Finding the balance between model complexity and performance: Using ventral striatal oscillations to classify feeding behavior in rats.

The ventral striatum (VS) is a central node within a distributed network that controls appetitive behavior, and neuromodulation of the VS has demonstrated therapeutic potential for appetitive disorders. Local field potential (LFP) oscillations recorded from deep brain stimulation (DBS) electrodes within the VS are a pragmatic source of neural systems-level information about appetitive behavior that could be used in responsive neuromodulation systems. Here, we recorded LFPs from the bilateral nucleus accumbens core and shell (subregions of the VS) during limited access to palatable food across varying conditions of hunger and food palatability in male rats. We used standard statistical methods (logistic regression) as well as the machine learning algorithm lasso to predict aspects of feeding behavior using VS LFPs. We were able to predict the amount of food eaten, the increase in consumption following food deprivation, and the type of food eaten. Further, we were able to predict whether the initiation of feeding was imminent up to 42.5 seconds before feeding began and classify current behavior as either feeding or not-feeding. In classifying feeding behavior, we found an optimal balance between model complexity and performance with models using 3 LFP features primarily from the alpha and high gamma frequencies. As shown here, unbiased methods can identify systems-level neural activity linked to domains of mental illness with potential application to the development and personalization of novel treatments.

Designing and evaluating an interprofessional education conference approach to antimicrobial education.

BACKGROUND: Arguably, Medical School curricula are deficient in learning opportunities related to the safe and effective use of medicines, in particular antimicrobials. Infection management is complex and multidisciplinary, and learning opportunities should reflect these principles. Aligned to the complexity of the subject matter, simulation and interprofessional based teaching are methods that can foster the collaborative skills required of future healthcare professionals. There have been calls to develop these methods in the teaching of safe prescribing and the management of infections; however, reports of such studies are limited. METHODS: We developed an interprofessional education (IPE) conference for second year undergraduate medical and pharmacy students based in the North East of England. We considered contact theory in the design of three small group interprofessional workshops, on the broad themes of antimicrobial stewardship, infection management and patient safety. A mixed methods approach assessed students' attitudes towards IPE, barriers and facilitators of learning, and perceived learning gains. Qualitative data from workshop evaluation forms were analysed thematically, while quantitative data were analysed descriptively and differences between medical and pharmacy cohorts analysed using unpaired two-tailed t-tests. RESULTS: 226/352 students returned the workshop evaluation forms (66% of pharmacy students, 62% of medical students). 281/352 students responded to a series of Likert scale questions on the value of interprofessional education (88% of pharmacy students, 70% of medical students). Students reported acquisition of knowledge and skills, including concepts and procedures related to infection management and antimicrobial prescribing, and the development of problem-solving and critical evaluation skills. Students reflected on their attitude towards interprofessional collaboration. They reported a greater understanding of the roles of other healthcare professionals, reflected on the importance of effective communication in ensuring patient safety, and were more confident to work in interprofessional teams after the conference. CONCLUSIONS: A robust IPE event, theoretically underpinned by contact theory and developed collaboratively, achieved interprofessional learning at scale and helped develop healthcare professionals willing to collaborate across disciplines. The resources, and evaluation insights based on the 3P (presage, process, and product) model of learning and teaching, will be of value to other educators who seek to develop theoretically-sound IPE interventions.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Making it work: the feasibility and logistics of delivering large-scale interprofessional education to undergraduate healthcare students in a conference format.

An interprofessional education conference was developed and delivered to undergraduate medical and pharmacy students to address training needs around appropriate antimicrobial prescribing, identification and management of sepsis, patient safety and interprofessional working. The day consisted of keynote lectures delivered by specialist speakers and three small group interprofessional teaching sessions exploring (1) the choice and prescribing of antimicrobials for a range of infections, (2) the diagnosis and management of sepsis utilising simulation methodology and (3) the discussion of a clinical error using significant event analysis. Students' attitudes and acceptance towards this educational intervention were assessed using a mixed methods evaluation. The delivery of an effective learning and teaching intervention in a conference format to a large cohort of pharmacy and medical students (n = 352) was found to be feasible. The logistics of organising an IPE conference of this scale were challenging but not insurmountable if sufficient staff and financial resources can be secured. Scheduling access to adequate teaching rooms and student timetabling were amongst the other important aspects affecting the success of such an event.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults.

Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.

A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients.

BACKGROUND: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. RESULTS: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). CONCLUSIONS: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients.

A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients.

BACKGROUND: Despite advances in the development of medications to treat alcohol dependence, few medications have been approved by the U.S. Food and Drug Administration. The use of certain anticonvulsant medications has demonstrated potential efficacy in treating alcohol dependence. Previous research suggests that the anticonvulsant levetiracetam may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, 130 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either levetiracetam extended-release (XR) or placebo and a Brief Behavioral Compliance Enhancement Treatment intervention. Levetiracetam XR was titrated during the first 4 weeks to 2,000 mg/d. This target dose was maintained during weeks 5 through 14 and was tapered during weeks 15 and 16. RESULTS: No significant differences were detected between the levetiracetam XR and placebo groups in either the primary outcomes (percent heavy drinking days and percent subjects with no heavy drinking days) or in other secondary drinking outcomes. Treatment groups did not differ on a number of nondrinking outcomes, including depression, anxiety, mood, and quality of life. The only difference observed was in alcohol-related consequences. The levetiracetam XR treatment group showed significantly fewer consequences than did the placebo group during the maintenance period (p = 0.02). Levetiracetam XR was well tolerated, with fatigue being the only significantly elevated adverse event, compared with placebo (53% vs. 24%, respectively; p = 0.001). CONCLUSIONS: This multisite clinical trial showed no efficacy for levetiracetam XR compared with placebo in reducing alcohol consumption in heavy drinking alcohol-dependent patients.

Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia.

We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.

Glutamine and GABA alterations in cingulate cortex may underlie alcohol drinking in a rat model of co-occurring alcohol use disorder and schizophrenia: an 1H-MRS study.

Alcohol use disorder commonly occurs in patients with schizophrenia and significantly worsens the clinical course of the disorder. The neurobiological underpinnings of alcohol drinking are not well understood. Magnetic resonance spectroscopy (MRS) has been used to assess the neurochemical substrates that may be associated with alcohol drinking in patients; however, the causal impact of these findings remains elusive, highlighting the need for studies in animal models. This study performed MRS in the neonatal ventral hippocampal lesioned (NVHL) rat model, a model of co-occurring schizophrenia and substance use disorders. NVHL lesions (or sham surgeries) were performed on post-natal day 7 and animals were given brief exposure to alcohol during adolescence (10% v/v in a 2-bottle choice design). Animals were re-exposed to alcohol during adulthood (20% v/v) until a stable drinking baseline was established, and then forced into abstinence to control for the effects of differential alcohol drinking. Animals were scanned for MRS after one month of abstinence. NVHL rats consumed significantly more alcohol than sham rats and in the cingulate cortex showed significantly higher levels of GABA and glutamine. Significantly lower GABA levels were observed in the nucleus accumbens. No differences between the NVHL and sham animals were observed in the hippocampus. Correlation analysis revealed that GABA and glutamine concentrations in the cingulate cortex significantly correlated with the rats' alcohol drinking prior to 30 days of forced abstinence. These findings suggest that a potential dysfunction in the glutamate/GABA-glutamine cycle may contribute to alcohol drinking in a rat model of schizophrenia, and this dysfunction could be targeted in future treatment-focused studies.

Outcomes from the Northeast England cohort of autosomal dominant polycystic kidney disease (ADPKD) patients on tolvaptan.

Autosomal dominant polycystic kidney disease (ADPKD) is a cause of end-stage kidney disease (ESKD). The vasopressin V2-receptor antagonist tolvaptan has been shown within randomized clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a Northeast England cohort of adult ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real-world clinic setting. Other inclusion criteria involved a pre-treatment decline in greater than 2.5 ml/min/1.73m2/year based on readings for a 3 year period, and ability to tolerate and maintain tolvaptan treatment for at least 12 months. We calculated based on eGFR slopes, predicted time to reach ESKD with and without tolvaptan therapy. The cohort of patients included 21 from the Northeast of England. The mean rate of eGFR decline prior to treatment was -6.02 ml/min/1.73m2/year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.47 ml/min/1.73m2/year, gaining a mean 8 years and 4 months delay to reach ESKD. The majority of patients (n=19) received and tolerated full dose tolvaptan (90 mg/30 mg). The real-life use of tolvaptan gave a dramatic improvement in eGFR slopes, much more than previously reported in clinical studies. These effects may be in part due to careful patient identification, selection and inclusion of patients who were able to tolerate tolvaptan therapy, excellent compliance with medication and a "tolvaptan clinic" effect where great personal care was given to these patients.