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Has in-person learning and virtual learning produced equivalent results when it comes to student achievement? How can a district be flexible with learning options but also strategic with how to best achieve student learning gains? This case-study examines how one district leveraged virtual learning and flexible learning options during COVID-19 and suggests the continuation of virtual learning as a means to provide a flexible learning option for students and families. COVID-19 provided many challenges for district leaders to effectively educate students during the 2020-2021 school year. Consequently, the pandemic provided those same district leaders with a variety of virtual learning strategies from which to study and adapt to maximize student achievement. As virtual school enrollment trends continue to increase nationally and chronic absenteeism continues to rise, flexible learning environment options become more appealing to districts focused on addressing students' needs in a post-pandemic environment.

Testing of ducks in Tennessee, United States, before introduction of highly pathogenic influenza A(H5N1) virus demonstrated a high prevalence of antibodies to influenza A virus but very low prevalence of antibodies to H5 (25%) or H5 and N1 (13%) subtypes. Antibody prevalence increased after H5N1 introduction.

Background: Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Methods: We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Results: We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Conclusions: JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. Funding: NIAMS, Global Down Syndrome Foundation. Clinical trial number: NCT04246372.

The authors describe a functional crosstalk between the p53 network and the integrated stress response through the p53 repressor PPM1D. Inhibition of PPM1D potentiates p53-dependent transactivation and apoptosis via induction of the HRI-eIF2α-ATF4 pathway.

Summary: Individuals with Down syndrome (DS) clinically manifest severe respiratory illnesses; however, there is a paucity of data on how DS influences homeostatic physiology of lung airway, and its reactive responses to pulmonary pathogens. We generated well-differentiated ciliated airway epithelia using tracheas from wild-type and Dp(16)1/Yey mice in vitro, and discovered that Dp(16)1/Yey epithelia have significantly lower abundance of ciliated cells, an altered ciliary beating profile, and reduced mucociliary transport. Interestingly, both sets of differentiated epithelia released similar quantities of viral particles after infection with influenza A virus (IAV). However, RNA-sequencing and proteomic analyses revealed an immune hyperreactive phenotype particularly for monocyte-recruiting chemokines in Dp(16)1/Yey epithelia. Importantly, when we challenged mice in vivo with IAV, we observed immune hyper-responsiveness in Dp(16)1/Yey mice, evidenced by higher quantities of lung airway infiltrated monocytes, and elevated levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid. Our findings illuminate mechanisms underlying DS-mediated pathophysiological changes in airway epithelium.

Abstract Avian influenza viruses can pose serious risks to agricultural production, human health, and wildlife. An understanding of viruses in wild reservoir species across time and space is important to informing surveillance programs, risk models, and potential population impacts for vulnerable species. Although it is recognized that influenza A virus prevalence peaks in reservoir waterfowl in late summer through autumn, temporal and spatial variation across species has not been fully characterized. We combined two large influenza databases for North America and applied spatiotemporal models to explore patterns in prevalence throughout the annual cycle and across the continental United States for 30 waterfowl species. Peaks in prevalence in late summer through autumn were pronounced for dabbling ducks in the genera Anas and Spatula, but not Mareca. Spatially, areas of high prevalence appeared to be related to regional duck density, with highest predicted prevalence found across the upper Midwest during early fall, though further study is needed. We documented elevated prevalence in late winter and early spring, particularly in the Mississippi Alluvial Valley. Our results suggest that spatiotemporal variation in prevalence outside autumn staging areas may also represent a dynamic parameter to be considered in IAV ecology and associated risks.

Abstract Background Cancer Care Delivery (CCD) research studies often require practice-level interventions that pose challenges in the clinical trial setting. The SWOG Cancer Research Network (SWOG) conducted S1415CD, one of the first pragmatic cluster-randomized CCD trials to be implemented through the National Cancer Institute (NCI) Community Oncology Program (NCORP), to compare outcomes of primary prophylactic colony stimulating factor (PP-CSF) use for an intervention of automated PP-CSF standing orders to usual care. The introduction of new methods for study implementation created challenges and opportunities for learning that can inform the design and approach of future CCD interventions. Methods The order entry system intervention was administered at the site level; sites were affiliated NCORP practices that shared the same chemotherapy order system. 32 sites without existing guideline-based PP-CSF standing orders were randomized to the intervention (n = 24) or to usual care (n = 8). Sites assigned to the intervention participated in tailored training, phone calls and onboarding activities administered by research team staff and were provided with additional funding and external IT support to help them make protocol required changes to their order entry systems. Results The average length of time for intervention sites to complete reconfiguration of their order sets following randomization was 7.2 months. 14 of 24 of intervention sites met their individual patient recruitment target of 99 patients enrolled per site. Conclusions In this paper we share seven recommendations based on lessons learned from implementation of the S1415CD intervention at NCORP community oncology practices representing diverse geographies and patient populations across the U. S. It is our hope these recommendations can be used to guide future implementation of CCD interventions in both research and community settings. Trial Registration NCT02728596 , registered April 5, 2016.

Summary: Inactivation of the p53 tumor suppressor, either by mutations or through hyperactivation of repressors such as MDM2 and MDM4, is a hallmark of cancer. Although many inhibitors of the p53-MDM2/4 interaction have been developed, such as Nutlin, their therapeutic value is limited by highly heterogeneous cellular responses. We report here a multi-omics investigation of the cellular response to MDM2/4 inhibitors, leading to identification of FAM193A as a widespread regulator of p53 function. CRISPR screening identified FAM193A as necessary for the response to Nutlin. FAM193A expression correlates with Nutlin sensitivity across hundreds of cell lines. Furthermore, genetic codependency data highlight FAM193A as a component of the p53 pathway across diverse tumor types. Mechanistically, FAM193A interacts with MDM4, and FAM193A depletion stabilizes MDM4 and inhibits the p53 transcriptional program. Last, FAM193A expression is associated with better prognosis in multiple malignancies. Altogether, these results identify FAM193A as a positive regulator of p53.

Abstract Understanding relationships between infection and wildlife movement patterns is important for predicting pathogen spread, especially for multispecies pathogens and those that can spread to humans and domestic animals, such as avian influenza viruses (AIVs). Although infection with low pathogenic AIVs is generally considered asymptomatic in wild birds, prior work has shown that influenza‐infected birds occasionally delay migration and/or reduce local movements relative to their uninfected counterparts. However, most observational research to date has focused on a few species in northern Europe; given that influenza viruses are widespread globally and outbreaks of highly pathogenic strains are increasingly common, it is important to explore influenza–movement relationships across more species and regions. Here, we used telemetry data to investigate relationships between influenza infection and movement behavior in 165 individuals from four species of North American waterfowl that overwinter in California, USA. We studied both large‐scale migratory and local overwintering movements and found that relationships between influenza infection and movement patterns varied among species. Northern pintails (Anas acuta) with antibodies to avian influenza, indicating prior infection, made migratory stopovers that averaged 12 days longer than those with no influenza antibodies. In contrast, greater white‐fronted geese (Anser albifrons) with antibodies to avian influenza made migratory stopovers that averaged 15 days shorter than those with no antibodies. Canvasbacks (Aythya valisineria) that were actively infected with influenza upon capture in the winter delayed spring migration by an average of 28 days relative to birds that were uninfected at the time of capture. At the local scale, northern pintails and canvasbacks that were actively infected with influenza used areas that were 7.6 and 4.9 times smaller than those of uninfected ducks, respectively, during the period of presumed active influenza infection. We found no evidence for an influence of active influenza infection on local movements of mallards (Anas platyrhynchos). These results suggest that avian influenza can influence waterfowl movements and illustrate that the relationships between avian influenza infection and wild bird movements are context‐ and species‐dependent. More generally, understanding and predicting the spread of multihost pathogens requires studying multiple taxa across space and time.

Trisomy 21, the genetic cause of Down syndrome, disrupts primary cilia formation and function, in part through elevated Pericentrin, a centrosome protein encoded on chromosome 21. Yet how trisomy 21 and elevated Pericentrin disrupt cilia-related molecules and pathways, and the in vivo phenotypic relevance remain unclear. Utilizing ciliogenesis time course experiments combined with light microscopy and electron tomography, we reveal that chromosome 21 polyploidy elevates Pericentrin and microtubules away from the centrosome that corral MyosinVA and EHD1, delaying ciliary membrane delivery and mother centriole uncapping essential for ciliogenesis. If given enough time, trisomy 21 cells eventually ciliate, but these ciliated cells demonstrate persistent trafficking defects that reduce transition zone protein localization and decrease sonic hedgehog signaling in direct anticorrelation with Pericentrin levels. Consistent with cultured trisomy 21 cells, a mouse model of Down syndrome with elevated Pericentrin has fewer primary cilia in cerebellar granule neuron progenitors and thinner external granular layers at P4. Our work reveals that elevated Pericentrin from trisomy 21 disrupts multiple early steps of ciliogenesis and creates persistent trafficking defects in ciliated cells. This pericentrosomal crowding mechanism results in signaling deficiencies consistent with the neurological phenotypes found in individuals with Down syndrome.

Abstract Seasonal subsidence induced by ground ice melt can be measured by interferometric synthetic aperture radar (InSAR) techniques to infer active layer thickness (ALT) in permafrost regions. The magnitude of subsidence depends on both how deep the soil thawed and how much ice/water content existed in the active layer soil. To provide the later, P‐band polarimetric synthetic aperture radar (PolSAR) backscatter is used due to its sensitivity to subsurface soil moisture and freeze/thaw conditions. In this study, which is the second in a two‐part series of Permafrost Dynamics Observatory (PDO), we exploit L‐band InSAR subsidence and P‐band PolSAR backscatter in a joint retrieval scheme to simultaneously estimate ALT and soil moisture profile of permafrost active layer. Both subsidence and backscatter are explicitly characterized by physics‐based models and share a common set of soil parameters including porosity and water saturation profiles. The PDO joint retrieval has been applied to the L‐ and P‐band SAR data acquired by National Aeronautics and Space Administration/Jet Propulsion Laboratory's Uninhabited Aerial Vehicle Synthetic Aperture Radar over Alaska and western Canada during the 2017 Arctic‐Boreal Vulnerability Experiment (ABoVE) airborne campaign. This high‐resolution (30 m) regional estimates of ALT and soil moisture profile spanning over the ABoVE study domain can help link the ground‐based field surveys with satellite observations to further understand the permafrost and active layer soil process dynamics to disturbances and climate change occurring across the northern circumpolar region.

Background: Concurrent therapeutic prescribing of prescription stimulants with opioid analgesics is increasing in the United States. Stimulant medication use is associated with increased risk for long-term opioid therapy (LTOT), and LTOT is associated with increased risk for opioid use disorder (OUD). Aims: To determine if stimulant prescriptions among those with LTOT (≥90 days) are associated with greater risk for opioid use disorder (OUD). Methods: This retrospective cohort study from 2010 to 2018 used a United States, nationally distributed Optum© analytics Integrated Claims-Clinical dataset. Patients ≥18 years of age, and free of prevalent OUD in the two years prior to index were eligible. All patients had a new ≥90-day opioid prescription. The index date was day 91. We compared risk for new OUD diagnoses in patients with and without a prescription stimulant overlapping LTOT. Entropy balancing and weighting controlled for confounding factors. Results: Patients (n = 5,712), were 57.7 (SD±14.9) years of age on average, majority female (59.8%) and 73.3% White race. Among patients with LTOT, 2.8% had overlapping stimulant prescriptions. Before controlling for confounding, dual stimulant-opioid prescriptions, compared to opioid only, were associated with OUD risk (HR = 1.75; 95%CI:1.17-2.61). After controlling for confounding, this association was no longer present (HR = 0.89; 95%CI:0.47-1.71). Results did not differ in sensitivity analyses limiting the cohort to those