Symmetry in Frontal But Not Motor and Somatosensory Cortical Projections.

The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes.

The development and internal validation of a multivariable model predicting 6-month mortality for people with opioid use disorder presenting to community drug services in England: a protocol.

Background: People with opioid use disorder have substantially higher standardised mortality rates compared to the general population; however, lack of clear individual prognostic information presents challenges to prioritise or target interventions within drug treatment services. Previous prognostic models have been developed to estimate the risk of developing opioid use disorder and opioid-related overdose in people routinely prescribed opioids but, to our knowledge, none have been developed to estimate mortality risk in people accessing drug services with opioid use disorder. Initial presentation to drug services is a pragmatic time to evaluate mortality risk given the contemporaneous routine collection of prognostic indicators and as a decision point for appropriate service prioritisation and targeted intervention delivery.

Superiority and cost-effectiveness of Individual Placement and Support versus standard employment support for people with alcohol and drug dependence: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

Background: Individual Placement and Support (IPS) is a specialist intervention to help people attain employment in the open competitive labour market. IPS has been developed in severe mental illness and other disabilities, but it is of unknown effectiveness for people with alcohol and drug dependence. The Individual Placement and Support-Alcohol and Drug (IPS-AD) is the first superiority trial to evaluate effectiveness and cost-effectiveness.

Symmetry in frontal but not motor and somatosensory cortical projections.

Neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision making, where lateralization of function may be less important. This study contrasted the topographic precision of cell type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes.

Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b.

Background: A key histopathological hallmark of Alzheimer's disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes.

Methods: In this work, we employed bioinformatics analysis-including pathway enrichment and causal reasoning-of an in vitro tauopathy model.

A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer's disease.

Cellular models recapitulating features of tauopathies are useful tools to investigate the causes and consequences of tau aggregation and the identification of novel treatments. We seeded rat primary cortical neurons with tau isolated from Alzheimer's disease brains to induce a time-dependent increase in endogenous tau inclusions. Transcriptomics of seeded and control cells identified 1075 differentially expressed genes (including 26 altered at two time points).

The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers.

Dopamine (DA) plays a key role in several central functions including cognition, motor activity, and wakefulness. Although efforts to develop dopamine receptor 1 (D1) agonists have been challenging, a positive allosteric modulator represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the dopamine receptor 1 positive allosteric modulator (D1PAM) mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al.

Fatal opioid overdoses during and shortly after hospital admissions in England: A case-crossover study.

Background: Hospital patients who use illicit opioids such as heroin may use drugs during an admission or leave the hospital in order to use drugs. There have been reports of patients found dead from drug poisoning on the hospital premises or shortly after leaving the hospital. This study examines whether hospital admission and discharge are associated with increased risk of opioid-related death.

The hospital admission profile of people presenting to specialist addiction services with problematic use of alcohol or opioids: A national retrospective cohort study in England.

Background: Over the past decade in England the rate of alcohol and opioid-related hospitalisation has increased alongside a simultaneous reduction in people accessing specialist addiction treatment. We aimed to determine the hospitalisation patterns of people presenting to addiction treatment with problematic use of alcohol or opioids, and estimate how individual sociodemographic characteristics and hospital admission diagnoses are associated with the rate of hospitalisation, death and successful completion of addiction treatment.

Methods: A national record linkage between Hospital Episode Statistics (HES) and the National Drug Treatment Monitoring System (NDTMS) captured lifetime hospital admission profiles of people presenting to addiction services in England in 2018/19.

Acute impact of self-guided mental imagery on craving in cocaine use disorder: a mixed-methods analysis of a randomized controlled trial.

Unlabelled: Mental imagery manipulations are used to treat several psychological disorders, but their utility in treating cocaine use disorder (CUD) is unknown. Using prompted re-experiences and simulations with contrasting valence, we assessed the acute impact of a deliberate mental imagery task on cocaine craving.

Design: A quantitative-qualitative 'mixed-methods' analysis of data collected for a randomized controlled trial that was stopped prematurely.

Reciprocal influences of tobacco use on illicit opioid and alcohol use during the first six-months of specialist addiction treatment.

Background: This is the first national study of lagged reciprocal associations between tobacco smoking frequency and change in illicit opioid or alcohol use frequency within six-months of treatment.

Methods: All adults admitted to publicly-funded specialist addiction treatment in England in 2018/19 and enrolled for at least six months for either opioid use disorder (OUD; n = 22,046; 82.4 % of those eligible) or alcohol use disorder (AUD; n = 15,251; 78.

National administrative record linkage between specialist community drug and alcohol treatment data (the National Drug Treatment Monitoring System (NDTMS)) and inpatient hospitalisation data (Hospital Episode Statistics (HES)) in England: design, method and evaluation.

Objectives: The creation and evaluation of a national record linkage between substance misuse treatment, and inpatient hospitalisation data in England.

Design: A deterministic record linkage using personal identifiers to link the National Drug Treatment Monitoring System (NDTMS) curated by Public Health England (PHE), and Hospital Episode Statistics (HES) Admitted Patient Care curated by National Health Service (NHS) Digital.

Setting And Participants: Adults accessing substance misuse treatment in England between 1 April 2018 and 31 March 2019 (n=268 251) were linked to inpatient hospitalisation records available since 1 April 1997.

Tobacco Smoking Rates in a National Cohort of People with Substance Use Disorder Receiving Treatment.

Background And Aim: The prevalence of tobacco smoking among individuals receiving treatment for substance use disorder (SUD) remains high. Respiratory disease and other harms are of prime concern to health policy-makers, given the contributory role played by tobacco smoking in the excess rates of premature mortality seen in individuals with SUD. The aim was to use SUD treatment data to investigate tobacco smoking prevalence among subgroups of adults over the course of treatment.

Quantitative propagation of assembled human Tau from Alzheimer's disease brain in microfluidic neuronal cultures.

Tau aggregation and hyperphosphorylation is a key neuropathological hallmark of Alzheimer's disease (AD), and the temporospatial spread of Tau observed during clinical manifestation suggests that Tau pathology may spread along the axonal network and propagate between synaptically connected neurons. Here, we have developed a cellular model that allows the study of human AD-derived Tau propagation from neuron to neuron using microfluidic devices. We show by using high-content imaging techniques and an in-house developed interactive computer program that human AD-derived Tau seeds rodent Tau that propagates trans-neuronally in a quantifiable manner in a microfluidic culture model.

Protocol for a multi-centre, definitive randomised controlled trial of the effectiveness of Individual Placement and Support for employment support among people with alcohol and drug dependence.

Background: Unemployment is highly prevalent in populations with alcohol and drug dependence and the employment support offered in addiction-treatment programmes is ineffective. Individual Placement and Support (IPS) is an evidence-based intervention for competitive employment. IPS has been extensively studied in severe mental illness and physical disabilities, but there have been no formal randomised controlled trials (RCTs) in alcohol and drug dependence.

A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic, remitting, and relapsing, inflammatory disease involving multiple organs, which exhibits abnormalities of both the innate and adaptive immune responses. A limited number of transcriptomic studies have characterized the gene pathways involved in SLE in an attempt to identify the key pathogenic drivers of the disease. In order to further advance our understanding of the pathogenesis of SLE, we used a novel Bayesian network algorithm to hybridize knowledge- and data-driven methods, and then applied the algorithm to build an SLE gene network using transcriptomic data from 1,760 SLE patients' RNA from the two tabalumab Phase III trials (ILLUMINATE-I & -II), the largest SLE RNA dataset to date.

Development of an Electrophysiological Assay for Kv7 Modulators on IonWorks Barracuda.

in vivo

Medicines associated with dependence or withdrawal: a mixed-methods public health review and national database study in England.

Background: Antidepressants, opioids for non-cancer pain, gabapentinoids (gabapentin and pregabalin), benzodiazepines, and Z-drugs (zopiclone, zaleplon, and zolpidem) are commonly prescribed medicine classes associated with a risk of dependence or withdrawal. We aimed to review the evidence for these harms and estimate the prevalence of dispensed prescriptions, their geographical distribution, and duration of continuous receipt using all patient-linked prescription data in England.

Methods: This was a mixed-methods public health review, comprising a rapid evidence assessment of articles (Jan 1, 2008, to Oct 3, 2018; with searches of MEDLINE, Embase, and PsycINFO, and the Cochrane and King's Fund libraries), an open call-for-evidence on patient experience and service evaluations, and a retrospective, patient-linked analysis of the National Health Service (NHS) Business Services Authority prescription database (April 1, 2015, to March 30, 2018) for all adults aged 18 years and over.

Pharmacological Modulation of Sleep Homeostasis in Rat: Novel Effects of an mGluR2/3 Antagonist.

Increasing vigilance without incurring the negative consequences of extended wakefulness such as daytime sleepiness and cognitive impairment is a major challenge in treating many sleep disorders. The present work compares two closely related mGluR2/3 antagonists LY3020371 and LY341495 with two well-known wake-promoting compounds caffeine and d-amphetamine. Sleep homeostasis properties were explored in male Wistar rats by manipulating levels of wakefulness via (1) physiological sleep restriction (SR), (2) pharmacological action, or (3) a combination of these.

TractaViewer: a genome-wide tool for preliminary assessment of therapeutic target druggability.

Summary: We present software to characterize and rank potential therapeutic (drug) targets with data from public databases and present it in a user-friendly format. By understanding potential obstacles to drug development through the gathering and understanding of this information, combined with robust approaches to target validation to generate therapeutic hypotheses, this approach may provide high quality targets, leading the process of drug development to become more efficient and cost-effective.

Availability And Implementation: The information we gather on potential targets concerns small-molecule druggability (ligandability), suitability for large-molecule approaches (e.

Automatic navigation system for the mouse brain.

Identification and delineation of brain regions in histologic mouse brain sections is especially pivotal for many neurogenomics, transcriptomics, proteomics, and connectomics studies, yet this process is prone to observer error and bias. Here we present a novel brain navigation system, named NeuroInfo, whose general principle is similar to that of a global positioning system (GPS) in a car. NeuroInfo automatically navigates an investigator through the complex microscopic anatomy of histologic sections of mouse brains (thereafter: "experimental mouse brain sections").

Genome-wide RNAseq study of the molecular mechanisms underlying microglia activation in response to pathological tau perturbation in the rTg4510 tau transgenic animal model.

Background: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer's disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks.

Whole mouse brain reconstruction and registration to a reference atlas with standard histochemical processing of coronal sections.

Advances in molecular neuroanatomical tools have expanded the ability to map in detail connections of specific neuron subtypes in the context of behaviorally driven patterns of neuronal activity. Analysis of such data across the whole mouse brain, registered to a reference atlas, aids in understanding the functional organization of brain circuits related to behavior. A process is described to image mouse brain sections labeled with standard histochemical techniques, reconstruct those images into a whole brain image volume and register those images to the Allen Mouse Brain Common Coordinate Framework.

Change in alcohol and other drug use during five years of continuous opioid substitution treatment.

Background: English national prospective, observational cohort study of patients continuously enrolled for five years in opioid substitution treatment (OST) with oral methadone and sublingual buprenorphine. This is a secondary outcome analysis of change in use of alcohol and other drug use (AOD) following identification of heroin use trajectories during OST.

Methods: All adults admitted to community OST in 2008/09 and enrolled to 2013/14 (n = 7717).

Author Correction: Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.

In the originally published version of this Article, the affiliation details for Eric E. Schadt and Radoslav Savic incorrectly omitted 'Sema4, a Mount Sinai venture, Stamford, Connecticut, USA'. This has been corrected in both the PDF and HTML versions of the Article.