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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia. METHODS: The vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed. RESULTS: The VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy. DISCUSSION: Our findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics.

Self-conscious emotions arise from evaluating the self through the eyes of others. Given that children with autistic traits may experience difficulties with understanding others' minds, they might show less attuned self-conscious emotions. Two-to-five-year-old children's (N = 98, M[subscript age] = 48.54 months, 50% girls, 92% White) self-conscious emotions (guilt, embarrassment, and shame-like avoidance) were observed after children "broke" the experimenter's favorite toy. Data were collected from March 2018 till June 2019. Children with more autistic traits showed less theory of mind (ToM), and more shame-like avoidance, but associations were not mediated by ToM. This provides initial evidence that children with more autistic traits may show disturbances in some but not all self-conscious emotions, which could hinder their social functioning.

Port-wine birthmarks (PWBs) are caused by somatic, mosaic mutations in the G protein guanine nucleotide binding protein alpha subunit q (GNAQ) and are characterized by the formation of dilated, dysfunctional blood vessels in the dermis, eyes, and/or brain. Cutaneous PWBs can be treated by current dermatologic therapy, like laser intervention, to lighten the lesions and diminish nodules that occur in the lesion. Involvement of the eyes and/or brain can result in serious complications and this variation is termed Sturge-Weber syndrome (SWS). Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models.

Situational Judgement Tests (SJTs) are increasingly implemented in medical school admissions. In this paper, we investigate the effects of vocational interests, previous academic experience, gender and age on SJT performance. The SJT was part of the selection process for the Bachelor's degree programme in Medicine at University of Groningen, the Netherlands. All applicants for the academic year 2015-2016 were included and had to choose between learning communities "Global Health" (n = 126), "Sustainable Care" (n = 149), "Intramural Care" (n = 225), or "Molecular Medicine" (n = 116). This choice was used as a proxy for vocational interest. In addition, all graduate-entry applicants for academic year 2015-2016 (n = 213) were included to examine the effect of previous academic experience on performance. We used MANCOVA analyses with Bonferroni post hoc multiple comparisons tests for applicant performance on a six-scenario SJT. The MANCOVA analyses showed that for all scenarios, the independent variables were significantly related to performance (Pillai's Trace: 0.02-0.47, p < 0.01). Vocational interest was related to performance on three scenarios (p < 0.01). Graduate-entry applicants outperformed all other groups on three scenarios (p < 0.01) and at least one other group on the other three scenarios (p < 0.01). Female applicants outperformed male applicants on three scenarios (p < 0.01) and age was positively related to performance on two scenarios (p < 0.05). A good fit between applicants' vocational interests and SJT scenario was related to better performance, as was previous academic experience. Gender and age were related to performance on SJT scenarios in different settings. Especially the first effect might be helpful in selecting appropriate candidates for areas of health care in which more professionals are needed.

Many different medical school selection processes are used worldwide. In this paper, we examine the effect of (1) participation, and (2) selection in a voluntary selection process on study performance. We included data from two cohorts of medical students admitted to Erasmus MC, Rotterdam and VUmc, Amsterdam, The Netherlands and compared them to previously published data from Groningen medical school, The Netherlands. All included students were admitted based on either (1) a top pre-university grade point average, or (2) a voluntary selection process, or (3) weighted lottery. We distinguished between lottery-admitted students who had participated in the voluntary selection process and had been rejected, and lottery-admitted students who had not participated. Knowledge test scores, study progress, and professionalism scores were examined using ANCOVA modelling, logistic regression, and Bonferroni post hoc multiple-comparison tests, controlling for gender and cohort. For written test grades, results showed a participation effect at Groningen medical school and Erasmus MC (p < 0.001), and a selection effect at VUmc (p < 0.05). For obtained course credits, results showed a participation effect at all universities (p < 0.01) and a selection effect at Groningen medical school (p < 0.005). At Groningen medical school, a participation effect seemed apparent in on time first-year completion (p < 0.05). Earlier reported selection and participation effects in professionalism scores at Groningen medical school were not apparent at VUmc. Top pre-university students performed well on all outcome measures. For both the participation effect and the selection effect, results differed between universities. Institutional differences in curricula and in the design of the selection process seem to mediate relations between the different admissions processes and performance. Further research is needed for a deeper understanding of the influence of institutional differences on selection outcomes.

Beyond the Last Utopia. About the historiography of human rights Human rights is a highly contested concept in both current public debates and recent historiography. In this review essay the historiographical debate about human rights, in particular invoked by Samuel Moyn’s Last Utopia (2010), is analysed by discussing three recent monographs: Mark Bradley’s The World Reimagined (2016), Steven L.B. Jensen’s The Making of International Human Rights (2016), and Marco Duranti’s The Conservative Human Rights Revolution (2017). Although these books offer valuable insights into the much- debated ‘global breakthrough’ and chronology of human rights, their main contribution has to be located elsewhere: in ‘provincializing’ the foreign policy of the United States (Bradley), in pointing to unknown but influential actors and issues in the history of the United Nations (Jensen), and in providing a new perspective on the early days of European integration (Duranti). Based on this analysis, it is argued that human rights and their chronology should no longer be considered as a historiographical field in isolation, but that human rights must be investigated as part of broader political ideologies and practices, as a tool of marginalized countries and groups, and as a concept that enables historians better to understand relations between developments at the local and translocal level, and domestic and foreign policies. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm. Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels. Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone − and thus rhythm in BAT function − resulted in adiposity. This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health. • Flattening of corticosterone rhythm blunts circadian activity of brown adipose tissue. • Disturbed corticosterone rhythm − rather than overexposure − is responsible for blunted brown adipose tissue activity. • The metabolic effect of flattened corticosterone levels is independent of adipocyte glucocorticoid receptor expression. • Long-term flattening of corticosterone levels results in increased adiposity in a female mouse model for metabolic syndrome. [ABSTRACT FROM AUTHOR]