviations from the medians of linear regressions of the canopy stratum with LiDAR metrics as explainable variables. The relevance of dynamic meteorological conditions in contrast to static environment conditions is analyzed. Our results suggest that an accurate account of the fuel model, including time-dependent wind and moisture maps, is mandatory to provide reliable predictions. Using a real case study (Concentaina’s extreme wildfire), we also illustrate the importance of assessing the impact of the firefighters’ mitigation efforts.

Summary: Background: With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need. Methods: Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.gov NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021. Findings: The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm. Interpretation: In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia. Funding: The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: Asthma is a chronic inflammatory disease that shows a time-of-day response to variations in symptoms/severity. However, how the lung circadian clock influences time-of-day response and sex-based differences in house dust mite (HDM)-induced airway inflammation and remodeling has not been thoroughly investigated. Objective: We sought to determine whether acute HDM exposure in wild-type mice shows time-of-day response and sex-based differences in allergic airway inflammation and circadian clock disruption in the lungs. Methods: Wild-type (C57BL/6J) and Rev-erbα knockout (KO) mice were exposed to either PBS or HDM (for 10 days) intranasally at Zeitgeber time (ZT0: 6 am; ZT12: 6 pm) and euthanized 48 hours after the last exposure. Acute HDM-induced time-of-day response and sex-based differences in lung inflammation, gated cytokines/chemokines, humoral and hormonal responses, and circadian clock gene expression were analyzed. Results: Acute HDM-exposed mice showed a time-of-day response and sex-based differences in exaggerated lung inflammation (inflammatory eosinophils and interstitial macrophages) at ZT12 when compared with ZT0. HDM-exposed female mice showed increased inflammatory response at ZT12, but HDM-exposed male mice showed comparatively lower inflammation with no time-of-day response. HDM-exposed female and male mice showed augmented IgE levels at ZT12 when compared with ZT0. Myeloid innate immunity panel, cytokines/chemokines, and mucin genes showed a time-of-day gating response at ZT0 and ZT12 in the HDM group. In addition, HDM exposure altered the expression of circadian clock genes in the lung, which was evident in female mice at ZT12. Overall, female mice showed significant time-of-day responses to all these parameters compared with male mice. Rev-erbα KO mice exposed to acute HDM showed exaggerated lung inflammation associated with increased IgE and proinflammatory cytokines in bronchoalveolar lavage fluid. Interestingly, HDM exposure causes reduced expression of clock genes in flow-sorted resident eosinophils but not alveolar macrophages. Acute HDM exposure reduced the nocturnal locomotor activity in mice 5 days post–HDM exposure until day 10. Conclusions: This study shows a time-of-day response to acute HDM exposure and sex-based differences in the severity of lung inflammation and humoral immune response associated with circadian clock disruption. Our findings support the use of separate female and male mice cohorts for preclinical studies to understand the molecular heterogeneity in asthma pathophysiology.

ABSTRACT: Objectives: To determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs). Methods: In a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected). Results: Study enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues. Conclusion: Oral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection. Trial registration: NCT04334148.

Background The phase 3 QUEST (NCT02414854) and TRAVERSE (NCT02134028) studies demonstrated the efficacy of dupilumab 200/300 mg versus placebo every 2 weeks for 52 weeks (QUEST) and dupilumab 300 mg up to an additional 96 weeks (TRAVERSE) in patients ≥12 years of age with uncontrolled, moderate-to-severe asthma. Overall, safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed long-term dupilumab efficacy for up to 3 years by exacerbation history. Patients and methods Unadjusted annualised severe exacerbation rates (AER) and change from parent study baseline (PSBL) in pre-bronchodilator forced expiratory volume in 1 s (FEV1) and 5-item Asthma Control Questionnaire (ACQ-5) score were assessed in patients with PSBL eosinophils ≥150 cells·µL−1 or fractional exhaled nitric oxide ≥20 ppb and 1 (n=624), 2 (n=344), or ≥3 (n=311) exacerbations in the year before enrolment in QUEST. Results In all three groups, dupilumab treatment progressively reduced AER range to 0.17–0.30 during TRAVERSE (Weeks 48–96), increased pre-bronchodilator FEV1 range by 0.28–0.49 L by Week 96 and improved asthma control (reduced ACQ-5 score range by 1.51–2.03 by Week 48). For patients who first received dupilumab upon TRAVERSE enrolment, AER decreased, and lung function and asthma control improved rapidly, as was observed upon initiation of dupilumab in QUEST. Dupilumab was efficacious regardless of exacerbation history. Conclusion For patients with uncontrolled, moderate-to-severe asthma with elevation of at least one type 2 biomarker, dupilumab treatment provides sustained, long-term reduction of exacerbation rates and improvements in lung function and asthma control irrespective of exacerbation history.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

This review article addresses the history, morphology, anatomy, medical management, and different surgical options for patients with double outlet right ventricle.

Summary: Circadian rhythms and sex differences are involved in the pathophysiology of asthma. Yet, there are no reports that simultaneously address the role of the circadian clock and sex-based differences in chronic house dust mite (HDM)-induced asthma. Here, we sought to determine if chronic HDM exposure during the resting phase (zeitgeber time: ZT0/6:00 a.m.) versus the active phase (ZT12/6:00 p.m.) differentially affects the circadian clock and alters asthma pathobiology in female and male mice. HDM exposure at ZT12 exaggerated infiltration of eosinophil subtypes and associated chemokines in females compared to males. Furthermore, HDM exposure augmented eosinophil chemokines, Th2 gene expression and cytokine release, and humoral immune response in females compared to males at ZT12. Concurrently, histopathological evaluation confirmed increased airway inflammation at ZT12 in both females and males. Overall, we showed a time-of-day response and sex-based differences in HDM-induced exaggerated asthmatic phenotypes (inflammation/remodeling) and circadian clock disruption in females compared to males.

The gaming industry plays a crucial role in the realm of entertainment within our society. However, from Monopoly to Flight Simulators, serious games have also been appealing tools for learning a new language, conveying values, or training skills. The resurgence of Artificial Intelligence (AI) and data science in the last decade presents a unique window of opportunity for its integration into video games. This integration is of particular interest due to the vast amount of data that can be collected through a game, which is needed to feed the AI algorithms. This paper aims to identify relevant research paths in the intersection of serious games, AI, and computational social science, particularly in their utilization as novel research tools to comprehend human behavior and society. To provide a comprehensive context, we also present an overview of the serious game research field identifying the most prominent application areas and analyzing applications of AI in serious games that hold great potential for computational social science research. The goal of our work is to establish a valuable framework for researchers interested in utilizing serious games as a novel tool for AI-supported social research.

High-Power electric grid networks require extreme security in their associated telecommunication network to ensure protection and control throughout power transmission. Accordingly, supervisory control and data acquisition systems form a vital part of any critical infrastructure, and the safety of the associated telecommunication network from intrusion is crucial. Whereas events related to operation and maintenance are often available and carefully documented, only some tools have been proposed to discriminate the information dealing with the heterogeneous data from intrusion detection systems and to support the network engineers. In this work, we present the use of deep learning techniques, such as Autoencoders or conventional Multiple Correspondence Analysis, to analyze and prune the events on power communication networks in terms of categorical data types often used in anomaly and intrusion detection (such as addresses or anomaly description). This analysis allows us to quantify and statistically describe high-severity events. Overall, portions of alerts around 5-10% have been prioritized in the analysis as first to handle by managers. Moreover, probability clouds of alerts have been shown to configure explicit manifolds in latent spaces. These results offer a homogeneous framework for implementing anomaly detection prioritization in power communication networks.

Abstract Background While inhaled corticosteroids (ICS) are considered the essential foundation of most asthma therapy, ICS inhaler nonadherence is a notoriously common problem and a significant cause of asthma-related morbidity. Partially acknowledging the problem of nonadherence, international organizations recently made paradigm-shifting recommendations that all patients with mild-to-moderate persistent asthma be considered for symptom-driven ICS-containing inhalers rather than relying on adherence to traditional maintenance ICS inhalers and symptom-driven short-acting beta-agonists (SABA). With this new approach, asthma patients are at least exposed to the important anti-inflammatory effects of ICS-containing inhalers when their symptom reliever inhaler is deployed due to acute symptoms. Methods This study will (Part 1) complete a pragmatic randomized controlled trial to evaluate if an inhaler strategy that utilizes symptom-driven ICS inhalers is particularly beneficial in maintenance ICS inhaler non-adherent asthma patients, and (Part 2) use a dissemination and implementation (D&I) science conceptual framework to better understand patients’ and providers’ views of inhaler nonadherence. This study, which will have an option of taking place entirely remotely, will use a Food and Drug Administration (FDA)-approved electronic sensor (Hailie® sensor) to monitor inhaler adherence and includes semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR). Discussion This study is assessing the problem of nonadherence using a D&I implementation science research lens while testing a new inhaler approach to potentially ameliorate the detrimental consequences of maintenance inhaler nonadherence. We hypothesize that the use of a symptom-driven ICS/LABA management strategy, as compared to traditional maintenance ICS treatment and symptom-driven SABA, will lead to improved adherence to an asthma treatment strategy, decreased asthma-related morbidity, less cumulative ICS exposure, and greater patient satisfaction with an inhaler approach. Trial registration ClinicalTrials.gov NCT05111262. Registered on November 8, 2021.

Background: Despite advances in diagnosis and treatment, the incidence and mortality of infective endocarditis (IE) have increased in recent decades. Studies on the risk factors for mortality in endocarditis in Latin America are scarce. Methods: This retrospective cohort study included 240 patients diagnosed with IE according to the modified Duke criteria who were admitted to two university hospitals in Rio de Janeiro, Brazil from January 2009 to June 2021. Poisson regression analysis was performed for trend tests. The multivariate Cox proportional hazards model was used to estimate the hazard ratio (HR) of predictors of in-hospital mortality. Findings: The median age was 55 years (IQR: 39–66 years), 57% were male, and 41% had a Charlson comorbidity index (CCI) score > 3. Healthcare-associated infective endocarditis (54%), left-sided native valve IE (77.5%), and staphylococcal IE (26%) predominated. Overall, in-hospital mortality was 45.8%, and mortality was significantly higher in the following patients: aged ≥ 60 years (53%), CCI score ≥ 3 (60%), healthcare-associated infective endocarditis (HAIE) (53%), left-sided IE (51%), and enterococcal IE (67%). Poisson regression analysis showed no trend in in-hospital mortality per year. The adjusted multivariate model determined that age ≥ 60 years was an independent risk factor for in-hospital mortality (HR = 1.9; 95% CI 1.2–3.1; p = 0.008). Interpretation: In this 12-year retrospective cohort, there was no evidence of an improvement in survival in patients with IE. Since older age is a risk factor for mortality, consensus is needed for the management of IE in this group of patients.

Background: Cough is the most reported symptom in the United States, with chronic refractory cough representing significant morbidity to patients. Zinc acetate may have beneficial effects in the cough reflex pathway. We sought to assess the safety and efficacy of zinc acetate in the management of chronic refractory cough. Study design and methods: This was a randomised, placebo-controlled, parallel-design pilot trial of individuals with chronic refractory cough. The effects of 6 weeks of zinc acetate versus placebo on quality of life and symptoms as measured by the Cough Quality-of-Life Questionnaire (CQLQ), Leicester Cough Questionnaire (LCQ), cough visual analogue score (C-VAS) and Global Assessment of Change in Cough (GACC) scores were evaluated. A futility analysis plan with a one-sided 80% confidence interval was used to compare treatment effect to published minimum clinically important differences (MCID) for each outcome. Results: 34 participants, 17 in each group, were enrolled and randomised. Participants were primarily white females with moderate–severe cough. Participants assigned to zinc acetate had a significant increase in serum zinc levels after 6 weeks, while those assigned to placebo did not. Both groups showed improvement in CQLQ, LCQ, C-VAS and GACC scores, but the treatment effects of zinc acetate versus placebo were small with confidence intervals that did not include the MCIDs. Interpretation: We observed no benefit of zinc therapy over placebo on cough symptoms or quality of life and conclude that larger trials of zinc for chronic cough are not warranted.

Abstract The mechanical and magnetic properties of polycrystalline nanoframes were investigated using atomistic molecular dynamics and micromagnetic simulations. The magneto-mechanical response of Fe hollow-like nanocubes was addressed by uniaxial compression carried out by nanoindentation. Our results show that the deformation of a nanoframe is dominated at lower strains by the compression of the nanostructure due to filament bending. This leads to the nanoframe twisting perpendicular to the indentation direction for larger indentation depths. Bending and twisting reduce stress concentration and, at the same time, increase coercivity. This unexpected increase of the coercivity occurs because the mechanical deformation changes the cubic shape of the nanoframe, which in turn drives the system to more stable magnetic states. A coercivity increase of almost 100 mT is found for strains close to 0.03, which are within the elastic regime of the Fe nanoframe. Coercivity then decreases at larger strains. However, in all cases, the coercivity is higher than for the undeformed nanoframe. These results can help in the design of new magnetic devices where mechanical deformation can be used as a primary tool to tailor the magnetic response on nanoscale solids.

This work presents the analysis of the stability of magnetic bimerons in a cylindrical nanotube. Through micromagnetic simulations, we study the influence of magnetic and geometrical parameters on the bimeron existence and size. The obtained results allow us to present diagram states showing the stability region of a bimeron as a function of the nanotube’s height and radius for different anisotropy and Dzyaloshinskii–Moriya interaction strengths. We also obtain two other magnetic states in the range of parameters where the bimeron is not stable: helicoidal and saturated states.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

Long-term conservation of Plant Genetic Resources (PGR) is a key priority for guaranteeing food security and sustainability of agricultural systems for current and future generations. The need for the secure conservation of genetic resources collections ex situ is critical, due to rapid and extreme climatic changes which are threatening and reducing biodiversity in their natural environments. The International Potato Center (CIP) conserves one of the most complete and diverse genetic resources collections of potato, with more than 7500 accessions composed of 4900 cultivated potato and 2600 potato wild relative accessions. The clonal conservation of cultivated potato, principally landraces, through in vitro or field collections is indispensable to maintain fixed allelic states, yet it is costly and labor-intensive. Cryopreservation, the conservation of biological samples in liquid nitrogen (-196°C), is considered the most reliable and cost-efficient long-term ex-situ conservation method for clonal crops. Over the last decade, CIP has built one of the largest potato cryobanks worldwide, cyopreserving more than 4000 cultivated potato accessions which represents 84% of the total cultivated potato collection currently conserved at CIP. In approximately, four years the entire potato collection will be cryopreserved. The development of an applied, robust cryopreservation protocol for potato, serves as a model for other clonally maintained crop collections. The CIP cryobank designs experiments with a high number of genetically diverse genotypes (70-100 accessions, seven cultivated species), to obtain reliable results that can be extrapolated over the collection as genotypes can often respond variably to the same applied conditions. Unlike most published reports on cryopreservation of plants, these large-scale experiments on potato are unique as they examine the acclimatization process of in vitro plants prior to, as well as during cryopreservation on up to ten times the number of genotypes conventionally reported in the published literature. As a result, an operational cryopreservation protocol for potato has advanced that works well across diverse potato accessions, not only with reduced processing time and costs, but also with an increased average full-plant recovery rate from 58% to 73% (+LN) for routine cryopreservation. The present article describes the composition of CIP’s cryobank, the cryopreservation protocol, methodology for the dynamic improvement of the operational protocol, as well as data collected on regeneration from long term cryopreserved potatoes.