Molecular mimicry in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases

Retrospective financial analysis of the mercury and air toxics standards compliance costs

This honors thesis studied the impacts of an Obama-era air regulation from the Environmental Protection Agency. This 2012 rule, the Mercury and Air Toxics Standards (MATS), regulates electric generators with coal- and oil-fired power plants. When the rule was put forward, it was the most expensive EPA rule of its time. Industry was concerned that the rule would be prohibitively expensive and negatively impact the ability of electric generators to stay in business while supplying reliable and affordable electricity. MATS is currently in effect, and all relevant generation is fully in compliance with the regulation. This research aimed to understand the actual impacts of the regulation on industry to gauge whether the regulation had the negative impacts industry predicted. This research employed retrospective analysis of financial disclosures from before, during, and after MATS in order to understand impacts to industry and how they changed over the course of the regulation. Though MATS-specific data was largely unavailable for the study group, this research found that the regulation was likely less worrisome and financially detrimental to utilities than industry had anticipated

Receipt of COVID-19 emergency funds and engagement in sex work during COVID-19 among people who use drugs: evidence from Vancouver, Canada

Abstract Background During the early period of the COVID-19 pandemic, public health orders disrupted income generation in numerous sectors and many governments provided emergency financial support. Access to government support and changes in engagement in sex work during the early period of the pandemic among people who use drugs (PWUD) are not well described. In the present study, we investigate the prevalence and correlates of engaging in sex work during the COVID-19 pandemic, among PWUD in Vancouver, Canada. Methods Data derived from three harmonized cohorts of PWUD. Using multivariable logistic regression, we characterized factors associated with engaging in sex work in the last month between July 17 and November 30, 2020. Reports of changes in frequency of engagement in sex work since the pandemic were also collected. Results Of the 864 individuals included in this analysis, 55 (6.4%) reported sex work engagement in the last month. Among these participants, 40.7% reported receiving COVID-19 income support in the past month vs. 52.7% of the rest of the sample, though receipt of income support in the past six months was similar between the two groups (72.2% vs. 75.7%, p = 0.624). In multivariable analysis, receipt of financial support in the last month was negatively associated with engagement in sex work in the last month (adjusted odds ratio [AOR] = 0.44 [95% confidence interval [CI]: 0.24–0.81]). Among 69 participants who responded to a question regarding changes in engagement in sex work, 38 (55.1%) reported a decrease, 11 (15.9%) reported an increase, 19 (27.5%) reported no change, and 1 (1.4%) reported cessation. Conclusions Findings document that engagement in sex work appears to have declined early in the pandemic. Participants who received income support in the past month were less likely to report recent engagement in sex work. Findings suggest that recent receipt of income support may have contributed to reductions in engagement in sex work. Additional investigation is warranted

The generative potential of mess in community-based participatory research with young people who use(d) drugs in Vancouver

Abstract Community-based participatory research (CBPR) is increasingly standard practice for critical qualitative health research with young people who use(d) drugs in Vancouver, Canada. One aim of CBPR in this context is to redress the essentialization, erasure, and exploitation of people who use(d) drugs in health research. In this paper, we reflect on a partnership that began in 2018 between three university researchers and roughly ten young people (ages 17–28) who have current or past experience with drug use and homelessness in Greater Vancouver. We focus on moments when our guiding principles of shared leadership, safety, and inclusion became fraught in practice, forcing us in some cases to re-imagine these principles, and in others to accept that certain ethical dilemmas in research can never be fully resolved. We argue that this messiness can be traced to the complex and diverse positionalities of each person on our team, including young people. As such, creating space for mess was ethically necessary and empirically valuable for our CBPR project.Medicine, Faculty ofOther UBCNon UBCMedicine, Department ofReviewedFacultyResearche

Extrathymic Aire-expressing cells support maternal-fetal tolerance

Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire +) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire + cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR

Harm reduction calls to action from young people who use drugs on the streets of Vancouver and Lisbon.

Vancouver, Canada, and Lisbon, Portugal, are both celebrated for their world-leading harm reduction policies and programs and regarded as models for other cities contending with the effects of increasing levels of drug use in the context of growing urban poverty. However, we challenge the notion that internationally celebrated places like Lisbon and Vancouver are meeting the harm reduction needs of young people who use drugs (YPWUD; referring here to individuals between the ages of 14 and 29). In particular, the needs of YPWUD in the context of unstable housing, homelessness, and ongoing poverty-a context which we summarize here as "street involvement"-are not being adequately met. We are a group of community and academic researchers and activists working in Vancouver, Lisbon, and Pittsburgh. Most of us identify as YPWUD and have lived and living experience with the issues described in this comment. We make several calls to action to support the harm reduction needs of YPWUD in the context of street involvement in and beyond our settings

Harm reduction calls to action from young people who use drugs on the streets of Vancouver and Lisbon

Vancouver, Canada, and Lisbon, Portugal, are both celebrated for their world-leading harm reduction policies and programs and regarded as models for other cities contending with the effects of increasing levels of drug use in the context of growing urban poverty. However, we challenge the notion that internationally celebrated places like Lisbon and Vancouver are meeting the harm reduction needs of young people who use drugs (YPWUD; referring here to individuals between the ages of 14 and 29). In particular, the needs of YPWUD in the context of unstable housing, homelessness, and ongoing poverty—a context which we summarize here as “street involvement”—are not being adequately met. We are a group of community and academic researchers and activists working in Vancouver, Lisbon, and Pittsburgh. Most of us identify as YPWUD and have lived and living experience with the issues described in this comment. We make several calls to action to support the harm reduction needs of YPWUD in the context of street involvement in and beyond our settings.Medicine, Faculty ofNon UBCMedicine, Department ofReviewedFacultyResearcherOthe

Validation of a murine proteome-wide phage display library for identification of autoantibody specificities

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling