Transfusion Indication Threshold Reduction (TITRe2) randomized controlled trial in cardiac surgery: statistical analysis plan.

Background: The Transfusion Indication Threshold Reduction (TITRe2) trial is the largest randomized controlled trial to date to compare red blood cell transfusion strategies following cardiac surgery. This update presents the statistical analysis plan, detailing how the study will be analyzed and presented. The statistical analysis plan has been written following recommendations from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, prior to database lock and the final analysis of trial data.

Adopting Evidence-Based Caregiver Training Programs in the Real World: Outcomes and Lessons Learned From the STAR-C Oregon Translation Study.

Objectives: This article describes the translation and evaluation of STAR-Community Consultants program (STAR-C), an evidence-based dementia caregiver training program, within the Oregon Department of Human Services.

Method: Staff from two regional Area Agencies on Aging (AAAs) were trained to implement all aspects of STAR-C, including screening, recruitment of caregiver/care-receiver dyads, and treatment delivery. Mailed assessments of caregiver depression, burden, and care-receiver mood, behavior, and quality of life were collected at pre-treatment, post-treatment, and 6-month follow-up.

Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology.

The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and ß-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin.

Loss of δ-catenin function in severe autism.

Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos.

Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain.

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach.

Liberal or restrictive transfusion after cardiac surgery.

Background: Whether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain.

Methods: We conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.

Implementation of NICE guidance on urinary tract infections in children in primary and secondary care.

Aim: To audit compliance with the 2007 National Institute of Clinical Excellence guidelines on the management of urinary tract infection in children under the age of 16 years across primary and secondary care services in England.

Methods: A retrospective multisite audit of 10 general practice, 3 paediatric, 2 paediatric emergency and 2 emergency general units. Four distinct geographical areas were represented.

Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress.

Maternal complications in pregnancy and wheezing in early childhood: a pooled analysis of 14 birth cohorts.

Background: Evidence on the effect of maternal complications in pregnancy on wheezing in offspring is still insufficient.

Methods: A pooled analysis was performed on individual participant data from fourteen European birth cohorts to assess the relationship between several maternal pregnancy complications and wheezing symptoms in the offspring. Exposures of interest included hypertension and preeclampsia, diabetes, as well as pre-pregnancy overweight (body mass index between 25 and 29.

Dynamic assessment of morphological awareness and third-grade literacy success.

Purpose: The purpose of this study was to examine a dynamic assessment with graduated prompts to assess morphological awareness and determine whether such a task was related to third-grade literacy success.

Method: A dynamic assessment of morphological awareness was adapted and administered to 54 third-grade students in addition to a norm-referenced language and literacy battery.

Results: A dynamic assessment of morphological awareness measured a range of performance including that of emerging morphological awareness abilities and provided rich linguistic insights for how best to scaffold and prompt for such a skill.

Respiratory consequences of late preterm birth.

In developed countries most preterm births occur between 34 and 37 weeks' gestation. Deliveries during this 'late preterm' period are increasing and, since even mild prematurity is now recognised to be associated with adverse health outcomes, this presents healthcare challenges. Respiratory problems associated with late preterm birth include neonatal respiratory distress, severe RSV infection and childhood wheezing.

Unique characteristics of informal hospice cancer caregiving.

Purpose: The purpose of this study was to describe the unique characteristics of informal hospice cancer caregiving.

Methods: Researchers conducted a secondary analysis of data drawn from a randomized clinical trial of an informal hospice caregiving intervention (N = 348). Demographic characteristics and measures of the informal caregiving experience of hospice patients and their informal caregivers were compared based on the patient's diagnosis using chi-square tests for association of categorical variables and t tests for continuous variables.

Cultural trends and eating disorders.

Purpose Of Review: Culture has long been recognized as significant to the cause and expression of eating disorders. We reviewed the recent literature about recent trends in the occurrence of eating disorders in different cultures.

Recent Findings: While historically, eating disorders were conceptualized as primarily afflicting Caucasian adolescent or young adult women within high-income, industrialized Western Europe and North America, eating disorders are increasingly documented in diverse countries and cultures worldwide.

Risk factors across the eating disorders.

This study sought to examine risk and onset patterns in anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Women with AN (n=71), BN (n=66), BED (n=160) and non-psychiatric controls (n=323) were compared retrospectively on risk factors, symptom onset, and diagnostic migration. Eating disorder groups reported greater risk exposure than non-psychiatric controls.

Coronary artery bypass grafting in high-RISk patients randomised to off- or on-Pump surgery: a randomised controlled trial (the CRISP trial).

Background: Coronary artery bypass grafting (CABG) is the treatment of choice for patients with multivessel coronary artery disease (CAD). Evidence from randomised controlled trials (RCTs) in low-risk populations shows that 'off-pump' CABG is at least as safe as 'on-pump' CABG, but high-quality trial data in high-risk populations are lacking.

Objectives: To test the hypothesis that, in high-risk patients, off-pump coronary artery bypass grafting (OPCABG) reduces mortality and morbidity without causing a higher risk of reintervention compared with on-pump coronary artery bypass grafting (ONCABG).

Innovative strategies for closing the mental health treatment gap globally.

Purpose Of Review: In the field of global mental health, an enormous gap between what we know and what we do exists in the delivery of clinical care. Creative and effective strategies that surmount the barriers to provision of mental healthcare are essential to improve the lives of millions affected by mental illness. This article provides a review of three classes of innovative strategies currently being developed and implemented to diminish the mental health treatment gap globally.

Protein tyrosine phosphatase 1B is a regulator of the interleukin-10-induced transcriptional program in macrophages.

Both pro- and anti-inflammatory cytokines activate the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway; however, they elicit distinct transcriptional programs. Posttranslational modifications of STAT proteins, such as tyrosine phosphorylation, are critical to ensure the differential expression of STAT target genes. Although JAK-STAT signaling is dependent on reversible tyrosine phosphorylation, whether phosphatases contribute to the specificity of STAT-dependent gene expression is unclear.

Prenatal development is linked to bronchial reactivity: epidemiological and animal model evidence.

Chronic cardiorespiratory disease is associated with low birthweight suggesting the importance of the developmental environment. Prenatal factors affecting fetal growth are believed important, but the underlying mechanisms are unknown. The influence of developmental programming on bronchial hyperreactivity is investigated in an animal model and evidence for comparable associations is sought in humans.

Point of care platelet activity measurement in primary PCI [PINPOINT-PPCI]: a protocol paper.

Background: Optimal treatment of acute ST-elevation myocardial infarction (STEMI) involves rapid diagnosis, and transfer to a cardiac centre capable of percutaneous coronary intervention (PCI) for immediate mechanical revascularisation. Successful treatment requires rapid return of perfusion to the myocardium achieved by thromboaspiration, passivation of the culprit lesion with stent scaffolding and systemic inhibition of thrombosis and platelet activation. A delicate balance exists between thrombosis and bleeding and consequently anti-thrombotic and antiplatelet treatment regimens continue to evolve.

Memory Care and Wellness Services: Efficacy of Specialized Dementia Care in Adult Day Services.

Purpose Of The Study: This investigation evaluated participant and caregiver outcomes of a program of specialized dementia adult day services (ADS; Memory Care and Wellness Services: MCWS).

Design And Methods: One hundred eighty-seven participant-caregiver dyads were enrolled in a quasiexperimental research investigation; 162 attended MCWS and 25 were comparison dyads that met eligibility criteria but did not have access to ADS within their communities. The objectives of this investigation were to evaluate whether MCWS improved quality of life, mood, behavior, or functional status for participants with dementia and whether caregivers experienced decreased stress, burden, or depression, compared with comparison dyads.

Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children.

Background: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.

Objectives: We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).

Methods: First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma.

Anxiety among informal hospice caregivers: an exploratory study.

Objective: This study examined the prevalence of clinically significant anxiety among informal hospice caregivers and identified the characteristics of caregivers who experienced anxiety of this severity.

Method: An exploratory secondary data analysis pooled from three separate studies of informal hospice caregivers (N = 433) was conducted. Researchers employed descriptive statistics to calculate anxiety prevalence and utilized logistic regression to model the associations between the covariates (i.