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Recent reports indicate the national principal attrition rate is at an all-time high. Scholars suggest a lack of responsive professional development as a leading factor in why principals leave the field. Further, the pandemic has exposed daily uncertainties for school leaders as they navigate new territory, bringing forth new considerations in how to best support their immediate needs and continued growth. While research shows that other fields, like healthcare and law enforcement, have utilized live and digital simulations for practitioners in technical skill development and responsive training, educational leadership has predominantly utilized passive simulation practice, like in-basket activities or role-playing during preparation programs. This article explores the current research regarding leadership development, providing context for the potential impact of simulation practice as a targeted professional development method that may extend beyond pre-service preparation and continue as learning pathways for in-service school leaders.

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway, rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.

INTRODUCTIONEmerging data suggests neoadjuvant chemotherapy for resectable pancreatic ductal adenocarcinoma (PDAC) is associated with improved survival. However, less than 40% demonstrate a meaningful radiographic response to NAC. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has emerged as a new modality to treat PDAC. We hypothesize that NAC plus EUS-RFA can be used in the management of resectable PDAC.METHODSProspective review of PDAC patients meeting criteria of resectable tumor anatomy that underwent NAC chemotherapy plus EUS-RFA followed by pancreatic resection. Radiographic imaging, perioperative and short-term outcomes were recorded. Surgical pathology specimens were analyzed for treatment response.RESULTSThree eligible patients with resectable PDAC received 4 months of neoadjuvant chemotherapy plus EUS-RFA. One month after completion of neoadjuvant treatment, all 3 patients underwent standard pancreaticoduodenectomy without complications. After a 6 week recovery, all patients completed 2 months of post-op adjuvant chemotherapy.CONCLUSIONSIn our institutional experience, this treatment protocol appears safe. Patients tolerated the combination of chemotherapy and endoscopic radiofrequency ablation. Patients underwent pancreatic resection with uneventful recovery. This novel neoadjuvant approach may provide a more effective alternative to chemotherapy alone.

This paper describes a pedagogical framework and a set of team-based learning (TBL) activities which can be applied to an interdisciplinary course comprised of a mix of engineering, design, and business students. The goal of the team-based learning (TBL) activities is to help students to appreciate both the benefits and the challenges of working in interdisciplinary teams. To enhance their interdisciplinary collaboration skills, students engage in a series of knowledge sharing and knowledge integration activities, based on the Jigsaw technique, a team-based learning methodology. These activities enable the students to recognize and reconcile their disciplinary differences and biases, which arise because of the cognitive diversity of the team. Students are assigned to interdisciplinary teams to identify and prototype an entrepreneurial opportunity. By the end of these activities, students are able to incorporate the perspectives of all three disciplines to develop an integrated team mental model (TMM) of the opportunity recognition and opportunity evaluation process.

In July of 2018 and 2019, wild fish health surveys were conducted along the Wisconsin and Minnesota portions of the upper Mississippi River. Spring viremia of carp virus (SVCV) was isolated from Common Carp Cyprinus carpio as well as a newly identified host species, the Quillback Carpiodes cyprinus. Sanger sequencing of the gene encoding for the G protein revealed a high similarity of the Quillback isolate to various SVCV isolates identified from Common Carp that were collected during earlier wild fish health surveys and mortality events in the USA. Despite annual monitoring, this virus has been infrequently identified. The speculative role of native fish and invertebrates in allowing the virus to persist for long periods without detection is discussed.

In November 2018, Vagococcus salmoninarum was identified as the causative agent of a chronic coldwater streptococcosis epizootic in broodstock brook trout (Salvelinus fontinalis) at the Iron River National Fish Hatchery in Wisconsin, USA. By February 2019, the epizootic spread to adjacent raceways containing broodstock lake trout (Salvelinus namaycush), whereby fish were found to be coinfected with Carnobacterium maltaromaticum and V. salmoninarum. To differentiate these two pathogens and determine the primary cause of the lake trout morbidity, a quantitative real-time PCR (qPCR) was developed targeting the C. maltaromaticum phenylalanyl-tRNA synthase alpha subunit (pheS) gene. The qPCR was combined with a V. salmoninarum qPCR, creating a duplex qPCR assay that simultaneously quantitates C. maltaromaticum and V. salmoninarum concentrations in individual lake trout tissues, and screens presumptive isolates from hatchery inspections and wild fish from national fish hatchery source waters throughout the Great Lakes basin. Vagococcus salmoninarum and C. maltaromaticum were co-detected in broodstock brook trout from two tribal hatcheries and C. maltaromaticum was present in wild fish in source waters of several national fish hatcheries. This study provides a powerful new tool to differentiate and diagnose two emerging Gram-positive bacterial pathogens.

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies.MethodsTo test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis.ResultsRFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses.ConclusionsThese data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease.Graphical Abstract

Over the course of the 21st century, a century in which the urbanization process of the previous one is ever on the rise, the novel smart city concept has rapidly evolved and now encompasses the broader aspect of sustainability. Concurrently, there has been a sea change in the domain of Earth observation (EO) where scientific and technological breakthroughs are accompanied by a paradigm shift in the provision of open and free data. While the urban and EO communities share the end goal of achieving sustainability, cities still lack an understanding of the value EO can bring in this direction, an next a consolidated framework for tapping the full potential of EO and integrating it in their operational modus operandi. The “SMart URBan Solutions for air quality, disasters and city growth” H2020 project (SMURBS/ERA-PLANET) sits at this scientific and policy crossroad, and, by creating bottom-up EO-driven solutions against an array of environmental urban pressures, and by expanding the network of engaged and exemplary smart cities that push the state-of-the-art in EO uptake, brings the international ongoing discussion of EO for sustainable cities closer to home and contributes in this discussion. This paper advocates for EO as an integral part of a smart and sustainable city and aspires to lead by example. To this end, it documents the project's impacts, ranging from the grander policy fields to an evolving portfolio of smart urban solutions and everyday city operations, as well as the cornerstones for successful EO integration. Drawing a parallel with the utilization of EO in supporting several aspects of the 2030 Agenda for Sustainable Development, it aspires to be a point of reference for upcoming endeavors of city stakeholders and the EO community alike, to tread together, beyond traditional monitoring or urban planning, and to lay the foundations for urban sustainability.

BackgroundLong term prognosis for pancreatic adenocarcinoma (PDAC) remains especially poor with an overall 5-year survival rate less than 9%. Endoscopic ultrasound (EUS) guided RFA (EUS-RFA) is an emerging technology and limited data exist regarding long-term outcomes of EUS-RFA for PDAC. In addition to thermal-induced coagulative necrosis and tissue damage, radiofrequency ablation (RFA) has potential to stimulate the host’s antitumor immunity. The aim of this study is to report long-term outcomes of EUS-RFA for unresectable PDAC.MethodsRetrospective chart review of adult patients with an established diagnosis of locally-advanced or metastatic PDAC undergoing EUS-RFA between October 2016 to March 2018 with long term follow up (>30 months). Patients included in the review underwent a total of 1-4 RFA sessions using the Habib EUS-RFA radiofrequency catheter. All patients were concurrently undergoing standard of care chemotherapy.Results10 patients (median age 62 years, male 70%) underwent EUS-RFA (Table 1). Location of the primary PDAC was in the head (4), neck (2), body (2), and tail (2). A total of 22 RFA sessions were performed with a range of 1-4 RFA sessions per patient. RFA was technically successful in all RFA sessions (100%). There were no major adverse events (bleeding, perforation, infection, pancreatitis) in immediate (up to 72 hours) and short-term follow up (4 week). Mild worsening of existing abdominal pain was noted during post-procedure observation in 12/22 (55%) of RFA treatments. Follow-up imaging after RFA treatment was available in 8/10 patients. Tumor progression was noted in 2 patients, whereas tumor regression was noted in 6 patients (>50% reduction in size in 3 patients). Median survival for the cohort was 20.5 months (95% CI, 9.93 to 42.2 months). Currently, 2 patients remain alive at 53 and 73 months follow-up since initial diagnosis. One patient had 3 cm PDAC with encasement of the portal confluence, abutment of the celiac axis, common hepatic and superior mesenteric artery. This patient had significant reduction in tumor size and underwent standard pancreaticoduodenectomy.ConclusionIn our experience, EUS-RFA was safe, well-tolerated and could be concurrently performed with standard of care chemotherapy. In this select cohort, median survival (20.5 months) was improved when compared to published survival based upon SEER database and clinical trials. Future prospective trials are needed to understand the role of EUS-RFA in overall management of PDAC.

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.Abstract Figure

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine(A) to inosine(I). A-to-I editing alters post-transcriptional RNA processing making ADAR1 a critical regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we specifically deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth likely due to malabsorption associated with exocrine pancreas insufficiency. Analyses of pancreases revealed ductal expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. In addition, we observed an increased prevalence of CD4+ T and natural killer cells in their splenic tissue. These results indicate an association between loss of pancreatic Adar1 with dysregulation of systemic immunity. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.Summary statementThis work defines the role of Adar1 in pancreatic development and homeostasis.

In 2018, Vagococcus salmoninarum was isolated from two lots of broodstock "coaster" brook trout (Salvelinus fontinalis) containing ~1,500 fish at the Iron River National Fish Hatchery, at which time it was identified as the causative agent of a chronic coldwater streptococcosis epizootic. Clinical signs included exophthalmia, lethargy, erratic swimming and loss of equilibrium. Female fish experienced disproportionately higher morbidity and mortality than male co-inhabitants, and routinely retained eggs following spawning. The most consistent gross clinical sign was heart pallor and turbid pericardial effusion. An attempted treatment using florfenicol was ineffective at halting the epizootic, which spanned more than a year and resulted in >50% mortality before remaining fish were culled. As there is no previous documentation of V. salmoninarum at this hatchery or in this species, it is still unclear what circumstances led to this epizootic. The inability to treat this chronic disease led to the loss of valuable broodstock, hampering ongoing fishery conservation efforts in the Great Lakes Basin.

This paper highlights two emerging models for how religious education is evolving in new venues to reach new audiences today. The first is an online course that equips a new generation of c...

Western spruce budworm (Choristoneura freemani Razowski, 2008) is the most widely distributed insect herbivore in western North American coniferous forests. By partially or completely defoliating tree crowns, budworms influence fluxes of water, nutrients, and organic carbon from forest canopies to soils and, in turn, soil chemistry. To quantify these effects, throughfall water, inorganic nitrogen (N), phosphorus (P), and dissolved organic carbon (DOC) concentrations, as well as fluxes and soil N and P concentrations, were measured in coniferous forest sites with high and background levels of budworm herbivory. Throughfall N and P concentrations and fluxes increased at sites with high budworm levels during and (or) immediately after larval-stage budworm feeding, indicating reduced uptake and (or) greater leaching from canopies as a result of budworm activity. Annual throughfall N fluxes (−1·year−1) and soil N concentrations were low regardless of herbivory level. In contrast, throughfall P was considerably greater at sites with high herbivory levels (2174 g P·ha−1·year−1) compared with those with background levels (1357 g P·ha−1·year−1), and this was reflected in nearly threefold higher soil P concentrations at sites with high budworm levels. Our findings suggest that by altering throughfall chemistry and soil N:P, budworms could influence elemental export from watersheds.

Heat waves and high air temperature are associated with increased morbidity and mortality. However, the majority of research conducted on this topic is focused on high income areas of the world. Although heat waves have the most severe impacts on vulnerable populations, relatively few studies have studied their impacts in low and middle income countries (LMICs). The aim of this paper is to review the existing evidence in the literature on the impact of heat on human health in LMICs. We identified peer-reviewed epidemiologic studies published in English between January 1980 and August 2018 investigating potential associations between high ambient temperature or heat waves and mortality or morbidity. We selected studies according to the following criteria: quantitative studies that used primary and/or secondary data and report effect estimates where ambient temperature or heat waves are the main exposure of interest in relation to human morbidity or mortality within LMICs. Of the total 146 studies selected, eighty-two were conducted in China, nine in other countries of East Asia and the Pacific, twelve in South Asia, ten in Sub-Saharan Africa, eight in the Middle East and North Africa, and seven in each of Latin America and Europe. The majority of studies (92.9%) found positive associations between heat and human morbidity/mortality. Additionally, while outcome variables and study design differed greatly, most utilized a time-series study design and examined overall heath related morbidity/mortality impacts in an entire population, although it is notable that the selected studies generally found that the elderly, women, and individuals within the low socioeconomic brackets were the most vulnerable to the effects of high temperature. By highlighting the existing evidence on the impact of extreme heat on health in LMICs, we hope to determine data needs and help direct future studies in addressing this knowledge gap. The focus on LMICs is justified by the lack of studies and data studying the health burden of higher temperatures in these regions even though LMICs have a lower capacity to adapt to high temperatures and thus an increased risk.

Cities face a wide variety of pressures, many of which negatively impact the health of both the environment and citizens and require an integrated smart city approach to address. By infusing state-of-the-art Earth observation (EO) into tools for cities, the SMart URBan Solutions for air quality, disasters and city growth (SMURBS) project produced a portfolio of smart solutions based off of and refined by continued engagement and co-design with stakeholders and cities to address real needs, gaps, and issues. This portfolio of EO-driven solutions serves as an openly available archive and depository of city solutions for environmental pressures and aims to enhance urban resilience and sustainability, and therefore, make cities smarter. Within this paper, we describe the SMURBS experience of bringing together city stakeholders and EO experts and building the portfolio of smart urban solutions, concluding with the six foundational aspects distilled from this experience to serve as a playbook for solution builders to ensure the production of fit-for-purpose and effective city solutions.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive microenvironment. Innovative therapeutic strategies are urgently needed to stop the progression of precancerous lesions into aggressive PDAC, which remains a lethal malignancy. The goal of this research project is to test the immunopreventive strategies by targeting the ectonucleotidase CD73, one of the gatekeeper enzymes responsible for adenosine production and the formation of immunosuppressive tumor microenvironment in this malignancy. We hypothesize that inhibition of CD73 will prevent pancreatic intraepithelial neoplasia (PanIN) formation and progression to PDAC by reversing immunosuppression. Materials and methods: A syngeneic PDAC mouse model was employed by injecting 100k murine pancreatic cancer (KPC) cells in flanks of C57BL/6 female mice. Oral gavage of AB680 (small molecule CD73 inhibitor) was given three days/week at 10mg/kg starting the day after KPC injections and tumor sizes were measured weekly. Toxicity was analyzed by serum ALT analysis. At the time of death 6 weeks post-KPC inoculation, tumor volume and mass were recorded. In another experiment, AB680 was administered 3 days/week at 10mg/kg for 5 weeks. CyTOF immunoprofiling of digested tumors from control and AB680 treated mice and HPLC analysis on serum from the time of death were performed. Results: In experiment 1, by week three of the study, there was a significant difference in tumor volume between the control and AB680 treated groups (P=0.02). However, in weeks 4-5 AB680 reduced tumor growth compared to vehicle controls, but the grouped statistical analysis was not significant. When observing individual tumors, there was a reduction in tumor size in 30% of the AB680 treated mice between weeks 3-5, but the difference was not statistically different. ALT analysis determined AB680 does not induce liver toxicity. For experiment 2 (3x/week treatment with AB680), there was a significant reduction in tumor growth. Activated CD8-positive T cells, dendritic cells, and macrophages were significantly increased in the syngeneic tumors from AB680 treated mice. The intratumoral adenosine levels were significantly decreased in AB680 treated mice compared to vehicle treated mice. Conclusion: We conclude oral gavage delivery of CD73 inhibitor AB680 at 10mg/kg (6x/week) reduces tumor growth in KPC syngeneic tumor bearing mice. Treatment with AB680 at 10mg/kg 3x/week significantly increases tumor doubling time, significantly alters intratumoral immune cell populations, and results in a significant decrease in intratumoral adenosine levels. In addition, we observed a significant increase in infiltration of activated CD8-positive T cells indicating oral gavage delivery using AB680 reverses immunosuppression in vivo. [Supported by NCI 75N91019D00021/75N91020F00002] Citation Format: Kanchan Singh, Vidhi Chandra, Lincoln Ballew, Tingting Mills, Erika Y. Faraoni, Trent Clark, Lana A. Vornik, Michelle I. Savage, Holger K. Eltzschig, Altaf Mohammed, Shizuko Sei, Powel H. Brown, Florencia McAllister, Jennifer Bailey-Lundberg. Preclinical testing of CD73 inhibitors for pancreatic cancer immunoprevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 719.

Here we present a case of a poorly controlled diabetic who developed extensive rhinocerebral mucormycosis. Systemic and intrathecal amphotericin were not able to improve his life threatening infection. Therefore, salvage therapy with intracavitary amphotericin B deoxycholate was used to instill antifungal therapy directly into the patient's brain abscess. For proper dosing of intracavitary amphotericin B deoxycholate, we devised a formula which can be theoretically applied for all intracavitary therapies. Unfortunately, the patient's family withdrew care 6 days after starting intracavitary amphotericin and efficacy of this therapy could not be evaluated.