29 research outputs found
An Exploration of Partnerships Between Disability Service Units and Academic Libraries
The University of Saskatchewanâs University Library has been partnering with its institutionâs Disability Services unit for almost twenty-five years to provide space and equipment for students with disabilities in some of its library locations. This partnership has grown from piloting a Kurzweil reader, to the development of multiple assistive technology and exam writing rooms, to the recent creation of a multi-purpose room. These library spaces complement spaces Disability Services has within its own office suite and reflect the growth in the number of students registered with them, a widening spectrum of disabilities, and a collaborative desire to make disability services and resources more accessible. A literature scan revealed a small number of articles about partnerships, many of which were in response to legislation. A survey directed at North American post-secondary institutionsâ Disability Services employees surfaced further information about partnerships, but did not reveal any common best practices. With the increase in the number of students with disabilities attending academic institutions and a changing landscape of what is defined as a disability, how and how well academic libraries and Disability Services units are partnering to respond to these changes appears to require further exploration and assessment
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 nonâcritically 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 (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree 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 supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (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 supportâfree 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
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Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.
PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes
The contribution of genetic and environmental influences on DNA methylation at autosomal sites differs as a function of average DNA methylation level at that location.
<p>Shown are estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) against mean DNA methylation level. The most heritable sites are characterized by intermediate levels of DNA methylation.</p
The contribution of additive genetic and environmental factors to levels of DNA methylation.
<p>Shown are the results from structural equation models to estimate the mean proportion of variance in DNA methylation explained by additive genetic effects (A), shared environmental effects (C) and unshared (or unique) environmental effects (E) across Illumina 450K probes. Results are presented separately for DNA methylation sites located on the autosomes and X-chromosome, and stratified by whether they have intermediate levels of DNAm and/or are âvariableâ.</p
DNA methylation at sites associated with tobacco smoking is strongly influenced by additive genetic factors.
<p>Shown is a series of density plots for estimates of (<b>a</b>) additive genetic effects (A), (<b>b</b>) shared environmental effects (C) and (<b>c</b>) non-shared environmental effects (E) at 97 differentially methylated positions (DMPs) associated with smoking (green). Also shown are density plots for A, C and E at âbackgroundâ sites not associated with smoking (red). Shown below is a series of scatterplots showing the correlation in DNA methylation between MZ twins (x-axis) against DZ twins (y-axis) for sites associated with smoking in (<b>d</b>) all twins, (<b>e</b>) concordant non-smokers (n = 503 twin-pairs), (<b>f</b>) twins discordant for smoking status (n = 123 twin-pairs) and (<b>g</b>) concordant smokers (n = 106 twin-pairs). The shaded area on each plot indicates the heritability estimate (using Falconerâs formula) for each site.</p
DNA methylation sites at which inter-individual variation is correlated across tissues are characterized by higher levels of heritability.
<p>(<b>a</b>) A density plot of heritability estimates for DNA methylation at sites split by the extent to which DNA methylation co-varies between whole blood and the prefrontal cortex using data from Hannon et al (2015). Heritability is significantly higher in probes where the cross-tissue covariation in DNA methylation is high (r<sup>2</sup> > 0.5, red). (<b>b-h</b>) An example of a probe (cg08449049) at which DNA methylation is strongly influenced by additive genetic effects and also co-varies between blood and multiple regions of the human brain. Shown are scatterplots of DNA methylation values at cg08449049 for (<b>b</b>) MZ (corr = 0.851) and <b>c)</b> DZ (corr = 0.364) twin pairs. Each point represents an individual twin-pair. (<b>d</b>) A boxplot of the distribution of DNA methylation levels at cg08449049 in blood and four brain regions (PFC = prefrontal cortex, EC = entorhinal cortex, STG = superior temporal gyrus, CER = cerebellum) from the same individual donors using data generated by Hannon et al (2015). (<b>e-h</b>) Scatterplots of the DNA methylation values in blood against the DNA methylation values in each of the four brain regions showing that there is significant covariation across tissues.</p
Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600âMutant Colorectal Cancer
PurposeTo evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).Patients and methodsA total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.ResultsOf 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.ConclusionThe combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted
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Genomic landscape of cell-free DNA in patients with colorectal cancer
"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights.Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164-73. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 127