1,328 research outputs found
Structured professional judgment to assist the evaluation and safety planning of suicide risk: The Risk of Suicide Protocol (RoSP)
Background: The Risk of Suicide Protocol (RoSP) is a structured professional judgment (SPJ) scheme designed in line with NICE guidelines to improve clinicians' ability to evaluate and manage suicide risk.
Aims: This study aimed to evaluate the efficacy of RoSP in two settings: (1) unexpected deaths of people in the community who were known to mental health services; and (2) an inpatient hospital specializing in the assessment and treatment of patients with personality disorder.
Method: In Study 1, information from a database of unexpected deaths (N = 68) within an NHS health board was used to complete a RoSP assessment (blind to cause of death) and information from the Coroner's Court was used to assign people to suicide vs. natural causes/accidental death. In Study 2, patients (N = 62) were assessed on the RoSP upon admission to hospital and their self-injurious behaviors were recorded over the first 3 months of admission.
Results: (1) Evaluations using RoSP were highly reliable in both samples (ICCs 0.93–0.98); (2) professional judgment based on the RoSP was predictive of completed suicide in the community sample (AUC = 0.83) and; (3) was predictive of both suicide attempts (AUC = 0.81) and all self-injurious behaviors (AUC = 0.80) for the inpatient sample.
Conclusion: RoSP is a reliable and valid instrument for the structured clinical evaluation of suicide risk for use in inpatient psychiatric services and in community mental health services. RoSP's efficacy is comparable to well-established structured professional judgment instruments designed to predict other risk behavior (e.g., HCR-20 and the prediction of violence). The use of RoSP for the clinical evaluation of suicide risk and safety-planning provides a structure for meeting NICE guidelines for suicide prevention and is now evidence-based
Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study
Purpose
To determine the 12-year risk of developing an ipsilateral breast event (IBE) for women with ductal carcinoma in situ (DCIS) of the breast treated with surgical excision (lumpectomy) without radiation.
Patients and Methods
A prospective clinical trial was performed for women with DCIS who were selected for low-risk clinical and pathologic characteristics. Patients were enrolled onto one of two study cohorts (not randomly assigned): cohort 1: low- or intermediate-grade DCIS, tumor size 2.5 cm or smaller (n = 561); or cohort 2: high-grade DCIS, tumor size 1 cm or smaller (n = 104). Protocol specifications included excision of the DCIS tumor with a minimum negative margin width of at least 3 mm. Tamoxifen (not randomly assigned) was given to 30% of the patients. An IBE was defined as local recurrence of DCIS or invasive carcinoma in the treated breast. Median follow-up time was 12.3 years.
Results
There were 99 IBEs, of which 51 (52%) were invasive. The IBE and invasive IBE rates increased over time in both cohorts. The 12-year rates of developing an IBE were 14.4% for cohort 1 and 24.6% for cohort 2 (P = .003). The 12-year rates of developing an invasive IBE were 7.5% and 13.4%, respectively (P = .08). On multivariable analysis, study cohort and tumor size were both significantly associated with developing an IBE (P = .009 and P = .03, respectively).
Conclusion
For patients with DCIS selected for favorable clinical and pathologic characteristics and treated with excision without radiation, the risks of developing an IBE and an invasive IBE increased through 12 years of follow-up, without plateau. These data help inform the treatment decision-making process for patients and their physicians
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Effect of rAd5-Vector HIV-1 Preventive Vaccines on HIV-1 Acquisition: A Participant- Level Meta-Analysis of Randomized Trial
Background
Three phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow–up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.
Methods
We included participant-level data from all three efficacy trials, and three Phase 1–2 trials evaluating the HVTN505 vaccine regimen. We predefined two co-primary analysis cohorts for assessing the vaccine effect on HIV-1 acquisition. The modified-intention-to-treat (MITT) cohort included all randomly assigned participants HIV-1 uninfected at study entry, who received at least the first vaccine/placebo, and the Ad5 cohort included MITT participants who received at least one dose of rAd5-HIV vaccine or rAd5-placebo. Multivariable Cox regression models were used to estimate hazard ratios (HRs) of HIV-1 infection (vaccine vs. placebo) and evaluate HR variation across vaccine regimens, time since vaccination, and subgroups using interaction tests.
Findings
Results are similar for the MITT and Ad5 cohorts; we summarize MITT cohort results. Pooled across the efficacy trials, over all follow-up time 403 (n = 224 vaccine; n = 179 placebo) of 6266 MITT participants acquired HIV-1, with a non-significantly higher incidence in vaccine recipients (HR 1.21, 95% CI 0.99–1.48, P = 0.06). The HRs significantly differed by vaccine regimen (interaction P = 0.03; MRKAd5 HR 1.41, 95% CI 1.11–1.78, P = 0.005 vs. DNA/rAd5 HR 0.88, 95% CI 0.61–1.26, P = 0.48). Results were similar when including the Phase 1–2 trials. Exploratory analyses based on the efficacy trials supported that the MRKAd5 vaccine-increased risk was concentrated in Ad5-positive or uncircumcised men early in follow-up, and in Ad5-negative or circumcised men later. Overall, MRKAd5 vaccine-increased risk was evident across subgroups except in circumcised Ad5-negative men (HR 0.97, 95% CI 0.58−1.63, P = 0.91); there was little evidence that the DNA/rAd5 vaccine, that was tested in this subgroup, increased risk (HR 0.88, 95% CI 0.61–1.26, P = 0.48). When restricting the analysis of Step and Phambili to follow-up time before unblinding, 114 (n = 65 vaccine; n = 49 placebo) of 3770 MITT participants acquired HIV-1, with a non-significantly higher incidence in MRKAd5 vaccine recipients (HR 1.30, 95% CI 0.89–1.14, P = 0.18).
Interpretation and Significance
The data support increased risk of HIV-1 infection by MRKAd5 over all follow-up time, but do not support increased risk of HIV-1 infection by DNA/rAd5. This study provides a rationale for including monitoring plans enabling detection of increased susceptibility to infection in HIV-1 at-risk populations
Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901
The Vehicle, Fall 1992
Table of Contents
DeconstructivismPeter F. Essigpage 5
Homecoming Pep RallyPeter F. Essigpage 6
McAfee GymnasiumWalt Howardpage 7
Morton ParkAnn Moutraypage 9
Why The Willows WeepPeter F. Essigpage 10
UntitledStephen P. Carmodypage 10
A Stranger\u27s MorningBen Hausmannpage 11
deMONSTERative pronounsJoAnna Wolaverpage 12
2.5%Jill S. Pilonpage 13
The BottleStacey Kruegerpage 14
Suppression Jean K. Graypage 15
ProgressStacey Kruegerpage 16
Daily LessonsJennifer Moropage 17
Sunset TheaterMichelle R. Hokepage 20
Eagle GT\u27sJarrod T. Shieldspage 21
New HouseRandy Lisspage 22
UntitledStephen P. Carmodypage 23
Renting Classics on a Saturday NightNancy Jamespage 24
UntitledJacqueline Hallpage 25
Alone While He SleepsSandy Beauchamppage 26
Sand and SeaThomas Schnarrepage 27
loveMichelle R. Hokepage 28
Backward Ass Junkie FunkSandy Beauchamppage 28
These Things You KeepTom McGrathpage 29
Springhill CrestRobert M. Reutherpage 30
The Pass OverLarry Irvinpage 31
The Stolen ChildTom McGrathpage 32
Before the Recycling KickWalt Howardpage 37
Authors\u27 Pagepage 38https://thekeep.eiu.edu/vehicle/1058/thumbnail.jp
Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901
Simplified Models for LHC New Physics Searches
This document proposes a collection of simplified models relevant to the
design of new-physics searches at the LHC and the characterization of their
results. Both ATLAS and CMS have already presented some results in terms of
simplified models, and we encourage them to continue and expand this effort,
which supplements both signature-based results and benchmark model
interpretations. A simplified model is defined by an effective Lagrangian
describing the interactions of a small number of new particles. Simplified
models can equally well be described by a small number of masses and
cross-sections. These parameters are directly related to collider physics
observables, making simplified models a particularly effective framework for
evaluating searches and a useful starting point for characterizing positive
signals of new physics. This document serves as an official summary of the
results from the "Topologies for Early LHC Searches" workshop, held at SLAC in
September of 2010, the purpose of which was to develop a set of representative
models that can be used to cover all relevant phase space in experimental
searches. Particular emphasis is placed on searches relevant for the first
~50-500 pb-1 of data and those motivated by supersymmetric models. This note
largely summarizes material posted at http://lhcnewphysics.org/, which includes
simplified model definitions, Monte Carlo material, and supporting contacts
within the theory community. We also comment on future developments that may be
useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results
from "Topologies for Early LHC Searches" workshop (SLAC, September 2010).
Supplementary material can be found at http://lhcnewphysics.or
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