Test-to-Stay After Exposure to SARS-CoV-2 in K-12 Schools

OBJECTIVES: We evaluated the safety and efficacy of a test-to-stay program for unvaccinated students and staff who experienced an unmasked, in-school exposure to someone with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Serial testing instead of quarantine was offered to asymptomatic contacts. We measured secondary and tertiary transmission rates within participating schools and in-school days preserved for participants. METHODS: Participating staff or students from universally masked districts in North Carolina underwent rapid antigen testing at set intervals up to 7 days after known exposure. Collected data included location or setting of exposure, participant symptoms, and school absences up to 14 days after enrollment. Outcomes included tertiary transmission, secondary transmission, and school days saved among test-to-stay participants. A prespecified interim safety analysis occurred after 1 month of enrollment. RESULTS: We enrolled 367 participants and completed 14-day follow-up on all participants for this analysis. Nearly all (215 of 238, 90%) exposure encounters involved an unmasked index case and an unmasked close contact, with most (353 of 366, 96%) occurring indoors, during lunch (137 of 357, 39%) or athletics (45 of 357, 13%). Secondary attack rate was 1.7% (95% confidence interval: 0.6%-4.7%) based on 883 SARS-CoV-2 serial rapid antigen tests with results from 357 participants; no tertiary cases were identified, and 1628 (92%) school days were saved through test-to-stay program implementation out of 1764 days potentially missed. CONCLUSION: After unmasked in-school exposure to SARS-CoV-2, even in a mostly unvaccinated population, a test-to-stay strategy is a safe alternative to quarantine

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Role of cAMP-Dependent Protein Kinase in Controlling Aggregation and Postaggregative Development inDictyostelium

AbstractWe have examined the role of cAMP-dependent protein kinase (PKA) in controlling aggregation and postaggregative development inDictyostelium.We previously showed that cells in which the gene encoding the PKA catalytic subunit has been disrupted (pkacat−cells) are unable to aggregate [S. K.O. Mann and R.A. Firtel (1991). A developmentally regulated, putative serine/threonine protein kinase is essential for development inDictyostelium. Mech. Dev.35, 89–102]. We show thatpkacat−cells are unable to activate adenylyl cyclase in response to cAMP stimulation due to the inability to express the aggregation-stage, G-protein-stimulated adenylyl cyclase (ACA). Constitutive expression of ACA from an actin promoter results in a high level of Mn2+-stimulated adenylyl cyclase activity and restores chemoattractant- and GTPγS-stimulated adenylyl cyclase activity but not the ability to aggregate. Similarly, expression of the constitutively active, non-G protein-coupled adenylyl cyclase ACG inpkacat−cells also does not restore the ability to aggregate, although ACG can complement cells in which theACAgene has been disrupted. These results indicate thatpkacat−cells lack multiple, essential aggregation-stage functions. As the mound forms, high, continuous levels of extracellular cAMP functioning through the cAMP serpentine receptors activate a transcriptional cascade that leads to cell-type differentiation and morphogenesis. The first step is the induction and activation of the transcription factor GBF and downstream postaggregative genes, followed by the induction of prestalk- and prespore-specific genes. We show thatpkacat−cells induce postaggregative gene expression in response to exogenous cAMP, but the level of induction of some of these genes, includingGBF,is reduced.SP60(a prespore-specific gene) is not induced andecmA(a prestalk-specific gene) is induced to very low levels. Expressing GBF constitutively inpkacat−cells restoresecmAexpression to a moderate level, butSP60is not detectably induced. Overexpression of PKAcat from the Actin 15 (Act15), ecmAprestalk, and thePKAcatpromoters inpkacat−cells results in significant aberrant spatial patterning of prestalk and prespore cells, as determined bylacZ reporter studies. Our studies identify new, essential regulatory roles for PKA in mediating multicellular development

Intellectual Property Rights: Governing Cultural and Educational Futures

This article uses Foucauldian theories of governmentality to examine ways in which intellectual property rights regimes are embedded within broad spectrums of global and globalising discourses and yet are enacted through changing subjectivities at the local level. Using the 2004 Australia–United States Free Trade Agreement as a case in point, it shows how culture, education, free trade, foreign policy, and national security intersect and have the potential to limit access to cultural knowledge and textual resources for young people and educators

In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.

Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite&nbsp;the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models