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Abstract Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer’s disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard −/− mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (−logEC50 ≥ 2) in 19,334 hospital patients was

Abstract TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.

The β-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a β-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (P

Aims: Severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) infection broadly affects organ homeostasis, including the haematopoietic system. Autopsy studies are a crucial tool for investigation of organ‐specific pathologies. Here we perform an in‐depth analysis of the impact of severe coronavirus disease 2019 (COVID‐19) on bone marrow haematopoiesis in correlation with clinical and laboratory parameters. Methods and results: Twenty‐eight autopsy cases and five controls from two academic centres were included in the study. We performed a comprehensive analysis of bone marrow pathology and microenvironment features with clinical and laboratory parameters and assessed SARS‐CoV‐2 infection of the bone marrow by quantitative polymerase chain reaction (qPCR) analysis. In COVID‐19 patients, bone marrow specimens showed a left‐shifted myelopoiesis (19 of 28, 64%), increased myeloid–erythroid ratio (eight of 28, 28%), increased megakaryopoiesis (six of 28, 21%) and lymphocytosis (four of 28, 14%). Strikingly, a high proportion of COVID‐19 specimens showed erythrophagocytosis (15 of 28, 54%) and the presence of siderophages (11 of 15, 73%) compared to control cases (none of five, 0%). Clinically, erythrophagocytosis correlated with lower haemoglobin levels and was more frequently observed in patients from the second wave. Analysis of the immune environment showed a strong increase in CD68+ macrophages (16 of 28, 57%) and a borderline lymphocytosis (five of 28, 18%). The stromal microenvironment showed oedema (two of 28, 7%) and severe capillary congestion (one of 28, 4%) in isolated cases. No stromal fibrosis or microvascular thrombosis was found. While all cases had confirmed positive testing of SARS‐CoV‐2 in the respiratory system, SARS‐CoV‐2 was not detected in the bone marrow by high‐sensitivity PCR, suggesting that SARS‐CoV‐2 does not commonly replicate in the haematopoietic microenvironment. Conclusions: SARS‐CoV‐2 infection indirectly impacts the haematological compartment and the bone marrow immune environment. Erythrophagocytosis is frequent and associated with lower haemoglobin levels in patients with severe COVID‐19. [ABSTRACT FROM AUTHOR]

BackgroundLung cancer is the leading cause of cancer death worldwide, with poor survival despite recent therapeutic advances. A better understanding of the complexity of the tumor microenvironment is needed to improve patients’ outcome.MethodsWe applied a computational immunology approach (involving immune cell proportion estimation by deconvolution, transcription factor activity inference, pathways and immune scores estimations) in order to characterize bulk transcriptomics of 62 primary lung adenocarcinoma (LUAD) samples from patients across disease stages. Focusing specifically on early stage samples, we validated our findings using an independent LUAD cohort with 70 bulk RNAseq and 15 scRNAseq datasets and on TCGA datasets.ResultsThrough our methodology and feature integration pipeline, we identified groups of immune cells related to disease stage as well as potential immune response or evasion and survival. More specifically, we reported a duality in the behavior of immune cells, notably natural killer (NK) cells, which was shown to be associated with survival and could be relevant for immune response or evasion. These distinct NK cell populations were further characterized using scRNAseq data, showing potential differences in their cytotoxic activity.ConclusionThe dual profile of several immune cells, most notably T-cell populations, have been discussed in the context of diseases such as cancer. Here, we report the duality of NK cells which should be taken into account in conjunction with other immune cell populations and behaviors in predicting prognosis, immune response or evasion.

Objective: The risk of suicide is higher among health care workers than other workers. This study investigated the association between social support and suicidal ideation and behavior during the COVID-19 pandemic among Brazilian health care workers. Methods: This study used data from 10,885 respondents to the first (time point 1 – between May and June of 2020) and second (time point 2 – between December 2020 and February 2021) cross-sectional online surveys about mental health and quality of life among Brazilian health care workers during the COVID-19 pandemic. The relationship between social support as the independent variable (time point 1) and suicidal ideation and behavior as the outcomes (time point 2) was investigated through logistic regression analysis. Results: Greater social support was associated with a significantly lower risk of reporting suicidal ideation and behavior in the month prior to follow-up assessment (adjusted OR: 0.71, 95%CI 0.66-0.76 and adjusted OR 0.61, 95%CI 0.54-0.68, respectively). These associations were independent of sex, age, feelings of loneliness, and self-reported psychiatric disorders. Conclusion: Social support is associated with a lower risk of suicidality among health care workers, and its protective role appears more closely related to suicidal behavior.

Summary: Background: Pseudomonas aeruginosa is a major cause of hospital-acquired and chronic infections, characterised by an extraordinary capacity to develop antimicrobial resistance through the selection of chromosomal mutations, leading to treatment failure. Here, we designed and tested a hybridisation-based capture system for the enrichment of genes of interest before sequencing to monitor resistant populations genomics directly from clinical samples. Methods: A panel for enrichment before sequencing of close to 200 genes related to P. aeruginosa antimicrobial resistance, multilocus sequence typing, mutability or virulence was designed, synthesised (KAPA HyperCap, Roche) and initially validated in vitro using a multidrug-resistant ST175 isolate and representative isolates from major P. aeruginosa clades. In vivo testing included ventilator associated pneumonia by MDR P. aeruginosa in ICU (3–10 sequential samples from 3 patients) and chronic respiratory infection by hypermutable P. aeruginosa in cystic fibrosis (8 sequential samples from a single patient covering a 4-year period). Results from direct sequencing with the enrichment panel were compared with those of whole genome sequencing (WGS) and phenotypic profiling of 10 isolated colonies per sample. Findings: In vitro assays confirmed the selectivity of the enrichment panel and the correct identification of the vast mutational resistome of ST175, including specific mutations even when introduced in a 1:100 proportion. In vivo performance was at least equivalent to sequencing 10 colonies per sample, including the accurate identification of the sequence types and the basal and acquired mutational resistome. To note, specific resistance mutations, such as those in ampC leading to resistance to novel β-lactams, could be traced even at frequencies of 1%. Moreover, the coselection of mutator populations and antibiotic resistance mutations, predicted in theoretical and in vitro studies, was evidenced in vivo. Interpretation: This proof-of-concept study demonstrates that resistance genomics of P. aeruginosa can be analysed directly from clinical samples, determining not only a considerable reduction in turnaround time and cost from a diagnostics perspective, but also an unprecedented potency for accurate monitoring of in vivo population dynamics in bacterial infections. Funding: Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU.

Objective: To test the factor structure, reliability, and validity of the Brazilian version of the Abbreviated Suicidal Narrative Inventory (SNI-38). Methods: We used an anonymous online questionnaire of the SNI-38 and self-report measures administered between November 2020 and October 2021 in the Brazilian community. Participants were recruited through social media advertisements. Confirmatory factor analysis (CFA) was performed to test the factor structure of the SNI-38. In addition, we assessed internal consistency and convergent validity against stressful life events, suicide crisis syndrome, suicidal ideation, and suicide attempts. Results: A total of 2,660 participants were included. The eight-factor model of the SNI-38 had a good model fit (χ2[637] = 7,473.98, p < 0.001, comparative fit index [CFI] = 0.99, Tucker-Lewis index [TLI] = 0.99, root mean squared error of approximation [RMSEA] = 0.07, standardized root mean residual [SRMR] = 0.06). Notably, all items were significantly and positively loaded onto their respective factors (factor loadings ≥ 0.45). The reliability of all subscales except for goal disengagement ranged from good to high. Furthermore, all subscales except goal disengagement showed positive correlations with variables such as suicide crisis syndrome, stressful life events, lifetime/past month suicidal ideation, and lifetime suicide attempts. Conclusion: These findings provide preliminary support for the validity of the Brazilian version of the SNI-38 as an appropriate, valid instrument for measuring suicidal narratives in Brazilian individuals.

Frequency combs are powerful tools for many applications and high performances are achieved by stabilizing these lasers. For operation in the mid‐infrared, quantum cascade lasers (QCL) are ideal candidates as they present numerous advantages. However, stabilized QCL‐combs lack a detailed characterization of their noise properties due to the sensitivity limits of current analyzing techniques. To overcome these challenges, what is believed to be the first tightly locked dual QCL‐comb system is developed. Its use is twofold. First, phase noise analysis of the dual‐comb signal shows residual phase noise below 600 mrad for all comb lines, and the comb coherence as well as the performances of the repetition frequency locking mechanism is characterized. Second, coherent averaging with a 7 × 105 Hz1/2 figure‐of‐merit system is demonstrated, which is compatible with high‐precision spectroscopy.

Resumo Objetivo Descrever o processo de elaboração e validação de conteúdo do instrumento para mensurar a intensificação do trabalho da enfermagem. Métodos Estudo metodológico realizado em cinco das oito etapas propostas por DeVellis. I - Determinar claramente o que se deseja medir; II – Gerar um pool de itens; III - Determinar o formato da medida; IV - Ter o conjunto de itens revisados por especialistas; V - Considerar a inclusão de itens de validação. A produção dos dados ocorreu no segundo semestre de 2021. Os participantes foram 18 trabalhadores de enfermagem na etapa exploratória (elaboração dos itens), 12 doutores que compuseram o comitê de juízes/especialistas e 43 trabalhadores de enfermagem na etapa do pré-teste. O processamento dos dados ocorreu principalmente pelo cálculo do Índice de Validade de Conteúdo. Resultados O instrumento está organizado em 60 itens, dispostos em sete domínios: Interface com o trabalho; Ritmo e exigências do trabalho; Condições para o trabalho; Relações interprofissionais; Aspectos institucionais; Repercussões do trabalho na saúde do trabalhador e; Condições clínicas do paciente. O índice de validade conteúdo variou de 0,44 a 1,00, sendo excluídos os itens com valor inferior a 0,80. No pré-teste com a população alvo, esta medida variou de 0,90 a 1,00. O instrumento em sua formação completa apresentou avaliação global de 0,95. Conclusão O instrumento foi considerado válido pelo comitê de juízes/especialistas e pela população alvo, constituindo-se em uma ferramenta inovadora a ser empregada para mensurar a intensificação do trabalho da enfermagem.

Resumo Objetivo Verificar e correlacionar a resiliência e o significado do trabalho em enfermeiros hospitalares no contexto da pandemia de COVID-19. Método Estudo descritivo e correlacional, realizado entre junho e novembro de 2021, com 164 enfermeiros de dois hospitais de São Paulo com os instrumentos a Escala de Resiliência Connor-Davidson e o Inventário do Significado do trabalho. Os dados foram analisados por meio da estatística descritiva e inferencial sendo adotados os seguintes testes: Teste de correlação de Pearson; Teste de Kruskal-Wallis; Teste t de Student; Teste de Dunn; Teste de correlação de Spearman; Análise de Variância Univariada; Teste de normalidade de Shapiro-Wilk; Teste de Levene. O valor de significância estatística adotado foi de 5% (p ≤ 0,05). Resultados Média de idade 37,54 anos (DP = 8,52), sendo 81,1% (133) do sexo feminino, média da resiliência 76,98 (DP=11,32). Correlações significativas positivas foram encontradas entre: escolaridade, idade e a resiliência com os atributos “Fonte de realização e independência econômica”, “Expressão de respeito e de acolhimento”, “Fonte de desafio, responsabilidade e sustento”, “Desafiar-se”, “Crescer economicamente”, “Sentir prazer e proteção”, “Contribuir socialmente e ser assistido” e “Ser reconhecido”; Conclusão Houve correlação da resiliência com o significado do trabalho, colaborando com o enfrentamento das adversidades encontradas na pandemia de COVID-19.

Objective: To evaluate the factor structure, reliability, and validity of the Brazilian version of the Suicide Crisis Inventory-2 (SCI-2) among Brazilian adults. Methods: The SCI-2 was cross-culturally adapted into Portuguese and administered to 2,265 Brazilian participants. Confirmatory factor analysis (CFA) was used to assess factor structure, internal consistency, convergent validity, and criterion validity by using measures such as suicidal narratives, stressful life events, suicidal ideation, and suicide attempts. Results: The revised one-factor model of the SCI-2 demonstrated an adequate, although not optimal, model fit (χ2[1539] = 31,442.79, p < 0.001, comparative fit index [CFI] = 0.99, Tucker-Lewis index [TLI] = 0.99, root mean square error of approximation [RMSEA] = 0.09, standardized root mean residual [SRMR] = 0.05). The revised five-factor model, on the other hand, demonstrated good fit (χ2[1529] = 14,174.86, p < 0.001, CFI = 1.00, TLI = 1.00, RMSEA = 0.06, SRMR = 0.04). Comparison of these two models indicated that the five-factor model had a better fit than the one-factor model. Both the total and subscale scores of the SCI-2 showed strong internal consistency and good convergent and criterion validity in relation to stressful life events, suicidal narratives (excluding the goal disengagement subscale), suicidal ideation, and suicide attempts. Conclusion: Our findings suggest that the Brazilian version of the SCI-2 is a valid tool for assessing symptoms of suicidal crisis syndrome.

Regulatory T cells (Treg) play a prominent role in utero tolerating non-inherited maternal antigens and in regulating immune responses against pathogens at birth. This study investigates Treg immunity in newborns in West Africa, where sepsis remains a major public health problem. Treg phenotypes on neonates subgroups with early-onset sepsis (EOS), presumed sepsis, and healthy newborn with and without prenatal risk factors were evaluated. Treg phenotypes varied according to prenatal conditions, with increase in Treg frequency and Foxp3 expression in healthy newborns with prenatal risk factors compared to those with none risk. Compared to healthy newborns with prenatal risk factors, EOS neonates had a significantly reduced frequency of Treg and Foxp3 expression. In the Treg pool, higher frequency of activated Treg was observed in EOS neonates, suggesting an in-utero activation upstream of the sepsis onset. Their migration to the infection site may explain the reduced frequency of circulating Integrin α4β1+ Treg suggestive of homing to the endothelial tissue. EOS neonates show increases expression of CTLA-4, PD-1 and CD39 on Treg, which negatively regulate the activation of effector T cells (Teff) corroborating by the lower frequency of Teff in EOS neonates. The higher frequency of CD39+ Treg and the lower frequency of integrinα4β1+ Treg in EOS non-survivor suggests that Treg exhaustement and endothelial homing are associated with outcome severity. Neonates developing EOS are born with an altered Treg phenotypic profile. Treg expression of CTLA-4, PD-1, CD39, and integrinα4β1 cell markers can be considered as early warning or diagnostic markers of EOS.

A complexidade dos comportamentos suicidas requer uma abordagem multifacetada para sua gestão, envolvendo a avaliação de fatores de risco e proteção, bem como intervenções apropriadas. A Associação Brasileira de Psiquiatria (ABP), por meio da sua Comissão de Emergências Psiquiátricas, elaborou diretrizes específicas para o manejo de pacientes com comportamento suicida, com foco em triagem, intervenção, prevenção e promoção da saúde mental. Embora a evidência disponível ainda apresente controvérsias e limitações, já é possível identificar a eficácia de certas intervenções para grupos específicos de pacientes. A recomendação atual inclui a combinação de várias técnicas, como o Plano de Segurança, que integra a avaliação de fatores de risco e proteção com medidas terapêuticas subsequentes. Destaca-se a necessidade de pesquisas adicionais para esclarecer abordagens com potencial específico para intervenção, visando sempre otimizar as estratégias de manejo do comportamento suicida e incorporá-las nas políticas públicas de saúde.

O suicídio é um grave problema de saúde pública com profundos impactos emocionais, sociais e econômicos. Este artigo aborda três estratégias essenciais para enfrentar essa questão: pós-venção, prevenção e promoção da saúde mental. Pós-venção envolve intervenções após um suicídio, oferecendo suporte às pessoas afetadas para mitigar traumas e prevenir novos casos. Programas de apoio psicológico e grupos de ajuda mútua são eficazes na redução do impacto negativo em famílias e comunidades. Prevenção consiste na identificação e redução de fatores de risco antes das tentativas de suicídio. Isso inclui triagem de risco, intervenções psicoterapêuticas, tratamento farmacológico e campanhas educativas que promovem a conscientização e reduzem o estigma dos transtornos mentais. O treinamento de profissionais de saúde e educação é crucial para a detecção precoce e intervenção. Promoção da saúde mental visa fortalecer fatores protetores e melhorar o bem-estar psicológico. Políticas públicas eficazes, acesso a serviços de saúde mental de qualidade e a criação de ambientes sociais e educacionais que promovam resiliência e apoio emocional são fundamentais. Iniciativas incluem programas de educação emocional nas escolas e campanhas comunitárias de conscientização. Este artigo enfatiza a necessidade de uma abordagem integrada que combine pós-venção, prevenção e promoção para o manejo eficaz do comportamento suicida, apresentando evidências e recomendações para a prática clínica e implementação em políticas públicas de saúde.

Este artigo detalha as diretrizes para a triagem e avaliação do comportamento suicida. A triagem envolve o uso de instrumentos ou protocolos para identificar indivíduos com comportamentos suicidas, podendo ser aplicada de forma independente ou como parte de uma avaliação de saúde mais ampla. Esta pode ser realizada de maneira manual ou eletrônica e aplicada seletivamente ou de forma universal a toda a população alvo. A avaliação do risco de suicídio deve ser conduzida por um médico e incluir questionários estruturados e conversas abertas com o paciente, familiares e amigos para obter uma visão completa do comportamento, fatores de risco e proteção, e histórico de cuidados de saúde mental. A eficácia da triagem e avaliação é aumentada quando combinada com estratégias de intervenção, como o Plano de Segurança, que integra a avaliação de riscos e a criação de um plano terapêutico individualizado.

Neste artigo serão avaliados os fatores de risco e proteção para futuras tentativas e suicídio completo. Atualmente, não há meios precisos que garantam a predição do desfecho de uma fatalidade relacionada ao comportamento suicida. Sendo assim, a anamnese, o exame psíquico e a avaliação dos fatores mencionados são as ferramentas atuais que auxiliam na tomada de decisão de pacientes em risco. Tais fatores de risco e proteção são identificados através de estudos epidemiológicos, caso-controle e coortes. O objetivo deste artigo será apresentar tais fatores que foram encontrados na revisão bibliográfica e que apresentam algum nível de evidência para serem utilizados na prática clínica.

Pretende-se, neste artigo, levantar algumas considerações acerca do conceito de fantasia, elaborado por Melanie Klein e expandido por Donald Winnicott, na tentativa de propor uma possível comparação teórica entre essas duas linhagens da psicanálise. Para tanto, apresentamos, ainda que de maneira breve, a concepção de desenvolvimento psíquico para esses dois autores, enumerando algumas aproximações e afastamentos. Por fim, apontamos as vantagens desse tipo de pesquisa comparativa e as suas respectivas dificuldades, destacando os aspectos que assinalam a singularidade da noção de fantasia no pensamento kleiniano e winnicottiano, assim como sua utilidade na narração de exemplos clínicos.

ABSTRACT Four species of non-tuberculous mycobacteria (NTM) rated as biosafety level 1 or 2 (BSL-1/BSL-2) organisms and showing higher genomic similarity with Mycobacterium tuberculosis (Mtb) than previous comparator species Mycobacterium kansasii and Mycobacterium marinum were subjected to genomic and phenotypic characterization. These species named Mycobacterium decipiens, Mycobacterium lacus, Mycobacterium riyadhense, and Mycobacterium shinjukuense might represent “missing links” between low-virulent mycobacterial opportunists and the highly virulent obligate pathogen Mtb. We confirmed that M. decipiens is the closest NTM species to Mtb currently known and found that it has an optimal growth temperature of 32°C–35°C and not 37°C. M. decipiens showed resistance to rifampicin, isoniazid, and ethambutol, whereas M. lacus and M. riyadhense showed resistance to isoniazid and ethambutol. M. shinjukuense was sensitive to all three first-line TB drugs, and all four species were sensitive to bedaquiline, a third-generation anti-TB drug. Our results suggest these four NTM may be useful models for the identification and study of new anti-TB molecules, facilitated by their culture under non-BSL-3 conditions as compared to Mtb. M. riyadhense was the most virulent of the four species in cellular and mouse infection models. M. decipiens also multiplied in THP-1 cells at 35°C but was growth impaired at 37°C. Genomic comparisons showed that the espACD locus, essential for the secretion of ESX-1 proteins in Mtb, was present only in M. decipiens, which was able to secrete ESAT-6 and CFP-10, whereas secretion of these antigens varied in the other species, making the four species interesting examples for studying ESX-1 secretion mechanisms.IMPORTANCEIn this work, we investigated recently identified opportunistic mycobacterial pathogens that are genomically more closely related to Mycobacterium tuberculosis (Mtb) than previously used comparator species Mycobacterium kansasii and Mycobacterium marinum. We confirmed that Mycobacterium decipiens is the currently closest known species to the tubercle bacilli, represented by Mycobacterium canettii and Mtb strains. Surprisingly, the reference strain of Mycobacterium riyadhense (DSM 45176), which was purchased as a biosafety level 1 (BSL-1)-rated organism, was the most virulent of the four species in the tested cellular and mouse infection models, suggesting that a BSL-2 rating might be more appropriate for this strain than the current BSL-1 rating. Our work establishes the four NTM species as interesting study models to obtain new insights into the evolutionary mechanisms and phenotypic particularities of mycobacterial pathogens that likely have also impacted the evolution of the key pathogen Mtb.

The purpose of this study was to conduct a naturalistic assessment of the efficacy of four distinct fast tranquilization techniques (intramuscular haloperidol, midazolam, haloperidol plus promethazine, or haloperidol plus midazolam) over a period of 12 h. The sample included 1603 people who were psychiatric emergency room patients at Hospital Geral de Palmas in Brazil between January 2018 and June 2022. The primary outcome was the number and proportion of patients who achieved the ideal response of the rapid tranquilization concept: tranquil without sedation in all assessments (measure by BARS scale), without restraint, without additional medication and without side effects. The secondary outcomes were mild agitation, tranquil or asleep over 12 h, the need for additional medication, use of physical restraints, and side effects. Among all patients, the proportion of rapid tranquilization over 12 h was 14.1% besides (32.9% for haloperidol, 29.2% for midazolam, 4.1% for haloperidol plus promethazine, and 5.4% for haloperidol plus midazolam) there is response some time in 97%. Logistic regression assessed the rapid tranquilization concept with to haloperidol as parameter: midazolam Exp(B) = 0.718 (95% CI 0.362–1.421), p = 0.341, had no difference; haloperidol plus promethazine Exp(B) = 0.011 (95% CI 0.004–0.026), p

Abstract The real‐life retrospective observational study CARMYN aimed at investigating the long‐term efficacy and safety of carfilzomib in combination with dexamethasone and lenalidomide (KRd, 159 patients). These patients (62% in first and 38% in second relapse, median age 62 yo) were treated between 02/2014 and 02/2017. Most had been pre‐exposed to bortezomib (98.2%) and to an IMID (75.4%). At the time of collection, 90% had permanently discontinued carfilzomib. Data collection was conducted from January to July 2021 in 27 participating sites, after a median of 39 months follow‐up. For patients treated with KRd, an overall response rate of 78.4% translated in a median progression free survival (PFS) of 24.0 months (95% CI 18.8–27.6) and a median overall survival (OS) of 51.1 months (95% CI 41.3–not reached). Results were poorer but difficult to interpret in the small cohort of Kd recipients. The study is one of the longest real‐life studies of carfilzomib treatment in patients in first or second relapse. CARMYN confirmed the real‐life long‐term efficacy of carfilzomib in combination with lenalidomide and dexamethasone with results similar to those of clinical trials. The KRd regimen is thus an option to consider for late relapses in the current context of MM management.

When developing a technology based on single-photon avalanche diodes (SPADs), the SPAD characterization is mandatory to debug, optimize and monitor the microfabrication process. This is especially true for the development of SPAD arrays 3D integrated with CMOS readout electronics, where SPAD testing is required to qualify the process, independently from the final CMOS readout circuit. This work reports on a characterization and monitoring platform dedicated to SPAD testing at die and wafer level, in the context of a 3D SPAD technology development. The platform relies on a dedicated integrated circuit made in a standard CMOS technology and used in different configurations from a prototype printed circuit board (die-level testing) to active probe cards (wafer-level mapping). The platform gives full access to SPAD characteristics in Geiger mode such as the dark noise, photon detection efficiency and timing resolution. The integrated circuit and its configuration are described in detail as well as results obtained on different SPAD test structures. In particular, the dark count rate mapping demonstrates the benefits of testing SPADs at wafer level at the R&D stage.

This study proposes a novel semi-supervised multi-label emotion classification approach for French tweets based on pseudo-labeling. Human subjectivity in emotional expression makes it difficult for a machine to learn. Therefore, it necessitates training supervised learning models on large datasets annotated by multiple annotators. However, creating such datasets can be costly and time-consuming. Moreover, aggregating annotations from multiple annotators to capture their collective emotional state adds complexity to the task. Semi-supervised learning techniques have shown effectiveness with limited datasets. Furthermore, Large language Models (LLMs), particularly Chat-GPT, have demonstrated superior annotation accuracy compared to annotations obtained from crowdsourcing platforms, when both are evaluated against expert-annotated data. This work introduces a novel approach for multi-label emotion classification of French tweets by leveraging pseudo-labels generated through Chat-GPT, a robust large language model. Using zero-shot, one-shot, and few-shot learning techniques, Chat-GPT annotates the unlabelled part of our dataset. These Chat-GPT-annotated pseudo-labels are then merged with manual annotations, facilitating the training of a multi-label emotion classification model via semi-supervised learning. Furthermore, within the context of our research, we present a new French tweet dataset, containing testimonials from people affected by an urban industrial incident. This dataset features 2,350 tweets, each manually annotated by three human annotators based on 8 pre-identified emotions. Benchmark results are presented for multi-label emotion classification models employing both fully supervised and semi-supervised approaches with pseudo-labeling. Our findings demonstrate the superiority of our approach for multi-label emotion classification over standard pseudo-labeling and an established baseline.

Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains of Mycobacterium tuberculosis (MTB) are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high-content imaging, we identified novel 1,2,4-oxadiazole-based compounds, which allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, MTB became even more sensitive to antituberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.

Background: Emotional stability is considered a protective factor for suicidal behavior. Nonetheless, suicidality is the result of a complex interaction of protective and risk factors, a key one being financial difficulties. We aimed to investigate the association between emotional stability and suicidality in Brazilian individuals during the COVID-19 pandemic, and the moderation role of financial hardship Methods: A total of 2140 participants, 79.4% women, answered an online survey from November 2020 to January 2021, containing questions about suicidality as well as concerning economic hardship. We conducted multiple regression and moderation analysis using SPSS PROCESS v3.5 Macro model 1 Results: The participants who reported not having presented suicidal ideation or suicide attempt in the previous month showed a significantly higher level of emotional stability. There was a significant interaction with financial hardship (p=0,006) for suicide attempt as the outcome, with significant association between emotional stability and suicide attempts only in the absence of financial hardship Limitations: The limitations of this study include the lack of control for distinct mental disorders and levels of financial problems Conclusion: The presence of financial hardship may suppress the protective role of emotional stability in suicidal behavior.

ABSTRACT Objective: To report on the experience and impressions of the Brazilian orthopedic trauma surgeons attending the Leadership Development Program (LDP) hosted by the Sociedade Brasileira do Trauma Ortopédico (SBTO) in Sao Paulo, Brazil on November 4, 2022. Methods: Forty-eight orthopedic trauma surgeons from five different regions throughout Brazil were provided a link to complete The Big Five Test, a validated online personality assessment. The questionnaire was available in Portuguese and was intended to provide a background on individual personality traits and their influence on interpersonal interactions. The LDP integrated content from literature reviews specific to Latin America, established leadership programs from leading business schools, and various subject matter experts. Prior to the start of the LDP, participants received a pre-course survey evaluating demographic information, a needs assessment, and the prioritization of leadership topics utilizing a 5-point Likert-scale. Attendees participated in the one-day, interactive LDP focusing on the fundamental principles of leadership development, communication, personal development, emotional intelligence and negotiation. Following the LDP, a post-course evaluation was administered to determine the participants’ overall experience, and suggestions for LDP improvement. Results: Forty-one of the forty-eight course participants completed the pre-course evaluation, whereas forty-six of the forty-eight participants completed the post-course evaluations. Overwhelmingly, the lack of opportunity was most prevalently reported as the main obstacle to attending a leadership course, as cited by 56% of respondents. Conclusion: Expanding the accessibility, diversity, and customizability of leadership programs can facilitate the development of personal tools needed to move healthcare forward. Critical topics include emotional intelligence and other differentiating leadership qualities that distinguish true transformational and servant leaders. Advancing leadership skills can stimulate networking, expose learners to experiential learning styles, inspire others to create positive change, and engender creative solutions for systematic improvements and health outcomes. Level of Evidence III; Individual Case-Control Studies.

Objective: to analyze the effects of a Mindfulness-based intervention on nurse leaders’ emotional intelligence and resilience. Method: a pilot study of a randomized crossover clinical trial. The sample (n=32) was randomized into Group A (n=18) and Group B (n=14) and evaluated at the pre-test, post-test and follow-up moments. The outcomes were assessed using the Emotional Intelligence Measure, the Connor-Davidson Resilience Questionnaire and the Five Facet Mindfulness Questionnaire, and analyzed using Generalized Linear Mixed Models. Results: a total of 32 nurses with a mean age of 42.6 years old were evaluated. The analyses showed significant interactions between the effects of the group x moment factors on the Self-motivation (p=0.005), Sociability (p

Abstract Robot swarms are generally considered to be composed of cooperative agents that, despite their limited individual capabilities, can perform difficult tasks by working together. However, in open swarms, where different robots can be added to the swarm by different parties with potentially competing interests, cooperation is but one of many strategies. We envision an information market where robots can buy and sell information through transactions stored on a distributed blockchain, and where cooperation is encouraged by the economy itself. As a proof of concept, we study a classical foraging task, where exchanging information with other robots is paramount to accomplish the task efficiently. We illustrate that even a single robot that lies to others—a so-called Byzantine robot—can heavily disrupt the swarm. Hence, we devise two protection mechanisms. Through an individual-level protection mechanism, robots are more sceptical about others’ information and can detect and discard Byzantine information, at the cost of lower efficiency. Through a systemic protection mechanism based on economic rules regulating robot interactions, robots that sell honest information acquire over time more wealth than Byzantines selling false information. Our simulations show that a well-designed robot economy penalises misinformation spreading and protects the swarm from Byzantine behaviour. We believe economics-inspired swarm robotics is a promising research direction that exploits the timely opportunity for decentralised economies offered by blockchain technology.

The respiratory microbiome may influence the development and progression of COPD by modulating local immune and inflammatory events. We aimed to investigate whether relative changes in respiratory bacterial abundance are also associated with systemic inflammation, and explore their relationship with the main clinical COPD phenotypes. Multiplex analysis of inflammatory markers and transcript eosinophil-related markers were analyzed on peripheral blood in a cohort of stable COPD patients (n = 72). Respiratory microbiome composition was analyzed by 16S rRNA microbial sequencing on spontaneous sputum. Spearman correlations were applied to test the relationship between the microbiome composition and systemic inflammation. The concentration of the plasma IL-8 showed an inverted correlation with the relative abundance of 17 bacterial genera in the whole COPD cohort. COPD patients categorized as eosinophilic showed positive relationships with blood eosinophil markers and inversely correlated with the degree of airway obstruction and the number of exacerbations during the previous year. COPD patients categorized as frequent exacerbators were enriched with the bacterial genera Pseudomonas which, in turn, was positively associated with the severity of airflow limitation and the prior year’s exacerbation history. The associative relationships of the sputum microbiome with the severity of the disease emphasize the relevance of the interaction between the respiratory microbiota and systemic inflammation.

Abstract Previous studies have shown that associations between obesity and other comorbidities favor worse outcomes in COVID-19. However, it is not clear how these factors interrelate and whether effects on men and women differ. We conducted an observational, cross-sectional study using a national COVID-19 inpatient database. We studied differences in direct and indirect effects of obesity and comorbidities according to sex and body mass index (BMI) categories in hospitalized COVID-19 patients in Brazil using path analysis models and logistic regression. For men, path analysis showed a direct association between BMI and death and a negative correlation of death and chronic cardiovascular disease (CCD). For women, the association of BMI and death was indirect, mediated by admission to the ICU and comorbidities and association with CCD was non-significant. In the logistic regression analyses, there was a positive association between death and BMI, age, diabetes mellitus, kidney and lung diseases and ICU admission. We highlight the need to consider the distinct impact of obesity and sex on COVID-19, of monitoring of BMI and of the design for specific male-targeted approaches to manage obesity.

Abstract This work investigated a green approach to obtain and stabilize Lavandula stoechas L. volatile organic compounds with sensory aroma characteristics by using alternative solvents, namely supercritical carbon dioxide (scCO2) and deep eutectic solvents (DES). The CO2 extracts were dispersed in different DES mixtures (betaine:ethylene glycol (1:3), betaine:glycerol (1:2), and glycerol:glucose (4:1)) and their stability was monitored during 6 months of storage at room temperature by monitoring the headspace (HS) profile. The CO2 extract was used as the control. It was initially determined that there was a dominant presence of oxygenated monoterpenes (67.33–77.50%) in the extracts. During storage, significant changes occurred in the samples’ HS, such as the decrease in terpene hydrocarbons which also affected the presence of oxygenated terpenes, which increased in certain cases. Moreover, the highest formation of new components was recorded in the control which could be an indicator of decreased stability. The DESs-CO2 were more stable than the CO2 control and among them, betaine:ethylene glycol stood out as the most adequate systems for maintaining the stability of L. stoechas HS components. For the visual estimation of similarities and dissimilarities among the samples, chemometric pattern recognition approaches were applied including the hierarchical cluster analysis, principal component analysis, and sum of ranking differences.

Abstract Control of magnetization and electric polarization is attractive in relation to tailoring materials for data storage and devices such as sensors or antennae. In magnetoelectric materials, these degrees of freedom are closely coupled, allowing polarization to be controlled by a magnetic field, and magnetization by an electric field, but the magnitude of the effect remains a challenge in the case of single-phase magnetoelectrics for applications. We demonstrate that the magnetoelectric properties of the mixed-anisotropy antiferromagnet LiNi1−x Fe x PO4 are profoundly affected by partial substitution of Ni2+ ions with Fe2+ on the transition metal site. This introduces random site-dependent single-ion anisotropy energies and causes a lowering of the magnetic symmetry of the system. In turn, magnetoelectric couplings that are symmetry-forbidden in the parent compounds, LiNiPO4 and LiFePO4, are unlocked and the dominant coupling is enhanced by almost two orders of magnitude. Our results demonstrate the potential of mixed-anisotropy magnets for tuning magnetoelectric properties.

Recombinant proteins are of great importance in modern society, mostly as biopharmaceutical products. However, challenging and complex processes with low production yield are major drawbacks. Normally, the optimization to overcome these obstacles is focused on bioreactor and purification processes, and the biomolecular aspects are neglected, seen as less important. In this work, we present how the 5′ mRNA secondary structure region can be relevant for translation and, therefore, protein production. For this, Escherichia coli BL21(DE3) clones, producing recombinant detoxified pneumolysin (PdT) with and without the N-terminal His-tag, were cultivated in 10-L bioreactors. Another version of the pdt gene (version 2) with synonymous changes in the 5′-end nucleotide sequence was also obtained. Protein production, plasmid stability, carbon sources, and acetic acid were quantified during the cultures. Furthermore, in silico mRNA analyses were performed using TIsigner and RNAfold. The results showed that the His-tag presence at the N-terminus generated a minimum 1.5-fold increase in target protein synthesis, which was explained by the in silico mRNA analyses that returned an mRNA secondary structure easier to translate and, therefore, higher protein production than without the His-tag. The pdt gene version 2 showed lower 5′ mRNA opening energy than version 1, allowing higher PdT production even without a tag. This work reveals that simple mRNA analyses during heterologous gene design and production steps can help reach high-recombinant protein titers in a shorter time than using only traditional bioprocess optimization strategies.

IntroductionWater scarcity is a challenge for sesame cultivation under rainfed conditions. In this scenario, a potential strategy to alleviate the water deficit is the application of plant growth-promoting bacteria. The objective of this study was to analyze the interaction of rhizobacteria with sesame cultivation under water deficit conditions.MethodsAn experiment was conducted in pots in a greenhouse using the BRS Morena sesame cultivar. The experimental design was completely randomized in a factorial scheme: 2 (irrigation regimes - daily irrigation and water deficit by suspending irrigation until 90% stomatal closure) x 6 (treatments with nitrogen or inoculants), with 5 replications. The types of fertilization were characterized by the addition of nitrogen (ammonium sulfate; 21% N), inoculants based on Bacillus spp. (pant001, ESA 13, and ESA 402), Agrobacterium sp. (ESA 441), and without nitrogen (control). On the fifth day after the suspension of irrigation, plant material was collected for gene expression analysis (DREB1 and HDZ7), activities of antioxidant enzymes (superoxide dismutase and catalase), relative proline content, and photosynthetic pigments. At the end of the crop cycle (about 85 days), production characteristics (root dry matter, aboveground dry matter, number of capsules, and thousand seed weight), as well as leaf nitrogen (N) and phosphorus (P) content, were evaluated.Results and DiscussionThere was a positive effect on both production and biochemical characteristics (proline, superoxide dismutase, catalase, and photosynthetic pigments). Regarding gene expression, most of the inoculated treatments exhibited increased expression of the DREB1 and HDZ7 genes. These biological indicators demonstrate the potential of rhizobacteria for application in sesame cultivation, providing nutritional supply and reducing the effects of water deficit.

O objetivo desse artigo é analisar como a construção da Usina Binacional de Itaipu produziu práticas e discursos capazes de constituir lazeres desviantes. A limitação do uso do território resultou na utilização do lazer como dispositivo por diferentes agentes. A retirada do local de moradia, a sensação de perda da liberdade de acesso ao rio, a transformação da região fluvial em centro turístico e mercadológico, o desejo de aventurar-se e a satisfação pela transgressão podem ser lidos como fatores associados ao lazer desviante no território fluvial.

Introdução: Acadêmicos de Educação Física podem estar particularmente expostos a avaliações da imagem corporal e estilo de vida. Objetivo: Avaliar a imagem corporal, o nível de atividade física e o estado nutricional, verificando as associações com o sexo e período do curso, de universitários de Educação Física em uma universidade pública brasileira. Materiais e Métodos: A amostra foi constituída de 352 universitários, homens e mulheres. A insatisfação e a percepção da imagem corporal foram avaliadas com a Escala de Silhuetas de Kakeshita e colaboradores (2009). O nível de atividade física foi avaliado com o Questionário Internacional de Atividade Física (IPAQ-C). O estado nutricional foi avaliado através do índice de massa corporal, razão cintura/quadril (RCQ) e razão cintura estatura (RCE). Foram realizadas análises descritivas, com média (±dp) e frequências. Diferenças entre os grupos (sexo e faixas de semestres) foram testadas por meio do teste de qui-quadrado, com nível de significância de 5%. Resultados: A idade média dos universitários foi de 23,6(±6,2), 92,3% foram considerados ativos/muito ativos, 44,2% e 77,6% apresentaram valores adequados de RCQ e RCE, respectivamente. Sobre a imagem corporal, 23,2% se apresentam como satisfeitos, 47,5% desejam reduzir sua silhueta e 29,5% desejam aumentar sua silhueta. Para a percepção corporal, 17,8% percebem-se como são, enquanto 47,9% percebem-se menores e 34,3% percebem-se maiores do que realmente são. Há um maior desejo de reduzir a silhueta entre as mulheres. Conclusão: Os universitários apresentaram níveis adequados de atividade física. Há um elevado número de universitários insatisfeitos com a imagem corporal, principalmente entre as mulheres.

Objetivo: Construir y validar un escenario de simulación clínica destinado a enseñar la gestión de conflictos a estudiantes universitarios de enfermería. Método: Estudio metodológico en el que se construyó un escenario de gestión de conflictos en la ciudad de São Paulo, SP, Brasil, en 2022, a partir de la revisión bibliográfica y de la experiencia pedagógica de los investigadores. La validación del contenido se llevó a cabo con jueces sobre el terreno mediante la técnica Delphi. Los datos se analizaron con un Índice de Validez del Contenido (IVC>80%). Resultados: el escenario describe la escena de un practicante de enfermería que pide al técnico de enfermería que bañe a un paciente en la cama. Esto está impregnado de conflictos interpersonales. En la validación del contenido participaron ocho expertos en simulación clínica y dos estudiantes de enfermería. Hubo tres rondas, alcanzando el IVC al 100%. Conclusión: el escenario fue validado y contribuirá a la enseñanza práctica de esta habilidad en los cursos de licenciatura.

Objective: Develop and validate a clinical simulation scenario for undergrad nursing students to learn conflict management. Method: Methodological study in which a conflict management scenario was constructed in the city of São Paulo, SP, Brazil, in 2022, based on the literature review and the pedagogical experience of the researchers. Content validation was carried out with judges in the field using the Delphi technique. The data was analyzed with a Content Validity Index (CVI>80%). Results: The scenario describes the scene of a nursing trainee asking the nursing technician to bathe a patient in bed. This is permeated by interpersonal conflicts. The content validation involved eight experts in clinical simulation and two nursing students. There were three "rounds," reaching IVC 100%. Conclusion: The scenario was validated and will contribute to the practical teaching of this skill in undergraduate courses.

Objetivo: construir e validar um cenário de simulação clínica voltado para o ensino do gerenciamento de conflitos para estudantes de graduação em enfermagem. Método: estudo metodológico no qual construiu-se um cenário de gerenciamento de conflitos, na cidade de São Paulo, SP, Brasil, em 2022, a partir da revisão de literatura e da experiência pedagógica dos pesquisadores. Realizou-se validação de conteúdo com juízes da área por meio da técnica Delphi. Os dados foram analisados com Índice de Validade de Conteúdo (IVC>80%). Resultados: o cenário descreve a cena de um estagiário de enfermagem que solicita ao técnico de enfermagem realizar um banho no leito de um paciente. Tal fato é permeado por conflitos interpessoais. A validação de conteúdo contou com oito experts em simulação clínica e dois estudantes de enfermagem. Houve três “rounds”, chegando ao IVC 100%. Conclusão: o cenário construído foi validado e contribuirá para o ensino prático desta competência na graduação.