Publications

The high transmissibility of SARS-CoV-2 Omicron subvariants was generally ascribed to immune escape. It remained unclear whether the emerging variants have gradually acquired replicative fitness in human respiratory epithelial cells. We sought to evaluate the replicative fitness of BA.5 and earlier variants in physiologically active respiratory organoids. BA.5 exhibited a dramatically increased replicative capacity and infectivity than B.1.1.529 and an ancestral strain wildtype (WT) in human nasal and airway organoids. BA.5 spike pseudovirus showed a significantly higher entry efficiency than that carrying WT or B.1.1.529 spike. Notably, we observed prominent syncytium formation in BA.5-infected nasal and airway organoids, albeit elusive in WT- and B.1.1.529-infected organoids. BA.5 spike-triggered syncytium formation was verified by lentiviral overexpression of spike in nasal organoids. Moreover, BA.5 replicated modestly in alveolar organoids, with a significantly lower titer than B.1.1.529 and WT. Collectively, the higher entry efficiency and fusogenic activity of BA.5 spike potentiated viral spread through syncytium formation in the human airway epithelium, leading to enhanced replicative fitness and immune evasion, whereas the attenuated replicative capacity of BA.5 in the alveolar organoids may account for its benign clinical manifestation.

Objetivo: analisar as evidências de validade do Burnout Assessment Tool (BAT) – Versão geral em uma amostra de trabalhadores de enfermagem brasileiros. Método: estudo transversal com amostragem não probabilística, realizado entre 3594 trabalhadores de enfermagem brasileiros. A validade do instrumento foi testada por meio da análise baseada na estrutura interna, nas relações com variáveis externas e no processo de resposta aos itens. Resultados: os modelos fatoriais do BAT – Versão geral mostraram adequado ajustamento aos dados. Entretanto, o modelo fatorial completo permitiu uma melhor compreensão da síndrome de burnout na amostra. Foi atestado que os fatores do BAT – Versão geral apresentaram correlações positivas com sintomas de depressão, ansiedade e estresse e negativas com a satisfação no trabalho e a satisfação geral com a vida. A análise das evidências de validade baseadas no processo de resposta aos itens revelou que o BAT – Versão geral funcionou adequadamente tanto no grupo de trabalhadores de enfermagem que relataram ter problemas emocionais ou psicológicos de saúde quanto no grupo de trabalhadores que negaram estes problemas. Conclusão: os resultados forneceram evidências robustas de validade do BAT – Versão geral em trabalhadores de enfermagem brasileiros.

Additional file 13. Table S12

<p>Correlation interactions and dysfunction score CD8+ T cells</p>

Abstract Background Despite major advances in the development of targeted therapies, precision (immuno)oncology approaches for patients with colorectal cancer continue to lag behind other solid cancers. Functional precision oncology – a strategy that is based on perturbing primary tumor cells from cancer patients with drugs – could provide an alternate road forward to personalize treatment. Methods We extend here the functional precision oncology paradigm to measuring phosphoproteome landscapes using patient-derived organoids (PDOs). We first employed steady-state multi-omics (exome sequencing, RNA sequencing, and proteomics) and single-cell characterization of the PDOs. The PDOs were then perturbed with kinase inhibitors (MEKi, PI3Ki, mTORi, TBKi, BRAFi, and TAKi), and large-scale phosphoproteomics profiling using data-independent acquisition was carried out. Further, we used imaging mass-cytometry-based single-cell proteomic profiling of the primary tumors to characterize cellular composition of the tumor-microenvironment (TME) and to quantify heterocellular signaling crosstalk. Results We show that kinase inhibitors induce profound off-target effects resulting in a crosstalk with oncogenic and immune-related pathways. Reconstruction of the topologies of the kinase networks revealed that the patient-specific rewiring of the central EGFR-RAS-MAPK network is unaffected by mutations. Moreover, we show non-genetic heterogeneity of the PDOs and patient- and inhibitor-specific upregulation of stemness and differentiation genes by kinase inhibitors. We complemented our functional profiling by spatial proteomics profiling of the primary tumors using imaging mass cytometry. We quantify spatial heterocellular crosstalk and tumor-immune cell interactions, showing an avoidance of PD1+ immune cells and PD-L1+ tumor cells. Conclusions Collectively, we provide a multi-modal framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno)-oncology in colorectal cancer.

The central aim of the present study among 572 Dutch employees was to examine whether burnout and its positive antipode—work engagement—could be differentiated on the basis of personality and temperament. We expected burnout to be characterized by high neuroticism and low extraversion, and engagement by low neuroticism and high extraversion. Additionally, we predicted that burnout would correlate negatively with the temperament traits (strength of excitation, strength of inhibition, and mobility), whereas work engagement would correlate positively. Discriminant analyses were used to distinguish burned-out and engaged employees from their non-burned-out and non-engaged counterparts, respectively. Results showed that high neuroticism is the core characteristic of burnout, whereas work engagement is characterized by low neuroticism in combination with high extraversion and high levels of mobility. Thus, personality and temperament make a difference as far as burnout and work engagement are concerned.

No abstract is provided for this article.