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Although intravenous immunoglobulin (IVIG) is highly effective in Kawasaki disease (KD), mechanisms are not understood and 10-20% of patients are treatment-resistant, manifesting a higher rate of coronary artery aneurysms. Murine models suggest that α2-6-linked sialic acid (α2-6Sia) content of IVIG is critical for suppressing inflammation. However, pro-inflammatory states also up-regulate endogenous levels of β-galactoside:α2-6 sialyltransferase-I (ST6Gal-I), the enzyme that catalyzes addition of α2-6Sias to N-glycans. We asked whether IVIG failures correlated with levels of α2-6Sia on infused IVIG or on the patient's own endogenous IgG.We quantified levels of α2-6Sia in infused IVIG and endogenous IgG from 10 IVIG-responsive and 10 resistant KD subjects using multiple approaches. Transcript levels of ST6GAL1, in patient whole blood and B cell lines were evaluated by RT-PCR. Plasma soluble (s)ST6Gal-I levels were measured by ELISA.There was no consistent difference in median sialylation levels of infused IVIG between groups. However, α2-6Sia levels in endogenous IgG, ST6GAL1 transcript levels, and ST6Gal-I protein in serum from IVIG-resistant KD subjects were lower than in responsive subjects at both pre-treatment and one-year time points (p

Recent outbreaks of Rift Valley fever in ruminant livestock, characterized by mass abortion and high mortality rates in neonates, have raised international interest in improving vaccine control strategies. Previously, we developed a reliable challenge model for sheep that improves the evaluation of existing and novel vaccines in sheep. This sheep model demonstrated differences in the pathogenesis of Rift Valley fever virus (RVFV) infection between two genetically-distinct wild-type strains of the virus, Saudi Arabia 2001 (SA01) and Kenya 2006 (Ken06). Here, we evaluated the pathogenicity of these two RVFV strains in mixed breed beef calves. There was a transient increase in rectal temperatures with both virus strains, but this clinical sign was less consistent than previously reported with sheep. Three of the five Ken06-infected animals had an early-onset viremia, one day post-infection (dpi), with viremia lasting at least three days. The same number of SA01-infected animals developed viremia at 2 dpi, but it only persisted through 3 dpi in one animal. The average virus titer for the SA01-infected calves was 1.6 logs less than for the Ken06-infected calves. Calves, inoculated with either strain, seroconverted by 5 dpi and showed time-dependent increases in their virus-neutralizing antibody titers. Consistent with the results obtained in the previous sheep study, elevated liver enzyme levels, more severe liver pathology and higher virus titers occurred with the Ken06 strain as compared to the SA01 strain. These results demonstrate the establishment of a virulent challenge model for vaccine evaluation in calves.

In the present study, we used a mouse model of chronic intermittent ethanol (CIE) exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC). In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs) in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC. Consistent with this, Western blot analysis of the postsynaptic density fraction showed that while there was no change in expression of the AMPA GluR1 subunit, NMDA NR1 and NRB subunits were significantly increased in CIE exposed mice when examined immediately after the last episode of alcohol exposure. Unexpectedly, this increase in NR1 and NR2B was no longer observed after 1-week of withdrawal in spite of a persistent increase in synaptic NMDA currents. Analysis of spines on the basal dendrites of layer V neurons revealed that while the total density of spines was not altered, there was a selective increase in the density of mushroom-type spines following CIE exposure. Examination of NMDA-receptor mediated spike-timing-dependent plasticity (STDP) showed that CIE exposure was associated with altered expression of long-term potentiation (LTP). Lastly, behavioral studies using an attentional set-shifting task that depends upon the mPFC for optimal performance revealed deficits in cognitive flexibility in CIE exposed mice when tested up to 1-week after the last episode of alcohol exposure. Taken together, these observations are consistent with those in human alcoholics showing protracted deficits in executive function, and suggest these deficits may be associated with alterations in synaptic plasticity in the mPFC.

There is an emergent body of scholarship about the specific ways in which Black women lead within the context of education. In the United States, women comprise three-quarters of the educational workforce. Yet, roughly four in five senior-level leaders in education are male. Although developments continue to be made, only very recently has significant advancement been made in what remains a historically male-dominated space. Black women represent the most educated group in today's workforce; yet, they represent a small fraction of leaders who ascend above the ranks of mid-level management. In response to this, we were compelled to add to the existing research in this sphere. Our paper incorporates social justice leadership theory as a frame for the study of Black women in the context of educational leadership. Employing a hermeneutic phenomenology, we interviewed four Black women in educational leadership to examine the intersecting factors (i.e. race and gender) that impact these women's ability to lead. Using in-depth, timed, semi-structured interviews, contributors reflected upon their unique experiences and perceptions as non-archetypal leaders. Participants' recounted stories of resilience, community, struggle, and perseverance revealed the need for more US-based research specific to the intricate leadership journeys of Black women in education.

Synthesizing the contributions in this issue, the authors with expertise as tenured faculty and student and academic affairs administrators offer radical, yet timely implications for practice intended to contribute to the emancipation of Black women at all levels in higher education. In so doing, these authors (re)imagine an academy that responds more judiciously to the material needs of Black women moving into the next twenty years.

Ecology and environmental (EE) biology has low representation of Black Indigenous and People of Color (BIPOC). Degree completion and career placement in EE often fail due to poor consideration of the intersections among student lived experiences and the academic support, peer community support, mentoring, and leadership development that they receive. The demographic composition of these disciplines, which are situated within the geosciences, differs from the composition of the broader society and will continue to do so until biases associated with the dominant culture are remedied. Lack of diverse representation leaves young people of color unable to visualize themselves in EE careers, which contributes to their not pursuing EE programs, majors, and career placement. As Black ecologists, we share narratives that include lessons gained from our individual journeys through undergraduate, graduate, and postdoctoral positions emphasizing experiences that supported our successful recruitment into our current academic positions. Throughout, we emphasize intersections of identity and persistence in EE. We assert that colorblind interventions to promote diverse participation in EE will be inadequate to affect meaningful increases in BIPOC participation. We highlight the value of diverse mentors, institutional support, and institutional commitment to diversity across multiple institutions. Additionally, we offer recommendations in support of BIPOC student retention in EE and the geosciences. Increasing diversity in EE will involve reassessment of how ecologists and environmental biologists are defined, interventions that support BIPOC retention at all career stages, and critical assessment of cultural biases in EE education and field experiences.

Using the state of Georgia as a backdrop, this paper highlights the current state of the GFSA (Gun-Free Schools Act) in the United States of America, initially enacted in 1994, 30 years later. The progress of school-based ZTPs (Zero Tolerance Policies) in practice shows that progress remains slow a quarter of a century later. In response, this paper looks at the origins of school-level ZTPs, the intended and unintended consequences and identifies strategies for making substantial progress moving forward. Using Georgia law and the Fulton County school system as drivers toward change, this paper looks at State, County, and Regional-level implementation of School-based ZTPs, in alignment with the GA legal standard, to add to the existing knowledge base in this realm. By pointing to what has and has not been working, this paper seeks to bring efficacious strategies for improvement to the forefront (i.e., increasing the use of positive, collaborative behavior interventions and supports, using aggregate data to reduce the number of disciplinary actions that force students out of the classroom, creating reasonable limits on the use of law enforcement in public schools) to allow all students to learn in environments that are safe, non-punitive, and impartial.

The authors of this article represent an interdisciplinary team that includes a literacy teacher educator, a high school economics teacher, a community-based math educator, and a math teacher educator. Responding to the needs and building from the strengths of the local community, we co-designed with youth a community-based FLE workshop that centered community cultural wealth. This framing helped us highlight for the youth, their families, and other community members that wealth includes non-material forms of capital, particularly for communities that have been historically underserved or under-resourced within financial and economic systems.

Adolescence is a dynamic and important period of brain development however, little is known about the long-term neurobiological consequences of alcohol consumption during puberty. Our previous studies showed that binge-pattern ethanol (EtOH) treatment during pubertal development negatively dysregulated the responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis, as manifested by alterations in corticotrophin-releasing hormone (CRH), arginine vasopressin (AVP), and corticosterone (CORT) during this time period. Thus, the primary goal of this study was to determine whether these observed changes in important central regulators of the stress response were permanent or transient. In this study, juvenile male Wistar rats were treated with a binge-pattern EtOH treatment paradigm or saline alone for 8 days. The animals were left undisturbed until adulthood when they received a second round of treatments consisting of saline alone, a single dose of EtOH, or a second binge-pattern treatment paradigm. The results showed that pubertal binge-pattern EtOH exposure induced striking long-lasting alterations of many HPA axis parameters. Overall, our data provide strong evidence that binge-pattern EtOH exposure during pubertal maturation has long-term detrimental effects for the healthy development of the HPA axis.

EtOH exposure in male rats increases corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus (PVN), a brain region responsible for coordinating stress and anxiety responses. In this study we identified the molecular mechanisms involved in mediating these effects by examining the direct effects of EtOH on CRH promoter activity in a neuronal cell line derived from the PVN (IVB). In addition, we investigated the potential interactions of EtOH and glucocorticoids on the CRH promoter by concomitantly treating cells with EtOH and the glucocorticoid receptor (GR) antagonist RU486, and by sequentially deleting GR binding sites within glucocorticoid response element (GRE) on the CRH promoter. Cells were transiently transfected with a firefly luciferase reporter construct containing 2.5 kb of the rat wild type (WT) or mutated CRH promoter. Our results showed that EtOH treatment induced a biphasic response in CRH promoter activity. EtOH exposure for 0.5 h significantly decreased promoter activity compared to vehicle treated controls, whereas promoter activity was significantly increased after 2.0 h of EtOH exposure. Treatment with RU486, or deletion of the GR binding sites 1 and 2 within the GRE, abolished the EtOH-induced increase in the promoter activity, however did not affect EtOH-induced decrease in CRH promoter activity at an earlier time point. Overall, our data suggest that alcohol exposure directly regulates CRH promoter activity by interfering with the normal feedback mechanisms of glucocorticoids mediated by GR signaling at the GRE site of the CRH promoter.

Fibroblast growth factors (FGFs) mediate a vast range of CNS developmental processes including neural induction, proliferation, migration, and cell survival. Despite the critical role of FGF signaling for normal CNS development, few reports describe the mechanisms that regulate FGF receptor gene expression in the brain. We tested whether FGF8 could autoregulate two of its cognate receptors, Fgfr1 and Fgfr3, in three murine cell lines with different lineages: fibroblast-derived cells (3T3 cells), neuronal cells derived from hippocampus (HT-22 cells), and neuroendocrine cells derived from hypothalamic gonadotropin-releasing hormone (GnRH) neurons (GT1-7 cells). GnRH is produced by neurons in the hypothalamus and is absolutely required for reproductive competence in vertebrate animals. Several lines of evidence strongly suggest that Fgf8 is critical for normal development of the GnRH system, therefore, the GT1-7 cells provided us with an additional endpoint, Gnrh gene expression and promoter activity, to assess potential downstream consequences of FGF8-induced modulation of FGF receptor levels. Results from this study suggest that the autoregulation of its cognate receptor represents a common downstream effect of FGF8. Further, we show that Fgfr1 and Fgfr3 are differentially regulated within the same cell type, implicating these two receptors in different biological roles. Moreover, Fgfr1 and Fgfr3 are differentially regulated among different cell types, suggesting such autoregulation occurs in a cell type-specific fashion. Lastly, we demonstrate that FGF8b decreases Gnrh promoter activity and gene expression, possibly reflecting a downstream consequence of altered FGF receptor populations. Together, our data bring forth the possibility that, in addition to the FGF synexpression group, autoregulation of FGFR expression by FGF8 represents a mechanism by which FGF8 could fine-tune its regulatory actions.

PurposeFertility preservation (FP) services are part of comprehensive care for those newly diagnosed with cancer. The capacity to offer these services to children and adolescents with cancer is unknown.MethodsA cross-sectional survey was sent to 220 Children's Oncology Group member institutions regarding institutional characteristics, structure and organization of FP services, and barriers to FP. Standard descriptive statistics were computed for all variables. The association between site-specific factors and selected outcomes was examined using multivariable logistic regression.ResultsOne hundred forty-four programs (65.5%) returned surveys. Fifty-three (36.8%) reported a designated FP individual or team. Sperm banking was offered at 135 (97.8%) institutions, and testicular tissue cryopreservation at 37 (27.0%). Oocyte and embryo cryopreservation were offered at 91 (67.9%) and 62 (46.6%) institutions, respectively; ovarian tissue cryopreservation was offered at 64 (47.8%) institutions. The presence of dedicated FP personnel was independently associated with the ability to offer oocyte or embryo cryopreservation (odds ratio [OR], 4.7; 95% CI, 1.7 to 13.5), ovarian tissue cryopreservation (OR, 2.7; 95% CI, 1.2 to 6.0), and testicular tissue cryopreservation (OR, 3.3; 95% CI, 1.4 to 97.8). Only 26 (18.1%) participating institutions offered all current nonexperimental FP interventions. Barriers included cost (70.9%), inadequate knowledge or training (60.7%), difficulty characterizing fertility risk (50.4%), inadequate staffing (45.5%), and logistics with reproductive specialties (38%-39%).ConclusionThis study provides the most comprehensive view of the current landscape of FP infrastructure for children and adolescents with cancer and demonstrates that existing infrastructure is inadequate to offer comprehensive services to patients. We discuss modifiable factors to improve patient access to FP.

ObjectiveWe sought to characterize the performance of inpatient and outpatient computerized clinical decision support (CDS) alerts aimed at reducing inappropriate benzodiazepine and nonbenzodiazepine sedative medication prescribing in older adults 18 months after implementation.MethodsWe reviewed the performance of two CDS alerts in the outpatient and inpatient settings in 2019. To examine the alerts' effectiveness, we analyzed metrics including overall alert adherence, provider-level adherence, and reasons for alert trigger and override.ResultsIn 2019, we identified a total of 14,534 and 4,834 alerts triggered in the outpatient and inpatient settings, respectively. Providers followed only 1% of outpatient and 3% of inpatient alerts. Most alerts were ignored (68% outpatient and 60% inpatient), while providers selected to override the remaining alerts. In each setting, the top 2% of clinicians were responsible for approximately 25% of all ignored or overridden alerts. However, a small proportion of clinicians (2% outpatient and 4% inpatient) followed the alert at least half of the time and accounted for a disproportionally large fraction of the total followed alerts. Our analysis of the free-text comments revealed that many alerts were to continue outpatient prescriptions or for situational anxiety.ConclusionOur findings highlight the importance of evaluation of CDS performance after implementation. We found large variation in response to the inpatient and outpatient alerts, both with respect to follow and ignore rates. Reevaluating the alert design by providing decision support by indication may be more helpful and may reduce alert fatigue.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

Inspired by Black and Chicana feminists who came before us and are leading our paths, we critically examine how to build solidarity among womyn of color faculty, support each other's political projects by uplifting critical raced-gendered epistemologies, and disrupt white supremacy that seeps into the everyday experiences in academia via neoliberal logics at predominantly white research-extensive universities. Through plática methodology, we demonstrate the importance of critical reflexivity, responsibility-taking, and our labor as womyn of color in academe; our complicity in protecting whiteness and patriarchy; and cultivating resistance through solidarity building as an active and on-going process.

This paper is a collation of the experiences of four Black women, all senior-level educational leaders in the United States of America. Considering the predominance of White males in educational leadership, our paper furthers the conversation around race-gender diversification in this realm. We employed a hermeneutic phenomenological approach, focusing on the intersections of race and gender, in the effort to challenge epistemological incongruencies within this context. Using in-depth, timed, semi-structured interviews, participants reflected on their journeys, experiences, and perceptions as non-archetypal leaders in education. In highlighting contributors' perspectives,our objective was to bring the matter of race-gender underrepresentation in educational leadership to the forefront. Study participants revealed the importance of visibility, education, collaboration, exposure, mentorship, pursuit, authenticity, and living one's truth in the move towards diversifying the educational leadership sphere. Participants' recollections underscore the need for more research specific to the journeys of non-typical educational leaders in the United States.

This article focuses on equitable leadership and its intersection with related yet distinct concepts salient to social justice pertinent to women and minorities in educational leadership. This piece is rooted and framed within the context of the United States of America, and the major concepts include identity, equity, and intersectionality--specific to the race-gender dyad--manifested within the realm of educational leadership. The objective is to examine theory and research in this area and to discuss the role they played in this study of the cultures of four Black women, all senior-level leaders within the realm of K-20 education in the United States. This work employed the tenets of hermeneutic phenomenology, focusing on the intersecting factors--race and gender, specifically--that impact these women's ability and capability to perform within the educational sector. The utilization of in-depth, timed, semi-structured interviews allowed participants to reflect upon their experiences and perceptions as Black women who have navigated and continue to successfully navigate the highest levels of the educational leadership sphere. Contributors' recounted stories of navigation within spaces in which they are underrepresented revealed the need for more research specific to the intricacies of Black women's leadership journeys in the context of the United States.

Many scholars call for teacher educators to provide experiences that can lead prospective teachers to adopt and implement culturally responsive pedagogy in mathematics classrooms. This qualitative investigation analyzed interviews from preservice secondary mathematics teachers using Hernandez, Shroyer, and Morales framework for culturally responsive mathematics teaching. Analysis of the data demonstrates how preservice teachers grapple with enacting a culturally responsive framework at practicum sites. Findings reveal that while some participants reported comfort implementing some aspects of culturally responsive practices at placement sites, others reported apprehension. The data suggests strategies for teacher educators interested in supporting culturally responsive teacher-learners through professional modeling.

This article is from a talk that was given on April 16, 2021, as the author's contribution for the anti-racism panel "Undoing BIPOC Erasure in the Academy: A Conversation about Race and Anti-Racism." The panel was hosted by the University of California Merced. Minor edits for print and publication have been made to the article for publication. The author discusses how the focus on Diversity, Equity, and Inclusion (DEI) programs and initiatives and inclusion work in the academy is not focused on resistance at all. The focus is always on complicity. As a black associate professor, she addresses how one works within a system, with the expectation of complicity, to change and resist the very system where one works.