Triangulating evidence from the GALENOS living systematic review on trace amine-associated receptor 1 (TAAR1) agonists in psychosis.

Background: Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis.

Aims: To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation.

Method: This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis).

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies.

Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

Background: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis.

New living evidence resource of human and non-human studies for early intervention and research prioritisation in anxiety, depression and psychosis.

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

Eyes on the enterprise: problematising the concept of a teaching-research nexus in UK higher education.

Existing research into the relationship between teaching and research in higher education is mainly normative and atheoretical, resulting in assumptions of a close and beneficial connection between them. We problematise the idea of a by undertaking a critical examination of the concept through the lens of educational ideologies to theorise the changes over time that shape the ways teaching and research are practised. Two hundred seven academic staff in the Humanities and Social Sciences were surveyed in 10 universities in England and Wales; the universities were identified as having strength in teaching, research, or in both.

Role of Guidance and Policy in Enhancing the Impact of Clinical Pharmacology in Drug Development, Regulation, and Use.

The Guidance and Policy Team (GPT) within the Office of Clinical Pharmacology (OCP) at the US Food and Drug Administration (FDA) was established in 2016 to ensure development and issuance of timely, relevant guidances and policies in the multidisciplinary field of clinical pharmacology. Here, we share our operational model for guidance development, describe our philosophy on collaboration, and detail the impact on clinical pharmacology guidances and policies with a goal of increasing transparency among stakeholders.

Regulation of the RNAPII Pool Is Integral to the DNA Damage Response.

In response to transcription-blocking DNA damage, cells orchestrate a multi-pronged reaction, involving transcription-coupled DNA repair, degradation of RNA polymerase II (RNAPII), and genome-wide transcription shutdown. Here, we provide insight into how these responses are connected by the finding that ubiquitylation of RNAPII itself, at a single lysine (RPB1 K), is the focal point for DNA-damage-response coordination. K ubiquitylation affects DNA repair and signals RNAPII degradation, essential for surviving genotoxic insult.

Transitioning From Volume to Value: Lessons Learned From the Dissolution of a Population Health Partnership.

In 2017, the authors published an article describing the experiences of Oregon Health & Science University (OHSU) as it adapted to new challenges of changing payment models, the imperative to manage the health of populations, and the desire to compete for statewide contracts. The authors described Propel Health, a multi-institution partnership created in 2013 to deliver the tools, methods, and support necessary for population health management. In the ensuing two years there were considerable changes to the structure and mission of Propel Health, ultimately resulting in its dissolution in January 2018.

Short-term Response to Treatment Targeting the Thoracolumbar Junction in Patients With Hip Pain: A Case Series.

Background: In patients presenting with hip and groin symptoms, evaluation and treatment of the thoracolumbar junction (TLJ) may be underutilized. The TLJ is less recognized as a source of pain referral in these regions. The purpose of this case series was to describe the management of 3 patients with primary hip and groin pain who were treated with interventions targeting the TLJ.

RNA polymerase II stalling at pre-mRNA splice sites is enforced by ubiquitination of the catalytic subunit.

Numerous links exist between co-transcriptional RNA processing and the transcribing RNAPII. In particular, pre-mRNA splicing was reported to be associated with slowed RNAPII elongation. Here, we identify a site of ubiquitination (K1246) in the catalytic subunit of RNAPII close to the DNA entry path.

HLA-A, B, DRB1, DQA1, DQB1 alleles and haplotype frequencies in Dene and Cree cohorts in Manitoba, Canada.

Background: First Nations in the Canadian province of Manitoba have disproportionately high rates of epidemic and endemic TB. Gene polymorphisms that modulate HLA Class I and II antigens are among the risk markers for TB, along with other biologic, and social determinants of health. HLA-A, B, DRB1, DQA1, DQB1 were typed in two Manitoba First Nation indigenous groups to identify and compare the frequency of gene polymorphisms that may influence susceptibility or resistance to TB.

Patterns of milk macronutrients and bioactive molecules across lactation in a western lowland gorilla (Gorilla gorilla) and a Sumatran orangutan (Pongo abelii).

In addition to nutrients, milk contains signaling molecules that influence offspring development. Human milk is similar in nutrient composition to that of apes, but appears to differ in other aspects such as immune function. We examine the longitudinal patterns across lactation of macronutrients, the metabolic hormone adiponectin, the growth factors epidermal growth factor (EGF) and transforming growth factor β2 (TGF-β2), and two receptors for these growth factors (EGF-R and TGF-β2-RIII) in milk samples collected between days 175 and 313 postpartum from a Sumatran orangutan (Pongo abelii) and between days 3 and 1,276 from a western lowland gorilla (Gorilla gorilla), and compare the results with human data from the literature.

Strand-specific, high-resolution mapping of modified RNA polymerase II.

Reversible modification of the RNAPII C-terminal domain links transcription with RNA processing and surveillance activities. To better understand this, we mapped the location of RNAPII carrying the five types of CTD phosphorylation on the RNA transcript, providing strand-specific, nucleotide-resolution information, and we used a machine learning-based approach to define RNAPII states. This revealed enrichment of Ser5P, and depletion of Tyr1P, Ser2P, Thr4P, and Ser7P in the transcription start site (TSS) proximal ~150 nt of most genes, with depletion of all modifications close to the poly(A) site.