The Initial Implementation Patterns of the C3 Framework in Maryland School Districts

This qualitative study examined the initial implementation patterns of the C3 Framework in Maryland school districts. The National Council for the Social Studies published the C3 Framework as a guide for state departments of education to revise social studies standards. This study sought to determine how district social studies leaders viewed the C3 Framework, how the district social studies leaders translated the C3 Framework in their districts, and why they chose to implement the C3 Framework as they did. The primary data sources were interviews and documents; the data were analyzed using constant comparative analysis to identify overarching attitudes toward the C3 Framework and implementation patterns. Policy implementation research specifically related to cognitive theory and capacity was used to help explain the implementation process. This study found that beliefs, financial and human resources, and time were the main factors influencing implementation. The study also found that how districts approach and support reform implementation for social studies might be different from how districts previously approached and supported new standards and curriculum in other content areas. In this study, all district social studies leaders focused primarily on disciplinary literacy components of the C3 Framework, specifically those related to history. District social studies leaders focused on document-based activities, student projects, and writing to source but few addressed the Inquiry Arc in a way that challenged or altered expected approaches to teaching and learning social studies. Many used the C3 Framework as leverage to justify the continued work and focus on historical thinking and other disciplinary literacy work in their districts. Most district social studies leaders used inquiry and disciplinary literacy as synonyms; the pattern suggests that further work to help educators distinguish between these related approaches to learning is necessary to help support the use of inquiry in the social studies. As more states use the C3 Framework in state standards, this study might help states and districts guide how they approach its implementation

Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA.

INTRODUCTION: Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic and predictive tool in cancer patient care. A growing number of gene targets have been identified as diagnostic or actionable, requiring the development of reliable technology that provides analysis of multiple genes in parallel. We have developed the InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for the identification of clinically-relevant somatic alterations at low frequency in ctDNA across a panel of 35 cancer-related genes. MATERIALS AND METHODS: We present analytical validation of the eTAm-Seq technology across two laboratories to determine the reproducibility of mutation identification. We assess the quantitative performance of eTAm-Seq technology for analysis of single nucleotide variants in clinically-relevant genes as compared to digital PCR (dPCR), using both established DNA standards and novel full-process control material. RESULTS: The assay detected mutant alleles down to 0.02% AF, with high per-base specificity of 99.9997%. Across two laboratories, analysis of samples with optimal amount of DNA detected 94% mutations at 0.25%-0.33% allele fraction (AF), with 90% of mutations detected for samples with lower amounts of input DNA. CONCLUSIONS: These studies demonstrate that eTAm-Seq technology is a robust and reproducible technology for the identification and quantification of somatic mutations in circulating tumor DNA, and support its use in clinical applications for precision medicine

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA

<div><p>Introduction</p><p>Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic and predictive tool in cancer patient care. A growing number of gene targets have been identified as diagnostic or actionable, requiring the development of reliable technology that provides analysis of multiple genes in parallel. We have developed the InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for the identification of clinically-relevant somatic alterations at low frequency in ctDNA across a panel of 35 cancer-related genes.</p><p>Materials and methods</p><p>We present analytical validation of the eTAm-Seq technology across two laboratories to determine the reproducibility of mutation identification. We assess the quantitative performance of eTAm-Seq technology for analysis of single nucleotide variants in clinically-relevant genes as compared to digital PCR (dPCR), using both established DNA standards and novel full-process control material.</p><p>Results</p><p>The assay detected mutant alleles down to 0.02% AF, with high per-base specificity of 99.9997%. Across two laboratories, analysis of samples with optimal amount of DNA detected 94% mutations at 0.25%-0.33% allele fraction (AF), with 90% of mutations detected for samples with lower amounts of input DNA.</p><p>Conclusions</p><p>These studies demonstrate that eTAm-Seq technology is a robust and reproducible technology for the identification and quantification of somatic mutations in circulating tumor DNA, and support its use in clinical applications for precision medicine.</p></div

Plot showing sensitivity and inter-operator variability of eTAm-Seq technology using low, medium and high input DNA.

<p>Experiments were performed in two laboratories (Laboratory 1 –upper; Laboratory 2 –lower) by different operators, performed on separate days and different NGS runs.</p

Sensitivity of the eTAm-Seq technology with 8000 amplifiable copies of DNA input per sample.

<p>Sensitivity of the eTAm-Seq technology with 8000 amplifiable copies of DNA input per sample.</p

Quantitative agreement of 5% AF and 1% AF reference standard spiked into plasma, and measured by eTAm-Seq technology and dPCR.

<p>Mean mutant AF (%) ± SD are displayed for each technology (n = 5* (5% AF standard); n = 6 (1% AF standard)). By spiking into plasma containing background wild-type DNA, the resulting mix was confirmed to contain lower AFs than the original reference standards (original mutant AF values 5% standard: 5% (<i>EGFR</i>); 6.3% (<i>KRAS</i>, <i>NRAS</i>, <i>PIK3CA</i>); 1% standard: 1% (<i>EGFR</i>), 1.3% (<i>KRAS</i>, <i>NRAS</i>, <i>PIK3CA</i>). (*1 data point omitted due to anomalous extraction efficiency).</p

InVision liquid biopsy tumor profiling panel.

<p>The coverage per gene is indicated, including hotspots, comprehensive or full coverage of coding regions (70%–100% tiling coverage) and CNVs. SNVs = Single Nucleotide Variants; Indels = short insertions or deletions; CNVs = Copy Number Variants.</p