Enabling robust assessment of QTc prolongation in early phase clinical trials

Since the implementation of the International Conference on Harmonization (ICH) E14 guideline in 2005, regulators have required a “thorough QTc” (TQT) study for evaluating the effects of investigational drugs on delayed cardiac repolarization as manifested by a prolonged QTc interval. However, TQT studies have increasingly been viewed unfavorably because of their low cost effectiveness. Several researchers have noted that a robust drug concentration‐QTc (conc‐QTc) modeling assessment in early phase development should, in most cases, obviate the need for a subsequent TQT study. In December 2015, ICH released an “E14 Q&As (R3)” document supporting the use of conc‐QTc modeling for regulatory decisions. In this article, we propose a simple improvement of two popular conc‐QTc assessment methods for typical first‐in‐human crossover‐like single ascending dose clinical pharmacology trials. The improvement is achieved, in part, by leveraging routinely encountered (and expected) intrasubject correlation patterns encountered in such trials. A real example involving a single ascending dose and corresponding TQT trial, along with results from a simulation study, illustrate the strong performance of the proposed method. The improved conc‐QTc assessment will further enable highly reliable go/no‐go decisions in early phase clinical development and deliver results that support subsequent TQT study waivers by regulators.     

Alone and adrift: The association between mass school shootings,school size,and student support

Background

School shootings have approached epidemic levels in recent years. While mental illness is undoubtedly involved in nearly all cases of mass school violence, we sought to determine how environmental context may exacerbate preexisting personal factors. The present study investigated the associations between mass school shootings, school enrollment size, student–teacher ratios, and student transitions.

Analysis of Blogs,Forums, and Social Networks

It is impossible to imagine the contemporary Internet without social media. Government agents, commercial, state, and social organizations, the opposition, and other citizens use social media as a giant turbine. Unfortunately, this turbine can also be used to spread disinformation as well as hostile propaganda on a mass scale. In this article we show how vulnerable social media are to infiltration by botnets with the goal of launching information attacks.     

The Peasant World in the Discourse of Generational Sorrow

This article spells out the methodological considerations and various procedural and methodological subtleties developed over the author's quarter century of sociological field studies of Russia's peasant worlds. Particular attention is paid to “voices from below”—peasant discursive formats that capture, in natural and undiluted form, the evolution of peasant practices constituting the core of everyday life. In particular, the phenomenon of generational sorrow and a special chronological nostalgia that functions as a “social gyroscope” is identified and discursively captured. This phenomenon is noteworthy and useful for its ability to retain a record of the productively longed for past in a rural community's collective memory and thereby influence new peasant worlds taking shape today.     

Family engagement within the context of assessment in child protection practice: The case of Estonia

Engagement in the context of child protection is of significant international interest, as the participation of family is a central notion in child and family social work. Drawing on in‐depth, semistructured interviews with a sample of 26 child protection workers in 1 region in Estonia, this article reports the findings of the participants' perspectives on family engagement in the context of child protection assessment. Child protection workers perceive the engagement related to 3 aspects: first, it is associated to the acts of the worker; second, it is associated to parental part of actions—depending on parents themselves; and third, engagement was seen as “doing together” with the family, referring to partnership. The aim of the engagement was mainly considered in the terms of empowerment—empowering family to cope on their own and to take charge of their lives. The negative image of child protection was recognised as one of the main barriers to the family engagement. Understanding the family and their situation was seen as the basis for a trusting relationship, being the most crucial factor to promoting family engagement.     

The Children First Program: The Effectiveness of a Parent Education Program for Divorcing Parents

This study evaluated the effectiveness of the 2nd and 3rd editions of the Children First parent education programs for parents experiencing divorce or separation. Participants were 678 parents experiencing separation or divorce in 2 Midwestern counties. Changes from pretest to posttest on participants’ knowledge, attitudes, and likelihood of adaptive coparenting were assessed. Both editions of the program had a significant positive effect on all 3 measures of adaptive coparenting. The effect sizes from pretest to posttest for the 2nd edition were small, whereas the effect sizes for the 3rd edition of the program were nearly twice as large. Superiority of the 3rd edition might be due to an increased focus on explicit training on adaptive coparenting behaviors.     

Do High School Students in India Gamble? A Study of Problem Gambling and Its Correlates

Studies from the West suggest that significant numbers of high school students gamble, despite it being illegal in this age group. To date, there have been no studies on the prevalence of gambling among senior high school and higher secondary school students in India. This study reports point prevalence of gambling and its psychosocial correlates among high school students in the State of Kerala, India. 5043 high school students in the age group 15–19 years, from 73 schools, were selected by cluster random sampling from the district of Ernakulam, Kerala, South India. They completed questionnaires that assessed gambling, substance use, psychological distress, suicidality, and symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Of a total of 4989 completed questionnaires, 1400 (27.9 %) high school students reported to have ever gambled and 353 (7.1 %) were problem gamblers. Of those who had ever gambled, 25.2 % were problem gamblers. Sports betting (betting on cricket and football) was the most popular form of gambling followed by the lottery. Problem gamblers when compared with non-problem gamblers and non-gamblers were significantly more likely to be male, have academic failures, have higher rates of lifetime alcohol and tobacco use, psychological distress, suicidality, history of sexual abuse and higher ADHD symptom scores. Gambling among adolescents in India deserves greater attention, as one in four students who ever gambled was a problem gambler and because of its association with a range of psychosocial variables.     

Family Caregiver Communication in the ICU: Toward a Relational View of Health Literacy

We interviewed 18 family caregivers about their communication experiences in the ICUs at an urban hospital. Analysis of their narratives suggests health literacy is important in family caregiver/healthcare provider communication, especially as complicated illnesses move the caregiver deeper into decision making. Using the domains of Yuen et al.’s conceptual model of caregiver health literacy (2015), we identified three themes within the context of ICU communication: agency, coordinated communication, and caregiver’s evolving role. We saw family caregivers negotiating domains of health literacy as they built upon knowledge of the patient’s needs, their rights as family caregivers, and the hierarchy of the professional staff. We found that these narratives represent co-created, or relational communication, rather than individual health literacy skills. Conceptualized in the transaction of relationship, health literacy is enacted; it is socially constructed and is the scaffolding upon which family caregivers make decisions, care for their loved one, and care for themselves.     

Comparison of Two Psycho-Educational Interventions Aimed at Preventing HIV and Promoting Sexual Health Among Portuguese Women

This study compares the efficacy of 2 psychoeducational interventions—ACCENT skills-based and didactic information only—to prevent HIV among Portuguese women. At posttest and follow-up, participants in both intervention groups (n = 127) were more knowledgeable about HIV than at baseline. Although both intervention groups showed an increase in self-reported condom use over time, differences were marginally stronger in the ACCENT group. Both intervention groups showed more positive results than the non-intervention control group (n = 33). The study suggests that HIV prevention interventions can produce significant changes when they target a set of knowledge, social, and cognitive variables relevant to sexual behavior change.     

Adaptive multiple importance sampling for Gaussian processes

In applications of Gaussian processes (GPs) where quantification of uncertainty is a strict requirement, it is necessary to accurately characterize the posterior distribution over Gaussian process covariance parameters. This is normally done by means of standard Markov chain Monte Carlo (MCMC) algorithms, which require repeated expensive calculations involving the marginal likelihood. Motivated by the desire to avoid the inefficiencies of MCMC algorithms rejecting a considerable amount of expensive proposals, this paper develops an alternative inference framework based on adaptive multiple importance sampling (AMIS). In particular, this paper studies the application of AMIS for GPs in the case of a Gaussian likelihood, and proposes a novel pseudo-marginal-based AMIS algorithm for non-Gaussian likelihoods, where the marginal likelihood is unbiasedly estimated. The results suggest that the proposed framework outperforms MCMC-based inference of covariance parameters in a wide range of scenarios.