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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

Abstract Background While the period from fledging through first breeding for waterbird species such as terns (e.g., genus Sterna, Sternula) is of great interest to researchers and conservationists, this period remains understudied due in large part to the difficulty of marking growing juveniles with radio transmitters that remain attached for extended periods. Methods In an effort to facilitate such research, we examined the impact of various combinations of harness types (backpack, leg-loop, and 3D-printed harnesses), harness materials (Automotive ribbon, Elastic cord, and PFTE ribbon), and transmitter types (center-weighted and rear-weighted) on a surrogate for juvenile terns, 28-day-old Japanese quail (Coturnix japonica; selected due to similarities in adult mass and downy feathering of juveniles), in a 30-day experiment. We monitored for abrasion at points of contact and tag gap issues via daily exams while also recording mass and wing cord as indices of growth. This study was designed to serve as an initial examination of the impacts of marking on the growth and development of young birds and does not account for any impacts of tags on movement or behavior. Results While we found that treatment (the specific combination of the transmitter type, harness type, and harness material) had no impact on bird growth relative to unmarked control birds (P ≥ 0.05), we did observe differences in abrasion and tag gap between treatments (P ≤ 0.05). Our results suggest that leg-loop harnesses constructed from elastic cord and backpack harnesses from PFTE ribbon are suitable options for long-term attachment to growing juveniles. Conversely, we found that automotive ribbon led to extensive abrasion with these small-bodied birds, and that elastic cord induced blisters when used to make a backpack harness. Conclusions While these results indicate that long-term tagging of juvenile birds is possible with limited impacts on growth, this work does not preclude the need for small-scale studies with individual species. Instead, we hope this provides an informed starting point for further exploration of this topic.

Background: Mycosis fungoides (MF) is a cutaneous lymphoma; most patients present with early, skin-limited disease and are managed by dermatologists. Objective: The purpose of this study was to systematically review and assess the evidence on topical treatments for early-stage (IA, IB, IIA) MF. Methods: We performed a literature search via MEDLINE, Embase, Web of Science, and Cochrane databases. Grading Recommendations Assessment, Development and Evaluation (GRADE) criteria were used to assess the certainty of the data. Results: Two searches yielded 1252 references; 26 met the inclusion criteria and included literature on nitrogen mustard, retinoids, corticosteroids, carmustine, fluorouracil, methotrexate-laurocapram, hexadecylphosphocholine, peldesine, ingenol mebutate, topical methotrexate with oxygen flow-assisted LP3 carrier, and resiquimod. Most studies were single intervention, observational series. Nitrogen mustard, with the most published reports, was effective with 12%-82% early-stage MF patients (total n > 1000) achieving complete remission (CR) (low certainty evidence). Clinical CR was achieved among 10%-60% treated with topical retinoids (low certainty evidence). Two moderate-sized retrospective case series on topical steroids had 18%-63% CR (low certainty evidence). Only single studies were available for the other therapies. Conclusions: For most outcomes of interest, the GRADE certainty for topical therapies for early-stage MF was low. Further randomized controlled trials and inclusion of quality of life indicators are needed.

Wild waterbirds, the natural reservoirs for avian influenza viruses, undergo migratory movements each year, connecting breeding and wintering grounds within broad corridors known as flyways. In a continental or global view, the study of virus movements within and across flyways is important to understanding virus diversity, evolution, and movement. From 2015 to 2017, we sampled waterfowl from breeding (Maine) and wintering (Maryland) areas within the Atlantic Flyway (AF) along the east coast of North America to investigate the spatio-temporal trends in persistence and spread of influenza A viruses (IAV). We isolated 109 IAVs from 1,821 cloacal / oropharyngeal samples targeting mallards (Anas platyrhynchos) and American black ducks (Anas rubripes), two species having ecological and conservation importance in the flyway that are also host reservoirs of IAV. Isolates with >99% nucleotide similarity at all gene segments were found between eight pairs of birds in the northern site across years, indicating some degree of stability among genome constellations and the possibility of environmental persistence. No movement of whole genome constellations were identified between the two parts of the flyway, however, virus gene flow between the northern and southern study locations was evident. Examination of banding records indicate direct migratory waterfowl movements between the two locations within an annual season, providing a mechanism for the inferred viral gene flow. Bayesian phylogenetic analyses provided evidence for virus dissemination from other North American wild birds to AF dabbling ducks (Anatinae), shorebirds (Charidriformes), and poultry (Galliformes). Evidence was found for virus dissemination from shorebirds to gulls (Laridae), and dabbling ducks to shorebirds and poultry. The findings from this study contribute to the understanding of IAV ecology in waterfowl within the AF.

Abstract Genomes computationally inferred from large metagenomic data sets are often incomplete and may be missing functionally important content and strain variation. We introduce an information retrieval system for large metagenomic data sets that exploits the sparsity of DNA assembly graphs to efficiently extract subgraphs surrounding an inferred genome. We apply this system to recover missing content from genome bins and show that substantial genomic sequence variation is present in a real metagenome. Our software implementation is available at https://github.com/spacegraphcats/spacegraphcats under the 3-Clause BSD License.

Abstract Background While nest attentiveness plays a critical role in the reproductive success of avian species, nest attentiveness data with high temporal resolution is not available for many species. However, improvements in both video monitoring and temperature logging devices present an opportunity to increase our understanding of this aspect of avian behavior. Methods To investigate nest attentiveness behaviors and evaluate these technologies, we monitored 13 nests across two Common Tern (Sterna hirundo) breeding colonies with a paired video camera - temperature logger approach, while monitoring 63 additional nests with temperature loggers alone. Observations occurred from May to August of 2017 on Poplar (Chesapeake Bay, Maryland, USA) and Skimmer Islands (Isle of Wight Bay, Maryland, USA). We examined data respective to four times of day: Morning (civil dawn‒11:59), Peak (12:00‒16:00), Cooling (16:01‒civil dusk), and Night (civil dusk‒civil dawn). Results While successful nests had mostly short duration off-bouts and maintained consistent nest attentiveness throughout the day, failed nests had dramatic reductions in nest attentiveness during the Cooling and Night periods (p 0.05), video-monitored nests did have significantly lower clutch sizes (p

Summary: Background: During the COVID-19 pandemic, Test-Trace-Isolate (TTI) programs have been recommended as a risk mitigation strategy. However, many governments have hesitated to implement them due to their costs. This study aims to estimate the cost-effectiveness of implementing a national TTI program to reduce the number of severe and fatal cases of COVID-19 in Colombia. Methods: We developed a Markov simulation model of COVID-19 infection combined with a Susceptible-Infected-Recovered structure. We estimated the incremental cost-effectiveness of a comprehensive TTI strategy compared to no intervention over a one-year horizon, from both the health system and the societal perspective. Hospitalization and mortality rates were retrieved from Colombian surveillance data. We included program costs of TTI intervention, health services utilization, PCR diagnosis test, productivity loss, and government social program costs. We used the number of deaths and quality-adjusted life years (QALYs) as health outcomes. Sensitivity analyses were performed. Findings: Compared with no intervention, the TTI strategy reduces COVID-19 mortality by 67%. In addition, the program saves an average of $1,045 and $850 per case when observed from the social and the health system perspective, respectively. These savings are equivalent to two times the current health expenditures in Colombia per year. Interpretation: The TTI program is a highly cost-effective public health intervention to reduce the burden of COVID-19 in Colombia. TTI programs depend on their successful and speedy implementation. Funding: This study was supported by the Colombian Ministry of Health through award number PUJ-04519-20 received by EPQ AVO and SDS declined to receive any funding support for this study. The contents are the responsibility of all the individual authors.

Abstract Aims To compare 12‐month clinical effectiveness of insulin glargine 300 units/mL (Gla‐300) versus first‐generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla‐100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla‐300 or Gla‐100/IDet) in a real‐world setting. Methods DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla‐300 (Gla‐300 switchers) and were propensity score‐matched (1:1) to patients who switched to Gla‐100 or IDet (Gla‐100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (

Marking birds with transmitters allows for the collection of data that are critical for fully understanding avian life history, but researchers must also be confident that performing such studies is as safe as possible for transmittered individuals. While much could be learned from tracking juveniles across dependency periods and first migration, doing so would require a harness-based attachment method which has not been evaluated on any species of juvenile tern. Therefore, we monitored the reproductive success and behavior of adult Common Terns (Sterna hirundo) and the growth and behavior of juvenile Common Terns after attaching transmitters to adults and juveniles with leg-loop harnesses made of elastic cord. We found that transmittered adults had similar reproductive success to untransmittered controls (hatching success for nests of transmittered adults = 0.553; nests of control adults = 0.665). Transmittered adults also expressed minimal behavioral differences from untransmittered controls when the groups were compared via paired treatment-control nest observations along with observations away from the nest. Transmittered juveniles had similar fledging success and growth rates to untransmittered control juveniles (fledging success for transmittered juveniles = 0.766; control juveniles = 0.817). Transmittered juveniles exhibited slight differences in behavior from controls, with increased rates of preening, although these differences did not appear to be detrimental. Finally, monitoring efforts during the breeding season following transmitter deployment found no difference in the return rate, nesting attempt rate, or hatching success rate based on treatment (P > 0.05). However, despite evidence of an individual retaining its transmitter into fall migration, no individuals retained their transmitters when resighted the following breeding season. While our results show that leg-loop harnesses made of elastic cord present a potential option for transmitter attachment to both adult and juvenile Common Terns, additional testing could provide further insight into potential long-term impacts.

Abstract Background Infectious disease forecasting aims to predict characteristics of both seasonal epidemics and future pandemics. Accurate and timely infectious disease forecasts could aid public health responses by informing key preparation and mitigation efforts. Main body For forecasts to be fully integrated into public health decision-making, federal, state, and local officials must understand how forecasts were made, how to interpret forecasts, and how well the forecasts have performed in the past. Since the 2013–14 influenza season, the Influenza Division at the Centers for Disease Control and Prevention (CDC) has hosted collaborative challenges to forecast the timing, intensity, and short-term trajectory of influenza-like illness in the United States. Additional efforts to advance forecasting science have included influenza initiatives focused on state-level and hospitalization forecasts, as well as other infectious diseases. Using CDC influenza forecasting challenges as an example, this paper provides an overview of infectious disease forecasting; applications of forecasting to public health; and current work to develop best practices for forecast methodology, applications, and communication. Conclusions These efforts, along with other infectious disease forecasting initiatives, can foster the continued advancement of forecasting science.

Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.

Summary: High-grade serous ovarian cancers (HGSOCs) arise from exfoliation of transformed cells from the fallopian tube, indicating that survival in suspension, and potentially escape from anoikis, is required for dissemination. We report here the results of a multi-omic study to identify drivers of anoikis escape, including transcriptomic analysis, global non-targeted metabolomics, and a genome-wide CRISPR/Cas9 knockout (GeCKO) screen of HGSOC cells cultured in adherent and suspension settings. Our combined approach identified known pathways, including NOTCH signaling, as well as novel regulators of anoikis escape. Newly identified genes include effectors of fatty acid metabolism, ACADVL and ECHDC2, and an autophagy regulator, ULK1. Knockdown of these genes significantly inhibited suspension growth of HGSOC cells, and the metabolic profile confirmed the role of fatty acid metabolism in survival in suspension. Integration of our datasets identified an anoikis-escape gene signature that predicts overall survival in many carcinomas. : Biological Sciences; Cell Biology; Cancer Systems Biology; Cancer Subject Areas: Biological Sciences, Cell Biology, Cancer Systems Biology, Cancer

Abstract Background The Fred Hutchinson Cancer Research Center has engaged an External Stakeholder Advisory Group (ESAG) in the planning and implementation of the TrACER Study (S1415CD), a five-year pragmatic clinical trial assessing the effectiveness of a guideline-based colony stimulating factor standing order intervention. The trial is being conducted by SWOG through the National Cancer Institute Community Oncology Research Program in 45 clinics. The ESAG includes ten patient partners, two payers, two pharmacists, two guideline experts, four providers and one medical ethicist. This manuscript describes the ESAG’s role and impact on the trial. Methods During early trial development, the research team assembled the ESAG to inform plans for each phase of the trial. ESAG members provide feedback and engage in problem solving to improve trial implementation. Each year, members participate in one in-person meeting, web conferences and targeted email discussion. Additionally, they complete a survey that assesses their satisfaction with communication and collaboration. The research team collected and reviewed stakeholder input from 2014 to 2018 for impact on the trial. Results The ESAG has informed trial design, implementation and dissemination planning. The group advised the trial’s endpoints, regimen list and development of cohort and usual care arms. Based on ESAG input, the research team enhanced patient surveys and added pharmacy-related questions to the component application to assess order entry systems. ESAG patient partners collaborated with the research team to develop a patient brochure and study summary for clinic staff. In addition to identifying recruitment strategies and patient-oriented platforms for publicly sharing results, ESAG members participated as co-authors on this manuscript and a conference poster presentation highlighting stakeholder influence on the trial. The annual satisfaction survey results suggest that ESAG members were satisfied with the methods, frequency and target areas of their engagement in the trial during project years 1–3. Conclusions Diverse stakeholder engagement has been essential in optimizing the design, implementation and planned dissemination of the TrACER Study. The lessons described in the manuscript may assist others to effectively partner with stakeholders on clinical research.

COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations.

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Summary: Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.

We describe the methods and decision from a health technology assessment of a new molecular test for bladder cancer (Cxbladder), which was proposed for adoption to our send-out test menu by urology providers. The Cxbladder health technology assessment report contained mixed evidence; predominant concerns were related to the test’s low specificity and high cost. The low specificity indicated a high false-positive rate, which our laboratory formulary committee concluded would result in unnecessary confirmatory testing and follow-up. Our committee voted unanimously to not adopt the test system-wide for use for the initial diagnosis of bladder cancer but supported a pilot study for bladder cancer recurrence surveillance. The pilot study used real-world data from patient management in the scenario in which a patient is evaluated for possible recurrent bladder cancer after a finding of atypical cytopathology in the urine. We evaluated the type and number of follow-up tests conducted including urine cytopathology, imaging studies, repeat cystoscopy evaluation, biopsy, and repeat Cxbladder and their test results. The pilot identified ordering challenges and suggested potential use cases in which the results of Cxbladder affected a change in management. Our health technology assessment provided an objective process to efficiently review test performance and guide new test adoption. Based on our pilot, there were real-world data indicating improved clinician decision-making among select patients who underwent Cxbladder testing.

Summary: The transcriptional repressor ΔNp63α is a potent oncogene widely overexpressed in squamous cell carcinomas (SCCs) of diverse tissue origins, where it promotes malignant cell proliferation and survival. We report here the results of a genome-wide CRISPR screen to identify pathways controlling ΔNp63α-dependent cell proliferation, which revealed that the small GTPase RHOA blocks cell division upon ΔNp63α knockdown. After ΔNp63α depletion, RHOA activity is increased, and cells undergo RHOA-dependent proliferation arrest along with transcriptome changes indicative of increased TGF-β signaling. Mechanistically, ΔNp63α represses transcription of TGFB2, which induces a cell cycle arrest that is partially dependent on RHOA. Ectopic TGFB2 activates RHOA and impairs SCC proliferation, and TGFB2 neutralization restores cell proliferation during ΔNp63α depletion. Genomic data from tumors demonstrate inactivation of RHOA and the TGFBR2 receptor and ΔNp63α overexpression in more than 80% of lung SCCs. These results reveal a signaling pathway controlling SCC proliferation that is potentially amenable to pharmacological intervention. : Abraham et al. employ a genome-wide CRISPR screening strategy to characterize the mechanism of action of the ΔNp63α oncogene in SCC. ΔNp63α suppresses TGFB2 expression and RHOA activity to drive SCC proliferation. TGFB2 is sufficient to impair SCC proliferation and necessary to enforce cell cycle arrest upon depletion of ΔNp63α. Keywords: p63, CRISPR screen, p53, lung cancer, head and neck carcinoma

Abstract Background A number of conservation and societal issues require understanding how species are distributed on the landscape, yet ecologists are often faced with a lack of data to develop models at the resolution and extent desired, resulting in inefficient use of conservation resources. Such a situation presented itself in our attempt to develop waterfowl distribution models as part of a multi-disciplinary team targeting the control of the highly pathogenic H5N1 avian influenza virus in China. Methods Faced with limited data, we built species distribution models using a habitat suitability approach for China’s breeding and non-breeding (hereafter, wintering) waterfowl. An extensive review of the literature was used to determine model parameters for habitat modeling. Habitat relationships were implemented in GIS using land cover covariates. Wintering models were validated using waterfowl census data, while breeding models, though developed for many species, were only validated for the one species with sufficient telemetry data available. Results We developed suitability models for 42 waterfowl species (30 breeding and 39 wintering) at 1 km resolution for the extent of China, along with cumulative and genus level species richness maps. Breeding season models showed highest waterfowl suitability in wetlands of the high-elevation west-central plateau and northeastern China. Wintering waterfowl suitability was highest in the lowland regions of southeastern China. Validation measures indicated strong performance in predicting species presence. Comparing our model outputs to China’s protected areas indicated that breeding habitat was generally better covered than wintering habitat, and identified locations for which additional research and protection should be prioritized. Conclusions These suitability models are the first available for many of China’s waterfowl species, and have direct utility to conservation and habitat planning and prioritizing management of critically important areas, providing an example of how this approach may aid others faced with the challenge of addressing conservation issues with little data to inform decision making.