57 research outputs found

    Behavioral Correlates for Quitting Opioids among Opioid-Dependent Pregnant and Non-Pregnant Women of Childbearing Age in Rural Appalachia

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    Background: The opioid epidemic is particularly worrisome in the pregnant population, wherein concerns are raised about the health of a mother and her child, resulting in an alarming incidence and prevalence of Neonatal Abstinence Syndrome (NAS). The 2016 National Survey on Drug Use and Health (NSDUH) show the rate of illicit psychoactive substance use among the females aged 12 or older was 15.5% in the past year. Among pregnant women aged 15 to 44, 6.3% were illicit psychoactive substance users. In Tennessee, the number of hospital discharged NAS cases from 2002 to 2013 increased from 1.50 to 16.6 cases per 1,000 live births. This number is triple the national incidence of NAS cases over the same time period. Between 2013 and 2016, at least 52.5% of children diagnosed with NAS in Tennessee have had exposure to one prescription drug, while 27.2% were exposed to a combination of prescribed medications and illicit substances. We examined the behavioral correlates that determine the wish to quit opioids or not to quit opioids among opioid-dependent pregnant and non-pregnant women in rural Appalachia. Methods: Ten women of childbearing age, whether pregnant or not, who were receiving prescribed opioids, were recruited to join the study. All the participating women were also receiving physician-managed Medication Assisted Treatment (MAT) therapy for the treatment of severe opioid use disorder, or are currently being prescribed an opioid medication. Study variables included age, Hamilton Depression Rating Scale (HAM-D), Visual Analogue Scale – Pain (VAS-P), the Modified Opiate Craving Scale (MOCS), the Visual Analog Commitment to Quit Opiates, the McGill Pain Index (MPI), prescriptions, tobacco and nicotine use, illicit substance use, the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES), and the Adverse Childhood Experience (ACE) questionnaire. The HAM-D, MOCS, MPI, and SOCRATES scores were log-transformed to approximate a normal distribution. Descriptive statistics and the Spearman’s rank correlation (with a 95% Confidence Interval) were conducted to examine significant behavioral correlates for quitting opioids. Results: Descriptive statistics show that women with higher HAM-D and MOCS scores are not likely to express willingness to quit opioids. There is a statistically significant strong positive correlation of 0.679 (pppp Conclusion: Women who recognize the need to quit opioids or are “taking steps” to quit are more likely to quit opioids. Women with high depression and pain scores are not likely to quit opioids. Non-opioid medications may reduce the number of opioid-dependent pregnant and non-pregnant women of childbearing age, and, in turn, lower the currently high incidence and prevalence rates of NAS

    A Suzaku Search for Non-thermal Emission at Hard X-ray Energies in the Coma Cluster

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    The brightest cluster radio halo known resides in the Coma cluster of galaxies. The relativistic electrons producing this diffuse synchrotron emission should also produce inverse Compton emission that becomes competitive with thermal emission from the ICM at hard X-ray energies. Thus far, claimed detections of this emission in Coma are controversial (Fusco-Femiano et al. 2004; Rossetti & Molendi 2004). We present a Suzaku HXD-PIN observation of the Coma cluster in order to nail down its non-thermal hard X-ray content. The contribution of thermal emission to the HXD-PIN spectrum is constrained by simultaneously fitting thermal and non-thermal models to it and a spatially equivalent spectrum derived from an XMM-Newton mosaic of the Coma field (Schuecker et al. 2004). We fail to find statistically significant evidence for non-thermal emission in the spectra, which are better described by only a single or multi-temperature model for the ICM. Including systematic uncertainties, we derive a 90% upper limit on the flux of non-thermal emission of 6.0x10^-12 erg/s/cm^2 (20-80 keV, for photon index of 2.0), which implies a lower limit on the cluster-averaged magnetic field of B>0.15 microG. Our flux upper limit is 2.5x lower than the detected non-thermal flux from RXTE (Rephaeli & Gruber 2002) and BeppoSAX (Fusco-Femiano et al. 2004). However, if the non-thermal hard X-ray emission in Coma is more spatially extended than the observed radio halo, the Suzaku HXD-PIN may miss some fraction of the emission. A detailed investigation indicates that ~50-67% of the emission might go undetected, which could make our limit consistent with these detections. The thermal interpretation of the hard Coma spectrum is consistent with recent analyses of INTEGRAL (Eckert et al. 2007) and Swift (Ajello et al. 2009) data.Comment: 12 pages, 10 figures, Accepted for publication in the Astrophysical Journa

    ChIP-seq analysis reveals distinct H3K27me3 profiles that correlate with transcriptional activity

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    Transcriptional control is dependent on a vast network of epigenetic modifications. One epigenetic mark of particular interest is tri-methylation of lysine 27 on histone H3 (H3K27me3), which is catalysed and maintained by Polycomb Repressive Complex 2 (PRC2). Although this histone mark is studied widely, the precise relationship between its local pattern of enrichment and regulation of gene expression is currently unclear. We have used ChIP-seq to generate genome-wide maps of H3K27me3 enrichment, and have identified three enrichment profiles with distinct regulatory consequences. First, a broad domain of H3K27me3 enrichment across the body of genes corresponds to the canonical view of H3K27me3 as inhibitory to transcription. Second, a peak of enrichment around the transcription start site (TSS) is commonly associated with ‘bivalent’ genes, where H3K4me3 also marks the TSS. Finally and most surprisingly, we identified an enrichment profile with a peak in the promoter of genes that is associated with active transcription. Genes with each of these three profiles were found in different proportions in each of the cell types studied. The data analysis techniques developed here will be useful for the identification of common enrichment profiles for other histone modifications that have important consequences for transcriptional regulation

    HBO1 is required for the maintenance of leukaemia stem cells.

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    Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings

    Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

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    Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

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

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    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

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
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