About the Authors: Jeffrey A. Bridge Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original ...draft, Writing – review & editing * E-mail: Jeff.Bridge@Nationwidechildrens.org Affiliations Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States of America, The Ohio State University College of Medicine, Columbus, OH, United States of America ORCID logo https://orcid.org/0000-0003-3726-8978 Joel B. Greenhouse Roles Conceptualization, Formal analysis, Methodology, Writing – review & editing Affiliation: Carnegie Mellon University, Pittsburgh, PA, United States of America Kelly J. Kelleher Roles Conceptualization, Investigation, Writing – review & editing Affiliations Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States of America, The Ohio State University College of Medicine, Columbus, OH, United States of America John V. Campo Roles Conceptualization, Investigation, Methodology, Supervision, Writing – review & editing Affiliation: West Virginia University, Morgantown, WV, United States of America Citation: Bridge JA, Greenhouse JB, Kelleher KJ, Campo JV (2020) Formal Comment: Romer study fails at following core principles of reanalysis. ...his forecasts will have less precision than ours. ...his suggestion that the interest of the producers of 13RW in “portraying the harmful effects of youth culture, especially on young women, may have had some benefits” 1 could be interpreted as gratuitous. ...our original analysis controlled for the secular trends that Romer mentions and was the product of interdisciplinary team science.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective: Little is known about the mental health care received by young people after an episode of deliberate self-harm. This study examined predictors of emergency department (ED) discharge, ...mental health assessments in the ED, and follow-up outpatient mental health care for Medicaid-covered youth with deliberate self-harm. Method: A retrospective longitudinal cohort analysis was conducted of national 2006 Medicaid claims data supplemented with the Area Resource File and a Substance Abuse and Mental Health Services Administration Medicaid policy survey of state policy characteristics focusing on ED treatment episodes by youth 10 to 19 years old for deliberate self-harm (n = 3,241). Rates and adjusted risk ratios (ARR) of discharge to the community, mental health assessments in the ED, and outpatient visits during the 30 days after the ED visit were assessed. Results: Most patients (72.9%) were discharged to the community. Discharge was inversely related to recent psychiatric hospitalization (ARR 0.75, 99% confidence interval CI 0.63-0.90). Thirty-nine percent of discharged patients received a mental health assessment in the ED and a roughly similar percentage (43.0%) received follow-up outpatient mental health care. Follow-up mental health care was directly related to recent outpatient (ARR 2.58, 99% CI 2.27-2.94) and inpatient (ARR 1.33, 99% CI 1.14-1.56) mental health care and inversely related to Hispanic ethnicity (ARR 0.78, 99% CI 0.64-0.95) and residence in a county with medium-to-high poverty rates (ARR 0.84, 99% CI 0.73-0.97). Conclusions: A substantial proportion of young Medicaid beneficiaries who present to EDs with deliberate self-harm are discharged to the community and do not receive emergency mental health assessments or follow-up outpatient mental health care. (Contains 5 tables.)
The aim of this study was to determine the external validity of Taekwondo-specific exercise protocols. 10 male international Taekwondo competitors (age 18±2 years) took part in a championship combat ...and an exercise protocol that simulated the activity pattern of Taekwondo combat. Heart rate and venous blood samples were obtained in both settings. Despite similarity in the activity profiles, the championship Taekwondo combats elicited higher (p<0.05) heart rate (188±8 beats.min - 1), plasma lactate (12.2±4.6 mmol.L - 1), glucose (10.3±1.1 mmol.L - 1), -glycerol (143.4±49.4 µmol.L - 1), -adrena-line (2.7±1.7 nmol.L - 1) and noradrenaline (14.3±9.4 nmol.L - 1) responses than the -Taekwondo exercise protocol (heart rate: 172±4 beats.min - 1; plasma lactate: 3.6±2.7 mmol.L - 1; glucose: 5.9±0.8 mmol.L - 1; glycerol: 77.7±21.3 µmol.L - 1; adrenaline: 0.6±0.2 nmol.L - 1 and noradrenaline: 3.0±1.1 nmol.L - 1). This discrepancy in the physiological responses appeared to be mediated by a reduced stress response in the Taekwondo exercise protocol. These findings suggest that Taekwondo-specific exercise protocols are not appropriate to study the physiological demands of Taekwondo. -Strategies designed to increase the stress response in this setting may be necessary to improve the external validity of this experimental framework.
CONTEXT The US Food and Drug Administration (FDA) has issued warnings that use of antidepressant medications poses a small but significantly increased risk of suicidal ideation/suicide attempt for ...children and adolescents. OBJECTIVE To assess the efficacy and risk of reported suicidal ideation/suicide attempt of antidepressants for treatment of pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders. DATA SOURCES AND STUDY SELECTION PubMed (1988 to July 2006), relevant US and British regulatory agency reports, published abstracts of important scientific meetings (1998-2006), clinical trial registries, and information from authors. Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine) in participants younger than 19 years with MDD, OCD, or non-OCD anxiety disorders. DATA EXTRACTION Information was extracted on study characteristics, efficacy outcomes, and spontaneously reported suicidal ideation/suicide attempt. DATA SYNTHESIS Twenty-seven trials of pediatric MDD (n = 15), OCD (n = 6), and non-OCD anxiety disorders (n = 6) were selected, and risk differences for response and for suicidal ideation/suicide attempt estimated by random-effects methods. Pooled risk differences in rates of primary study-defined measures of responder status significantly favored antidepressants for MDD (11.0%; 95% confidence interval {CI}, 7.1% to 14.9%), OCD (19.8% 95% CI, 13.0% to 26.6%), and non-OCD anxiety disorders (37.1% 22.5% to 51.7%), corresponding to a number needed to treat (NNT) of 10 (95% CI, 7 to 15), 6 (4 to 8), and 3 (2 to 5), respectively. While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs placebo (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 95% CI, 77 to 1000), the pooled risk differences within each indication were not statistically significant: 0.9% (95% CI, −0.1% to 1.9%) for MDD, 0.5% (−1.2% to 2.2%) for OCD, and 0.7% (−0.4% to 1.8%) for non-OCD anxiety disorders. There were no completed suicides. Age-stratified analyses showed that for children younger than 12 years with MDD, only fluoxetine showed benefit over placebo. In MDD trials, efficacy was moderated by age, duration of depression, and number of sites in the treatment trial. CONCLUSIONS Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.
Evidence for proximal risk factors for suicide is based on case–control psychological autopsy studies, with these reports showing that mood and substance use disorders are the most prevalent mental ...disorders among suicide decedents worldwide and are associated with marked risk. However, moderators of risk and the degree of risk associated with (nonalcohol) drug use disorder are unknown. A comprehensive search was used to identify 35 case–control psychological autopsy studies published worldwide over a 30‐year period that were metaanalyzed using random effects models. Major depression, odds ratio (95% confidence interval) = 9.14 (5.53, 15.09), and drug use disorder, OR (95% CI) = 7.18 (3.22, 16.01), had large effect sizes, among other results. Risk estimates associated with major depression were greater in studies with a larger proportion of women and those conducted in Asia compared with other regions. There was no evidence of publication bias or that any one study had a disproportionate impact on findings. Risk for suicide associated with major depression appears to be moderated by sex and/or world region. Drug use disorder is a potent risk factor, illustrating the importance of assessing drug use in clinical risk assessment.
Abstract
Pharmacologically disrupting fear memory reconsolidation dramatically reduces fear behaviour. For example, 2–3 min of tarantula exposure followed by 40 mg of propranolol HCl (i.e., a ...reconsolidation intervention) abruptly decreased spider avoidance, an effect that persisted one year later. However, the success of reconsolidation interventions is not guaranteed: Pavlovian fear-conditioning research shows that the window to target memory reconsolidation is small and easy to miss. If exposure is too long to trigger reconsolidation, but too short for extinction learning, an inactive transitional limbo state occurs, rendering the fear memory unchanged and insensitive to amnesic agents. In this pre-registered study, we aimed to find this behaviourally-controlled boundary condition. Spider-fearful participants underwent a ~3 min (
n
= 23) or ~14 min (
n
= 20) exposure to a tarantula, intended to trigger reconsolidation or the limbo state respectively, followed by 40 mg of propranolol. We expected greater spider fear reduction after 3 than 14 min of exposure. Unexpectedly, there were no group differences on any outcome measures. In both groups, Bayesian analysis revealed a marked reduction in fear behaviour towards a generalisation stimulus (a house spider) accompanied by lower self-reported distress, with a sharp decline in spider fear scores two days after treatment that persisted one year later. Possible explanations include that the boundary conditions of reconsolidation are wider in older and stronger memories than experimentally-induced fears, or that alternative processes caused the treatment effects. Although the mechanism is unclear, these results carry a tentative promising message for the potential of brief reconsolidation-targeting interventions to mitigate irrational fears.
Detection of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma is important for classification and prognostication. In situ hybridization (ISH) is a commonly used HR-HPV-specific ...test that targets viral RNA or DNA. The College of American Pathologists (CAP) provides proficiency testing for laboratories performing HR-HPV ISH.
To compare the analytical performance of RNA- and DNA-based ISH methods on CAP HR-HPV proficiency tests.
Data from the 2016-2018 CAP HPV ISH proficiency testing surveys were reviewed. These surveys consist of well-characterized samples with known status for HR-HPV, including 1 to 2 copies, 50 to 100 copies, 300 to 500 copies, and no copies of HR-HPV per cell.
Ninety-five participants submitted 1268 survey results from 20 cores. Overall, RNA ISH had a significantly higher percentage of correct responses than DNA ISH: 97.4% (450 of 462) versus 80.6% (650 of 806) (
< .001). This disparity appears to be the consequence of a superior sensitivity of RNA ISH compared to DNA ISH for samples with 1 to 2 and with 50 to 100 copies of HR-HPV per cell: 95.2% (120 of 126) versus 53.8% (129 of 240),
< .001, respectively, and 100% (89 of 89) versus 76.3% (119 of 156),
< .001, respectively.
An assessment of CAP HR-HPV proficiency test performance indicates that RNA ISH shows significantly higher accuracy than DNA ISH owing to higher analytical sensitivity of RNA ISH in tumors with low (1-2 copies per cell) to intermediate (50-100 copies per cell) HR-HPV viral copy numbers. These data support the use of RNA over DNA ISH in clinical laboratories that perform HR-HPV testing as part of their testing algorithms.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The companion diagnostic test for checkpoint inhibitor immune therapy is an immunohistochemical test for PD-L1. The test has been shown to be reproducible for expression in tumor cells, but not in ...immune cells. Immune cells were used in the IMpassion130 trial which showed PD-L1 expression was associated with a better outcome. Two large studies have been done assessing immune cell PD-L1 expression in lung cancer. Here, we reanalyze one of those studies, to show that, even with an easier scoring method, there is still only poor agreement between assays and pathologist for immune cell PD-L1 expression.
The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite ...response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite.
Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.
A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes.
These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Accurate clinical assessment of a patient's response to treatment for glioblastoma multiforme (GBM), the most malignant type of primary brain tumor, is undermined by the wide patient-to-patient ...variability in GBM dynamics and responsiveness to therapy. Using computational models that account for the unique geometry and kinetics of individual patients' tumors, we developed a method for assessing treatment response that discriminates progression-free and overall survival following therapy for GBM. Applying these models as untreated virtual controls, we generate a patient-specific "Days Gained" response metric that estimates the number of days a therapy delayed imageable tumor progression. We assessed treatment response in terms of Days Gained scores for 33 patients at the time of their first MRI scan following first-line radiation therapy. Based on Kaplan-Meier analyses, patients with Days Gained scores of 100 or more had improved progression-free survival, and patients with scores of 117 or more had improved overall survival. Our results demonstrate that the Days Gained response metric calculated at the routinely acquired first post-radiation treatment time point provides prognostic information regarding progression and survival outcomes. Applied prospectively, our model-based approach has the potential to improve GBM treatment by accounting for patient-to-patient heterogeneity in GBM dynamics and responses to therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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