Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism‐of‐action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug ...sensitivity measurements for 397 unique anti‐cancer drugs with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein–protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin–protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on‐target and off‐target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss‐of‐fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss‐of‐function screens can elucidate mechanism‐of‐action to advance drug development.
Synopsis
This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response.
CRISPR screens reveal important aspects of drug mechanism‐of‐action, specifically in the context of cellular activity, isoform specificity, off‐target and polypharmacological effects.
By leveraging protein interaction networks that underlie drug‐responses, novel drug‐target interactions involving anti‐apoptotic MCL1 inhibitors are identified.
Improved pharmacogenomic biomarker discovery using two independent and orthogonal cell viability screens.
This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response.
The goal of this study was to determine whether youth in foster care with natural mentors during adolescence have improved young adult outcomes.
We used data from waves I to III of the National ...Longitudinal Study of Adolescent Health (1994-2002). Individuals who reported that they had ever been in foster care at wave III were included. Youth were considered mentored when they reported the presence of a nonparental adult mentor in their life after they were 14 years of age and reported that the relationship began before 18 years of age and had lasted for at least 2 years. Outcomes were assessed at wave III and included measures of education/employment, psychological well-being, physical health, and participation in unhealthy behaviors as well as a summary measure representing the total number of positive outcomes.
A total of 310 youth met the inclusion criteria; 160 youth were mentored, and 150 youth were nonmentored. Demographic characteristics were similar for mentored and nonmentored youth. Mentored youth were more likely to report favorable overall health and were less likely to report suicidal ideation, having received a diagnosis of a sexually transmitted infection, and having hurt someone in a fight in the past year. There was also a borderline significant trend toward more participation in higher education among mentored youth. On the summary measure, mentored youth had, on average, a significantly greater number of positive outcomes than nonmentored youth. CONCLUSIONS; Mentoring relationships are associated with positive adjustment during the transition to adulthood for youth in foster care. Strategies to support natural mentoring relationships for this population should be developed and evaluated.
The distribution and organisation of benthic organisms on tropical reefs are typically heterogenous yet display distinct zonation patterns across depth gradients. However, there are few datasets ...which inform our understanding of how depth zonation in benthic community composition varies spatially among and within different reef systems. Here, we assess the depth zonation in benthic forereef slope communities in the Central Indian Ocean, prior to the back-to-back bleaching events in 2014–2017. We compare benthic communities between shallow (5–10 m) and deep (20–25 m) sites, at two spatial scales: among and within 4 atolls. Our analyses showed the variation in both major functional groups and hard coral assemblages between depth varied among atolls, and within-atoll comparisons revealed distinct differences between shallow and deep forereef slope communities. Indicator taxa analyses characterising the hard coral community between depths revealed a higher number of coral genera characteristic of the deep forereef slopes (10) than the shallow forereef slopes (6). Only two coral genera consistently associated with both depths across all atolls, and these were Acropora and Porites. Our results reveal spatial variation in depth zonation of benthic communities, potentially driven by biophysical processes varying across depths and atolls, and provide a baseline to understand and measure the impacts of future global climate change on benthic communities across depths.
•Significant depth-by-atoll interactions drove benthic community structure.•CCA, turf algae, sponge and soft coral cover were highest on deep reefs.•Hard coral, dead coral and bare substrate cover were highest on shallow reefs.•Acropora, Stylophora and Pocillopora characterised shallow reefs.•Acropora and Porites consistently associated with both shallow and deep reef zones.
Foster youth are at risk of poor adult outcomes. Research on the role of mentoring relationships for this population suggests the value of strategies that increase their access to adult sources of ...support, both while in foster care and as they reach adulthood. We conducted semi-structured, individual qualitative interviews with 23 former foster youth ages 18–25 regarding their relationships with supportive non-parental adults. We sought to identify factors that influence the formation, quality, and duration of these relationships and to develop testable hypotheses for intervention strategies. Findings suggest several themes related to relationship formation with non-parental adults, including barriers (e.g., youth's fears of being hurt) and facilitators (e.g., patience from the adult). Distinct themes were also identified relating to the ongoing development and longevity of these relationships. Youth also described multiple types of support and positive contributions to their development. Proposed intervention strategies include systematic incorporation of important non-parental adults into transition planning, enhanced training and matching procedures within formal mentoring programs, assistance for youth to strengthen their interpersonal awareness and skills, and the targeting of specific periods of need when linking youth to sources of adult support. Recommended research includes the development, pilot-testing, and evaluation of proposed strategies.
► Positive impacts from relationships with non-parental adults are described. ► Barriers and facilitators of these relationships are highlighted. ► Factors influencing developing and ongoing relationships appear to be distinct. ► Strategies to better capitalize on support from non-parental adults are proposed.
ABSTRACT
Transdiagnostic models of psychopathology address many of the shortcomings common to categorical diagnostic systems. These empirically derived models conceptualize psychopathology as a few ...broad interrelated and hierarchically arranged dimensions, with an overarching general psychopathology dimension, the p‐factor, at the apex. While transdiagnostic models are gaining prominence in mental health research, the lack of available tools has limited their clinical translation. The present study explored the potential of creating transdiagnostic scales from the joint factor structure of the Personality Assessment Inventory, Alternative Model of Personality Disorder trait scales (AMPD), and the clinical scales of the SPECTRA: Indices of Psychopathology (SPECTRA). Exploratory factor analysis in a clinical sample (n = 212) identified five factors corresponding to the Negative Affect/Internalizing, Detachment, Antagonism/Externalizing, Disinhibition/Externalizing, and Thought Disorder transdiagnostic dimensions. Goldberg's “Bass‐Ackward” method supported a hierarchical structure. Five composite transdiagnostic scales were created by summing each factor's highest loading PAI and SPECTRA scales. A global psychopathology scale was created by summing the five composite scales. All the composite scales demonstrated adequate internal consistency. Correlations between the composite scales and the NEO Five‐Factor Inventory‐3 provide initial validity evidence for four composite and global scales. The composite thought disorder scale had no conceptually corresponding NEO domain. Clinical implications and study limitations are discussed.
The Alternative Model for Personality Disorders (AMPD) in Section III of the fifth edition of the
; American Psychiatric Association, 2013) conceptualizes personality pathology as a combination of ...impairment (Criterion A) and traits (Criterion B). One measure used to develop Criterion A was the Social Cognition and Object Relations Scale - Global Rating Method (SCORS-G), which is a multidimensional, object-relational clinician-rated measure of personality functioning. Although there are conceptual links between the AMPD and SCORS-G dimensions, there exists no research examining the relationship. To address this, we examined associations between the SCORS-G dimensions and measures of the AMPD constructs in a large, archival dataset of outpatients and inpatients. More pathological scores on SCORS-G dimensions reflecting self- and interpersonal functioning were associated with greater pathological traits and impairment. Overall, results support further investigation into SCORS-G as a useful measure in AMPD research and assessment.
Left ventricular assist devices (LVADs) require anticoagulation therapy with vitamin K antagonists to reduce the risk of thrombotic events. The quality of anticoagulation may be assessed by the time ...in therapeutic range (TTR). We analyzed a retrospective cohort of LVAD patients at a single institution from January 2012 to September 2014. Primary outcomes included TTR during the study time period and TTR 30 days preceding a bleeding or thrombotic event. Fifty-one patients (mean age 57.0 ± 14.6 years; 78% male) had an overall TTR of 52%. Median international normalized ratio (INR) preceding a bleeding and thrombotic event was 2.7 and 2.2, respectively (p = 0.049). In the 30 days before an event, patients with a bleeding event were more likely to be on low-dose aspirin (37% vs. 12%; p = 0.018) and spend a higher proportion of time above therapeutic range (41% vs. 17%; p = 0.007) compared with those with thrombotic events. The association between a greater percentage of time above therapeutic range in the 30 days before a bleeding event demonstrates the importance of avoiding a supratherapeutic INR in the LVAD patient population and the usefulness of TTR as a measure of the overall quality of anticoagulation and monitoring in an LVAD cohort.
Abstract Purpose To determine the prevalence of anxiety and depressive disorders in youth with asthma compared with a control sample of youth and to determine the sociodemographic and clinical ...characteristics associated with having one or more anxiety/depressive disorders among youth with asthma. Methods A telephone interview was offered to all youth aged 11–17 years with asthma (N = 781) and a random sample of similar aged controls (N = 598) enrolled in a Health Maintenance Organization. The C-DISC-4.0 was used to diagnose anxiety and depressive disorders and reliable and valid questionnaires were used to assess severity of anxiety and depressive symptoms. Automated diagnostic, pharmacy and health use data were used to measure asthma treatment intensity, asthma severity and nonasthmatic medical comorbidity. One parent was interviewed to assess sociodemographic variables, child/adolescent psychiatric symptoms and to confirm the asthma diagnosis. Results In all, 16.3% of youth with asthma compared with 8.6% of youth without asthma met DSM-IV criteria for one or more anxiety and depressive disorders (OR = 1.92, 95% CI = 1.13–3.28). Independent factors associated with a significantly higher likelihood of meeting criteria for one or more anxiety or depressive disorders included female gender OR = 1.96 (95% CI = 1.27, 3.03), living in a single-parent household, OR = 1.96 (95% CI = 1.26, 3.07), more parent-reported externalizing behaviors OR = 1.03 (95% CI = 1.01, 1.05), more recent diagnosis of asthma OR = 0.94 (95% CI = 0.89, 0.98), and more impairment on the asthma physical health scale OR = 0.95 (95% CI = 0.94, 0.96). Conclusions Youth with asthma have an almost twofold higher prevalence of comorbid DSM-IV anxiety and depressive disorders compared with control youth. Clinical factors associated with meeting criteria for one or more anxiety and depressive included more recent asthma diagnosis, more impairment on the asthma physical health scale, and increased externalizing behaviors.
Patients with a primary mental health condition account for nearly 10% of pediatric hospitalizations nationally, but little is known about the quality of care provided for them in hospital settings. ...Our objective was to develop and test medical record-based measures used to assess quality of pediatric mental health care in the emergency department (ED) and inpatient settings.
We drafted an evidence-based set of pediatric mental health care quality measures for the ED and inpatient settings. We used the modified Delphi method to prioritize measures; 2 ED and 6 inpatient measures were operationalized and field-tested in 2 community and 3 children's hospitals. Eligible patients were 5 to 19 years old and diagnosed with psychosis, suicidality, or substance use from January 2012 to December 2013. We used bivariate and multivariate models to examine measure performance by patient characteristics and by hospital.
Eight hundred and seventeen records were abstracted with primary diagnoses of suicidality (
= 446), psychosis (
= 321), and substance use (
= 50). Performance varied across measures. Among patients with suicidality, male patients (adjusted odds ratio: 0.27,
< .001) and African American patients (adjusted odds ratio: 0.31,
= .02) were less likely to have documentation of caregiver counseling on lethal means restriction. Among admitted suicidal patients, 27% had documentation of communication with an outside provider, with variation across hospitals (0%-38%;
< .001). There was low overall performance on screening for comorbid substance abuse in ED patients with psychosis (mean: 30.3).
These new pediatric mental health care quality measures were used to identify sex and race disparities and substantial hospital variation. These measures may be useful for assessing and improving hospital-based pediatric mental health care quality.
PDF
