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. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making.

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., 2021). Herein, we describe the effects of mevidalen on sleep and wakefulness in humanized dopamine receptor 1 (hD1) mice and in sleep-deprived healthy male volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent [3-100 mg/kg, orally (PO)] fashion when measured during the light (zeitgeber time 5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice after prior sleep deprivation and delayed sleep onset by 5.5- and 15.2-fold compared with vehicle-treated animals, after the 20 and 60 mg/kg PO doses, respectively, when compared with vehicle-treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, and 75 mg) separated from placebo at the first 2-hour postdose time point with a circadian effect at the 6-hour postdose time point. Sleep wakefulness should be considered a translational biomarker for the dopamine receptor 1 positive allosteric modulator mechanism. SIGNIFICANCE STATEMENT: This is the first translational study describing the effects of a selective dopamine receptor 1 positive allosteric modulator (D1PAM) on sleep and wakefulness in the human dopamine receptor 1 mouse and in sleep-deprived healthy male volunteers. In both species, drug exposure correlated with sleep latency, supporting the use of sleep-wake activity as a translational central biomarker for D1PAM. Wake-promoting effects of D1PAMs may offer therapeutic opportunities in several conditions, including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders.

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. Moreover, we were able to convert this model to a medium-throughput format allowing the user to handle 16 two-chamber devices simultaneously in the footprint of a standard 96-well plate. Furthermore, we show that a small molecule inhibitor of aggregation can block the trans-neuronal transfer of Tau aggregates, suggesting that the system can be used to evaluate mechanisms of Tau transfer and find therapeutic interventions.

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. METHODS AND FINDINGS: We conducted a case-crossover study of opioid-related deaths in England. Our study included 13,609 deaths between January 1, 2010 and December 31, 2019 among individuals aged 18 to 64. For each death, we sampled 5 control days from the period 730 to 28 days before death. We used data from the national Hospital Episode Statistics database to determine the time proximity of deaths and control days to hospital admissions. We estimated the association between hospital admission and opioid-related death using conditional logistic regression, with a reference category of time neither admitted to the hospital nor within 14 days of discharge. A total of 236/13,609 deaths (1.7%) occurred following drug use while admitted to the hospital. The risk during hospital admissions was similar or lower than periods neither admitted to the hospital nor recently discharged, with odds ratios 1.03 (95% CI 0.87 to 1.21; p = 0.75) for the first 14 days of an admission and 0.41 (95% CI 0.30 to 0.56; p < 0.001) for days 15 onwards. 1,088/13,609 deaths (8.0%) occurred in the 14 days after discharge. The risk of opioid-related death increased in this period, with odds ratios of 4.39 (95% CI 3.75 to 5.14; p < 0.001) on days 1 to 2 after discharge and 2.09 (95% CI 1.92 to 2.28; p < 0.001) on days 3 to 14. 11,629/13,609 deaths (85.5%) did not occur close to a hospital admission, and the remaining 656/13,609 deaths (4.8%) occurred in hospital following admission due to drug poisoning. Risk was greater for patients discharged from psychiatric admissions, those who left the hospital against medical advice, and those leaving the hospital after admissions of 7 days or more. The main limitation of the method is that it does not control for time-varying health or drug use within individuals; therefore, hospital admissions coinciding with high-risk periods may in part explain the results. CONCLUSIONS: Discharge from the hospital is associated with an acute increase in the risk of opioid-related death, and 1 in 14 opioid-related deaths in England happens in the 2 weeks after the hospital discharge. This supports interventions that prevent early discharge and improve linkage with community drug treatment and harm reduction services.

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. METHODS: We used the English National Drug Treatment Monitoring System (NDTMS) to examine number of days tobacco had been smoked in the previous month in adults receiving SUD treatment (N = 106,472, median length of treatment 157 days). RESULTS: At baseline (treatment start), 48.7% reported smoking tobacco; the highest rate was observed in opiate users (61%). Overall, the level of smoking at the latest assessment was 48.5%. Reductions (of between 5 and 7%) were observed among those who finished treatment but only within the final stages of treatment. A 5% increase in smoking was observed in those still in treatment within the study timeframe. CONCLUSIONS: This study identifies the potential for a greater emphasis on reducing tobacco consumption within SUD treatment, for example, by offering all smokers within SUD treatment smoking cessation support as part of their SUD treatment programme.

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.g. antibodies) or new modalities (e.g. antisense oligonucleotides, siRNA or PROTAC), feasibility (availability of resources such as assays and biological knowledge) and potential safety risks (adverse tissue-wise expression, deleterious phenotypes). This information can be termed 'tractability'. We provide visualization tools to understand its components. TractaViewer is available from https://github.com/NeilPearson-Lilly/TractaViewer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Modelling maintenance of wakefulness in rats: comparing potential non-invasive sleep-restriction methods and their effects on sleep and attentional performance.

While several methods have been used to restrict the sleep of experimental animals, it is often unclear whether these different forms of sleep restriction have comparable effects on sleep-wake architecture or functional capacity. The present study compared four models of sleep restriction, using enforced wakefulness by rotation of cylindrical home cages over 11 h in male Wistar rats. These included an electroencephalographic-driven 'Biofeedback' method and three non-invasive methods where rotation was triggered according to a 'Constant', 'Decreasing' or random protocol based upon the 'Weibull' distribution fit to an archival Biofeedback dataset. Sleep-wake architecture was determined using polysomnography, and functional capacity was assessed immediately post-restriction with a simple response latency task, as a potential homologue of the human psychomotor vigilance task. All sleep restriction protocols resulted in sleep loss, behavioural task disengagement and rebound sleep, although no model was as effective as real-time electroencephalographic-Biofeedback. Decreasing and Weibull protocols produced greater recovery sleep than the Constant protocol, mirrored by comparably poorer simple response latency task performance. Increases in urinary corticosterone levels following Constant and Decreasing protocols suggested that stress levels may differ between protocols. Overall, these results provide insight into the value of choosing a specific sleep restriction protocol, not only from the perspective of animal welfare and the use of less invasive procedures, but also translational validity. A more considered choice of the physiological and functional effects of sleep-restriction protocols in rodents may improve correspondence with specific types of excessive daytime sleepiness in humans.

A population PK model for citalopram and its major metabolite, N-desmethyl citalopram, in rats.

A population PK model was developed in order to simultaneously describe citalopram and its major metabolite, n-desmethyl citalopram, plasma concentrations in two different strain of rats after intravenous (IV) and oral (PO) administration of citalopram. Citalopram was administered to Sprague-Dawley (SD) rats at doses: 0.3, 1, 3, and 10 mg/kg IV and 10 mg/kg PO. The compound was dosed orally to Wistar rats at doses: 0.3, 1, 3, 10, 30 and 60 mg/kg. Plasma samples were collected for citalopram and metabolite. Pharmacokinetic analyses were conducted using NONMEM 7.2. Values below the quantification limit (BLQ < 0.1 ng/mL) were included in the analyses and treated as censored information. The disposition of citalopram was best described by a 3-compartment model and its desmethyl metabolite by a 2-compartment model. Several models for the absorption rate were explored (e.g. first, zero order and combined first and zero order absorption, Michaelis-Menten, lag time) in combination with dose and/or time dependent covariate effects. Dose dependent oral bioavailability properties were also identified in this analysis. Citalopram IV clearance and metabolite formation rate were adequately described as linear processes. Metabolite clearance was adequately described using a Michaelis-Menten clearance with different parameters depending on the strain. This analysis demonstrates a very complex absorption/metabolism process explaining the highly non-linear pharmacokinetics observed across all the doses. This is the first combined parent/metabolite population PK analysis in both SD and Wistar rats over a wide range of IV and PO dosages for citalopram, a compound that exhibits highly nonlinear oral pharmacokinetics in rats.

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. This study aims to develop and internally validate a model to estimate 6-month mortality risk for people with opioid use disorder from prognostic indicators recorded at initial assessment in drug services in England. METHODS: An English national dataset containing records from individuals presenting to drug services between 1 April 2013 and 1 April 2023 (n > 800,000) (the National Drug Treatment Monitoring System (NDTMS)) linked to their lifetime hospitalisation and death records (Hospital Episode Statistics-Office of National Statistics (HES-ONS)). Twelve candidate prognostic indicator variables were identified based on literature review of demographic and clinical features associated with increased mortality for people in treatment for opioid use disorder. Variables will be extracted at initial presentation to drug services with mortality measured at 6 months. Two multivariable Cox regression models will be developed one for 6-month all-cause mortality and one for 6-month drug-related mortality using backward elimination with a fractional polynomial approach for continuous variables. Internal validation will be undertaken using bootstrapping methods. Discrimination of both models will be reported using Harrel's c and d-statistics. Calibration curves and slopes will be presented comparing expected and observed event rates. DISCUSSION: The models developed and internally validated in this study aim to improve clinical assessment of mortality risk for people with opioid use disorder presenting to drug services in England. External validation in different populations will be required to develop the model into a tool to assist future clinical decision-making.

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. Methods: IPS-AD was a pragmatic, parallel-group, multi-centre, randomised, controlled, phase 3 trial of standard employment support (treatment-as-usual [TAU]) versus IPS. IPS was offered as a single episode for up to 13 months. The study was done at seven community treatment centres for alcohol and drug dependence in England. Study participants were adults (18-65 years), who had been enrolled for at least 14 days in treatment for alcohol use disorder (AUD), opioid use disorder (OUD), or another drug use disorder (DUD; mostly cannabis and stimulants); were unemployed or economically inactive for at least six months; and wished to attain employment in the open competitive labour market. After random allocation to study interventions, the primary outcome was employment during 18-months of follow-up, analysed by mixed-effects logistic regression, using multiple imputation for the management of missing outcome data. There were two cost-effectiveness outcomes: a health outcome expressed as a quality adjusted life year (QALY) using £30,000 and £70,000 willingness-to-pay [WTP] thresholds; and additional days of employment, with a WTP threshold of £200 per day worked. The study was registered with ISRCTN (ISRCTN24159790) and is completed. Findings: Between 8 May 2018 and 30 September 2019, 2781 potentially eligible patients were identified. 812 were excluded before screening, and 1720 participants were randomly allocated to TAU or IPS. In error, nine participants were randomised to study interventions on two occasions-so data for their first randomisation was analysed (modified intention-to-treat). A further 24 participants withdrew consent for all data to be used (full-analysis set therefore 1687 participants [70.1% male; mean age 40.8 years]; TAU, n = 844; IPS, n = 843 [AUD, n = 610; OUD, n = 837; DUD, n = 240]). Standard employment support was received by 559 [66.2%] of 844 participants in the TAU group. IPS was received by 804 [95.37%] of 843 participants in the IPS group. IPS was associated with an increase in attainment of employment compared with TAU (adjusted odds ratio [OR] 1.29; 95% CI 1.02-1.64; p-value 0.036). IPS was effective for the AUD and DUD groups (OR 1.48; 95% CI 1.14-1.92; p-value 0.004; OR 1.45, 95% CI 1.03-2.04, p-value 0.031, respectively), but not the OUD group. IPS returned an incremental QALY outcome gain of 0.01 (range 0.003-0.02) per participant with no evidence of cost-effectiveness at either WTP threshold-but QALY gains were cost-effective for the AUD and DUD groups at the £70,000 WTP threshold (probability 0.52 and 0.97, respectively). IPS was cost-effective for additional days of employment (probability 0.61), with effectiveness relating to the AUD group only (probability >0.99). Serious Adverse Events were reported by 39 participants (13 [1.5%] of 844 participants in the TAU group and 23 [2.7%] of 43 participants in the IPS group). There was a total of 25 deaths (1.5%; 9 in the TAU group and 16 in the IPS group)-none judged related to study interventions. Interpretation: In this first superiority randomised controlled trial of IPS in alcohol and drug dependence, IPS helped more people attain employment in the open competitive labour market than standard employment support. IPS was cost-effective for a QALY health outcome (£70,000 WTP threshold) for the AUD and DUD groups, and for additional days of employment for the AUD group (£200 per day worked WTP threshold). Funding: UK government Work and Health Unit.

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. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure. RESULTS: Combining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled "Superpathway of cholesterol biosynthesis" and "Granulocyte adhesion and diapedesis". With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins. CONCLUSIONS: This study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.

Symmetry in frontal but not motor and somatosensory corticocortical and corticostriatal circuitry.

Neocortex and striatum are topographically organized by cortical areas representing sensory and motor functions, where primary cortical areas are generally used as models for other cortical regions. But different cortical areas are specialized for distinct purposes, with sensory and motor areas 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 ipsilateral and contralateral projections from cortex based on the injection site location. While sensory cortical areas had strongly topographic outputs to ipsilateral cortex and striatum, they were weaker and not as topographically strong to contralateral targets. Motor cortex had somewhat stronger projections, but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to cortex and striatum. This contralateral connectivity reflects on the pathways in which corticostriatal computations might integrate input outside closed basal ganglia loops, enabling the two hemispheres to act as a single unit and converge on one result in motor planning and decision making.

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). These were enriched for lipid/steroid metabolism and neuronal/glial cell development genes. 50 genes were correlated with tau inclusion formation at both transcriptomic and proteomic levels, including several microtubule and cytoskeleton-related proteins such as Tubb2a, Tubb4a, Nefl and Snca. Several genes (such as Fyn kinase and PTBP1, a tau exon 10 repressor) interact directly with or regulate tau. We conclude that this neuronal model may be a suitable platform for high-throughput screens for target or hit compound identification and validation.

Orientation of hatchling loggerhead sea turtles to regional magnetic fields along a transoceanic migratory pathway.

Young loggerhead sea turtles (Caretta caretta) from the east coast of Florida, USA, undertake a transoceanic migration around the North Atlantic Gyre, the circular current system that flows around the Sargasso Sea. Previous experiments indicated that loggerhead hatchlings, when exposed to magnetic fields replicating those that exist at five widely separated locations along the migratory pathway, responded by swimming in directions that would, in each case, help turtles remain in the gyre and advance along the migratory route. In this study, hatchlings were exposed to several additional magnetic fields that exist along or outside of the gyre's northern boundary. Hatchlings responded to fields that exist within the gyre currents by swimming in directions consistent with their migratory route at each location, whereas turtles exposed to a field that exists north of the gyre had an orientation that was statistically indistinguishable from random. These results are consistent with the hypothesis that loggerhead turtles entering the sea for the first time possess a navigational system in which a series of regional magnetic fields sequentially trigger orientation responses that help steer turtles along the migratory route. By contrast, hatchlings may fail to respond to fields that exist in locations beyond the turtles' normal geographic range.

Ultrathin self-assembled fibrin sheets.

Fibrin polymerizes into the fibrous network that is the major structural component of blood clots and thrombi. We demonstrate that fibrin from three different species can also spontaneously polymerize into extensive, molecularly thin, 2D sheets. Sheet assembly occurs in physiologic buffers on both hydrophobic and hydrophilic surfaces, but is routinely observed only when polymerized using very low concentrations of fibrinogen and thrombin. Sheets may have been missed in previous studies because they may be very short-lived at higher concentrations of fibrinogen and thrombin, and their thinness makes them very difficult to detect. We were able to distinguish fluorescently labeled fibrin sheets by polymerizing fibrin onto micro-patterned structured surfaces that suspended polymers 10 microm above and parallel to the cover-glass surface. We used a combined fluorescence/atomic force microscope system to determine that sheets were approximately 5 nm thick, flat, elastic and mechanically continuous. Video microscopy of assembling sheets showed that they could polymerize across 25-microm channels at hundreds of microm(2)/sec (approximately 10(13) subunits/s x M), an apparent rate constant many times greater than those of other protein polymers. Structural transitions from sheets to fibers were observed by fluorescence, transmission, and scanning electron microscopy. Sheets appeared to fold and roll up into larger fibers, and also to develop oval holes to form fiber networks that were "pre-attached" to the substrate and other fibers. We propose a model of fiber formation from sheets and compare it with current models of end-wise polymerization from protofibrils. Sheets could be an unanticipated factor in clot formation and adhesion in vivo, and are a unique material in their own right.

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

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. SETTING: UK National Health Service addictions treatment clinic and outpatient clinical research facility (laboratory). PARTICIPANTS: Adults with CUD. The original target sample was 120. All participants enrolled at the point the original trial was stopped were included (38 enrolled, 31 completed study). INTERVENTIONS: Personalized (3-minute) cue-exposure (handling cocaine paraphernalia and watching video of drug preparation), immediately followed by a single 5-minute, audio-recorded, self-guided and verbally described imagery task with random assignment to one of four conditions: two mental imagery memory re-experiences (positive image before initiation to cocaine use or a negative image of a 'worst time' adverse cocaine use episode) or two future simulations (positive theme of recovery from CUD or negative theme of worsened CUD). MEASUREMENTS: Task transcripts were rated for imagery detail using five dimensions using a six-point scale of imagery detail (ID) (total score = 0-25) and thematically coded. The outcome measure was cocaine craving using the Craving Experiences Questionnaire-strengths version (CEQ-S11; score = 0-110) reported at baseline, arrival at the laboratory, and immediately after the cue-exposure and mental imagery tasks. FINDINGS: A mixed-effects, longitudinal, restricted linear regression, with the past-positive imagery condition as referent, showed main effects of reduced craving after the imagery task (b = -29.2, 95% confidence interval (CI) = -45.3 to -13.1, P-value < 0.001) and increased craving for the future-negative task (b = 14.2, 95% CI = 0.1-28.4, P-value 0.049). There was a future-negative task by post-imagery craving interaction (b = 28.1, 95% CI = 0.1-56.1, P-value 0.049). A theory-driven, deductive/inductive qualitative analysis of the transcripts revealed six major themes: sensory characteristics, CUD vicious cycle, self-care, emotions and appraisals, social role and CUD recovery. Positively themed simulations included interpersonal connections and rewarding activity; negative images included personal adversity, with appraisals of self-criticism and hopelessness. Transcripts with more imagery detail were not associated with significantly greater reductions in craving in the positive or negative imagery task (r = -0.32, 95% CI = -0.69 to 0.13 and r = 0.06, 95% CI = -0.58 to 0.53, respectively). CONCLUSION: In people with cocaine use disorder, after cue-exposure, a self-guided imagery task with positive themes reduced craving, whereas mental imagery simulating worsened cocaine use disorder did not appear to.

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. Latent class analysis assigned individuals to clusters based on the ICD-10 diagnosis coded as primary reason for admission. Negative binomial, and multilevel logistic regression models determined if outcomes differed due to sociodemographic characteristics or assigned diagnostic clusters. FINDINGS: Inpatient data were available for 64,840 alcohol patients, and 107,296 opioid patients. The most common reasons for admission were alcohol withdrawal (n = 20,024 (5.3% of alcohol-cohort admissions)), and unspecified illness (n = 11,387 (2.1% of opioid-cohort admissions)). Seven diagnostic clusters were identified for each substance cohort. People with admissions predominantly relating to mental and behavioural disorders, and injuries or poisonings had significantly higher hospitalisation rates (adjusted IRR 7.06 (95%CI 6.72-7.42);p < 0.001), higher odds of death during addiction treatment (adjusted OR 2.71 (95%CI 2.29-3.20);p < 0.001) and lower odds of successful treatment completion (adjusted OR 0.72 (95%CI 0.68-0.76);p < 0.001). INTERPRETATION: This is the first study to interrogate national hospitalisation patterns within people presenting to addiction services with problematic use of alcohol or opioids. Having identified high-risk, high-cost individuals with increased hospital usage, and increased odds of death, future work should focus on targeting appropriate interventions, to improve their health outcomes and prevent unnecessary hospital readmission. FUNDING: The work was funded by the Medical Research Council (MRC).

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; 78.8 % of those eligible). Two cross-lagged panel models estimated, separately for OUD and AUD patients, the relationships between smoking at admission and change in main drug over six months, and between main drug use at admission and change in smoking over six months. RESULTS: Within the OUD cohort, illicit opioid use frequency reduced from 17.7 days to 8.0 days and smoking tobacco remained at 18.8 days. After controlling for available covariates, higher smoking frequency at admission was associated with a relative increase in illicit opioid use at six-months (0.02 days [95 % CI 0.00-0.03]). Within the AUD cohort, alcohol use frequency reduced from 21.2 days to 14.4 days while smoking tobacco reduced from 12.6 days to 11.5 days. Higher smoking frequency at admission was associated with a relative increase in alcohol use at six-months (0.03 days [95 % CI 0.02-0.04]) and higher alcohol use frequency at admission was associated with a relative increase in smoking at six-months (0.04 [95 % CI 0.02-0.06]), controlling for available covariates. CONCLUSIONS: Higher smoking frequency at admission is associated with higher illicit opioid and alcohol use frequency after six-months of specialist addiction treatment.

Effectiveness of community treatments for heroin and crack cocaine addiction in England: a prospective, in-treatment cohort study.

BACKGROUND: Addiction to heroin and crack cocaine is debilitating and persistent, but such disorders are treatable. We present the first effectiveness study of the main community interventions for addiction to heroin and crack cocaine in England, using data from the National Drug Treatment Monitoring System (NDTMS). METHODS: The study cohort consisted of all adults with a heroin or crack cocaine addiction, or both, who started pharmacological treatment (n=18 428 patients) or psychosocial treatment (n=2647) between Jan 1 and Nov 30, 2008, received at least 6 months' treatment or were discharged by the study endpoint (May 31, 2009), and had outcome data submitted to the NDTMS. Effectiveness was assessed from change in days of heroin or crack cocaine use, or both in the 28 days before the start of treatment and in the 28 days before review. FINDINGS: 14 656 clients-74% of the cohort eligible for analysis at review with available data-were analysed at the study endpoint. During the 28 days before review, 37% (5016/13 542) of heroin users abstained from heroin and 52% (3941/7636) of crack cocaine users abstained from crack cocaine. A higher proportion of users of heroin only abstained than did users of both heroin and crack cocaine (42% [2465/5863] vs 33% [2551/7679]; OR 1.46, 95% CI 1.36-1.56), and more users of crack cocaine only abstained than did users of both drugs (57% [295/522] vs 51% [3646/7114]; 1.24, 1.03-1.48). Overall heroin use reduced by 14.5 days (95% CI 14.3-14.7) and crack cocaine use by 7.7 days (7.5-7.9). For clients given pharmacological treatment, reduction in days of heroin use was smaller for users of both heroin and crack cocaine than for users of heroin alone (p<0.0001), but this differential effectiveness was not recorded for psychosocial treatment in heroin or crack cocaine users compared with users of both drugs. INTERPRETATION: The first 6 months of pharmacological or psychosocial treatment is associated with reduced heroin and crack cocaine use, but the effectiveness of pharmacological treatment is less pronounced for users of both drugs. New strategies are needed to treat individuals with combined heroin and crack cocaine addiction. FUNDING: National Treatment Agency for Substance Misuse.

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. The Individual Placement and Support for Alcohol and Drug Dependence (IPS-AD) study should determine whether IPS for patients with alcohol use disorder (AUD), opioid use disorder (OUD) and other drug use disorder is effective. DESIGN/METHODS: The IPS-AD study is a seven-site, pragmatic, two-arm, parallel-group, superiority RCT. IPS-AD includes a realist process evaluation. Eligible patients (adult, unemployed or economically inactive for at least 6 months and wishing to obtain open job market employment and enrolled in ongoing community treatment-as-usual (TAU; the control condition) in England for AUD, OUD and other drug use disorders) will be randomised (1:1) to receive TAU and any standard employment support, or TAU plus IPS (the experimental condition) for 9 months with up to 4 months of in-work support. The primary outcome measure will be competitive employment status (at least 1 day (7 h)) during an 18-month follow-up, determined by patient-level, trial-data-linkage with national tax and state benefit databases. From meta-analysis, an 18% target difference on this measure of vocational effectiveness (for the experimental intervention) and a two-sided 5% level of statistical significance, will require a minimum target sample of 832 participants to achieve 90% power for a pre-registered, mixed-effects, multi-variable logistic regression model. A maximum-likelihood multiple-imputation approach will manage missing outcome data. IPS-AD has six vocational secondary outcome measures during the 18-month follow-up: (1) total time in competitive employment (and corresponding National Insurance contributions and tax paid); (2) time from randomisation to first competitive employment; (3) number of competitive job appointments; (4) job tenure (length of longest held competitive employment); (5) sustained employment (tenure in a single appointment for at least 13 weeks); and (6) job search self-efficacy. A primary cost-benefit analysis and a secondary cost-effectiveness analysis will be done using the primary outcome and secondary vocational outcomes, respectively and will include addiction treatment and social and health outcomes and their associated reference costs. The process evaluation will address IPS implementation and delivery. DISCUSSION: The IPS-AD study is the first large-scale, multi-site, definitive, superiority RCT of IPS for people with alcohol and drug dependence. Findings from the study will have substantial implications for service delivery. TRIAL REGISTRATION: ISRCTN Registry, ID: ISRCTN24159790. Registered on 1 February 2018.