Reversal learning in those with early psychosis features contingency-dependent changes in loss response and learning.

INTRODUCTION: People with psychotic disorders commonly feature broad decision-making impairments that impact their functional outcomes. Specific associative/reinforcement learning problems have been demonstrated in persistent psychosis. But these phenotypes may differ in early psychosis, suggesting that aspects of cognition decline over time. METHODS: The present proof-of-concept study examined goal-directed action and reversal learning in controls and those with early psychosis. RESULTS: Equivalent performance was observed between groups during outcome-specific devaluation, and reversal learning at an 80:20 contingency (reward probability for high:low targets). But when the low target reward probability was increased (80:40) those with early psychosis altered their response to loss, whereas controls did not. Computational modelling confirmed that in early psychosis there was a change in punishment learning that increased the chance of staying with the same stimulus after a loss, multiple trials into the future. In early psychosis, the magnitude of this response was greatest in those with higher IQ and lower clinical severity scores. CONCLUSIONS: We show preliminary evidence that those with early psychosis present with a phenotype that includes altered responding to loss and hyper-adaptability in response to outcome changes. This may reflect a compensatory response to overcome the milieu of corticostriatal changes associated with psychotic disorders.

Development of the Sepsis-Associated Adverse Outcomes in Pregnancy Score.

OBJECTIVE: This study aimed to develop and evaluate a scoring system-called the Sepsis-Associated Adverse Outcomes in Pregnancy (SAAP) Score-to identify individuals with maternal infection that have composite maternal adverse outcomes (CMAO). STUDY DESIGN: Using the International Classification of Disease codes, we identified pregnant and postpartum (up to 6 weeks after birth) individuals admitted at our center with a primary diagnosis of infection. The primary outcome was CMAO which included any of the following: maternal intensive care unit admission, surgical intervention, vasopressor use, acute respiratory distress syndrome, pulmonary edema, mechanical ventilation, high-flow nasal cannula, disseminated intravascular coagulation, dialysis, organ failure, venous thromboembolism, or maternal death. Regularized logistic regression was used to identify variables that best discriminate CMAO status. Variables were chosen for inclusion following evaluation of statistical and clinical significance. Model performance was evaluated using area under the curve (AUC) with 95% confidence intervals (CIs), sensitivity, specificity, and predictive values. RESULTS: Of the 23,235 deliveries during the study period, 227 (0.9%) individuals met inclusion criteria and among them CMAO occurred in 39.2% (95% CI: 33.1-45.7%). The SAAP score consisted of six variables (white blood cell count, systolic blood pressure, respiratory rate, heart rate, lactic acid, and abnormal diagnostic imaging) with scores ranging from 0 to 11 and a score of ≥7 being abnormal. An abnormal SAAP score had an AUC of 0.80 (95% CI: 0.74-0.86) for CMAO. The sensitivity and specificity of the SAAP score for CMAO was 0.71 (95% CI: 0.60-0.80) and 0.73 (95% CI: 0.64-0.80), respectively. The positive predictive value was 0.62 (95% CI: 0.52-0.72) and negative predictive value was 0.79 (95% CI: 0.71-0.86). CONCLUSION: Pending external validation, the sixth variable SAAP score may permit early recognition of pregnant and postpartum individuals with infection who are likely to develop adverse maternal outcomes. KEY POINTS: · Sepsis is a leading cause of maternal morbidity and mortality.. · Early recognition improves maternal sepsis outcomes.. · The SAAP score may permit early recognition of maternal adverse outcomes due to infection..

Impairments in goal-directed action and reversal learning in a proportion of individuals with psychosis.

Cognitive impairment in psychosis is one of the strongest predictors of functional decline. Problems with decision-making processes, such as goal-directed action and reversal learning, can reflect cortico-striatal dysfunction. The heterogenous symptoms and neurobiology observed in those with psychosis suggests that specific cognitive phenotypes may reflect differing causative mechanisms. As such, decision-making performance could identify subgroups of individuals with more severe cortico-striatal dysfunction and help to predict their functional decline. The present work evaluated the relationship between goal-directed action, reversal learning, and symptom profiles in those with psychosis. We assessed decision-making processes in healthy controls (N = 34) and those with persistent psychosis (N = 45), subclassifying subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. Impaired decision-making also was associated with reduced levels of grandiosity and increased problems with abstract thinking. These findings suggest that prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis. Moreover, these impairments would have significant functional implications in terms of planning and abstract thinking.

Suitability of a Low-Cost Wearable Sensor to Assess Turning in Healthy Adults.

Background: Turning is a complex measure of gait that accounts for over 50% of daily steps. Traditionally, turning has been measured in a research grade laboratory setting, however, there is demand for a low-cost and portable solution to measure turning using wearable technology. This study aimed to determine the suitability of a low-cost inertial sensor-based device (AX6, Axivity) to assess turning, by simultaneously capturing and comparing to a turn algorithm output from a previously validated reference inertial sensor-based device (Opal), in healthy young adults. Methodology: Thirty participants (aged 23.9 ± 4.89 years) completed the following turning protocol wearing the AX6 and reference device: a turn course, a two-minute walk (including 180° turns) and turning in place, alternating 360° turn right and left. Both devices were attached at the lumbar spine, one Opal via a belt, and the AX6 via double sided tape attached directly to the skin. Turning measures included number of turns, average turn duration, angle, velocity, and jerk. Results: Agreement between the outcomes from the AX6 and reference device was good to excellent for all turn characteristics (all ICCs > 0.850) during the turning 360° task. There was good agreement for all turn characteristics (all ICCs > 0.800) during the two-minute walk task, except for moderate agreement for turn angle (ICC 0.683). Agreement for turn outcomes was moderate to good during the turns course (ICCs range; 0.580 to 0.870). Conclusions: A low-cost wearable sensor, AX6, can be a suitable and fit-for-purpose device when used with validated algorithms for assessment of turning outcomes, particularly during continuous turning tasks. Future work needs to determine the suitability and validity of turning in aging and clinical cohorts within low-resource settings.

Adjunctive Garcinia mangostana Linn. (Mangosteen) Pericarp for Schizophrenia: A 24-Week Double-blind, Randomized, Placebo Controlled Efficacy Trial: Péricarpe d'appoint Garcinia mangostana Linn (mangoustan) pour la schizophrénie : un essai d'efficacité de 24 semaines, à double insu, randomisé et contrôlé par placebo.

OBJECTIVES: Garcinia mangostana Linn. ("mangosteen") pericarp contains bioactive compounds that may target biological pathways implicated in schizophrenia. We conducted a double-blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp, compared to placebo, in the treatment of schizophrenia. METHODS: People diagnosed with schizophrenia or schizoaffective disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), recruited across 2 sites (Brisbane and Victoria, Australia), were randomized to receive 24 weeks of adjunctive mangosteen pericarp (1,000 mg/day) or matched placebo. The primary outcome measure was the Positive and Negative Symptom Scale total score. Secondary outcomes included positive and negative symptoms, general psychopathology, clinical global severity and improvement, participant reported overall improvement, depressive symptoms, functioning, quality of life, and safety data at 24 and 28 weeks (4 weeks postdiscontinuation). Data were collected from July 2016 to February 2019. RESULTS: Baseline assessments were conducted on 148 people (mangosteen = 74, placebo = 74); data analyses were conducted on 136 (92%) participants with postbaseline data. The treatment group had significantly higher symptom severity compared to placebo, and both groups significantly improved on all symptom, functioning, and quality of life measures over time. No between-group differences were found for the rate of change between baseline and 24 or 28 weeks. CONCLUSION: Despite promising preclinical and clinical work, our results do not support mangosteen pericarp extract as an adjunctive treatment for schizophrenia or schizoaffective disorder.

Analysis of the use of a mobile simulation unit using the principles of a managed educational network.

INTRODUCTION: One of the challenges of delivering safe, reliable, quality health care is ensuring the workforce have access to the right training at the right time wherever they are practising. Like other high reliability fields, healthcare education has recognised the important role of simulation based education in embedding a culture of readiness for practice. Managed clinical networks (MCNs) have a proven track record in enhancing services for patients. Adapting this approach to ensuring the healthcare workforce has access to the right training at the right time can provide a more equitable national approach to simulation based education. One of the advantages of the MCN concept has been the flexibility to respond to local needs while reliably delivering national standards. METHODS: This article shares 5 years of data from a mobile simulation unit (MSU) analysed using the principles of a national managed educational network (MEN). An action research approach was used to identify how the MSU was changing the delivery of simulation based education as part of a national MEN for clinical skills education. One of the key deliverables of the Scottish Clinical Skills Strategy was to support the training needs of the National Health Service workforce, particularly in remote and rural Scotland. The MSU was proposed as part of the solution to the 'inequity of provision of clinical skills education using simulation'. Between 2014 and 2018, data were collected by the Clinical Skills Managed Educational Network (CSMEN) team on the performance of the MSU. Venues visited, job titles of participants and courses attended (a mix of local and national) were recorded by the venue hosts and collated by CSMEN staff. RESULTS: Evidence of the impact of the MSU using the seven MEN principles to analyse the data (functioning with explicit management arrangements, embedding systems of accountability, agreed expected outcomes, using an evidence base, having a multiprofessional and multidisciplinary focus, engaging in a system of dissemination, generating better value for money and engaging in research and development) are shared. CONCLUSION: Few examples of mobile simulation facilities exist in the UK, and none have the longevity of the CSMEN MSU. The results of the analysis supported the business case for an upgraded new MSU and identified the need to explore in more depth the variation in impact across the venues visited. However, some localities did not use the MSU during 2014-2018 and there are still some unanswered questions around its impact in some venues, which require further exploration.

Randomized controlled trial of social cognition and interaction training compared to befriending group.

BACKGROUND: Deficits in social cognition are common in people with schizophrenia and are associated with impaired functioning. Finding effective interventions to address these deficits is a priority. Social Cognition Interaction Training (SCIT) is a psychosocial intervention that has demonstrated acceptability and feasibility in various health care settings. Larger, well-designed randomized controlled trials are needed to examine the effectiveness of this intervention. DESIGN: A randomized controlled trial. METHODS: One hundred and twenty adults diagnosed with schizophrenia spectrum disorder were randomized to receive SCIT (n = 61) or Befriending Therapy (BT) (n = 59). Both intervention groups were delivered weekly for 2 hr over 12 weeks. Neurocognitive assessment was completed at baseline. Participants completed assessments of social cognition, social functioning, and meta-cognition at baseline, post-intervention, and 3-month follow-up. RESULTS: There were no clinically significant differences between group outcomes on any measure of social cognition or social functioning. There was a trend for both groups to improve over time but not at a level of statistical significance. CONCLUSIONS: SCIT did not show any additional benefits on measures of social cognition compared to Befriending Therapy for people with schizophrenia spectrum disorder. The findings are discussed in terms of potential improvements to the programme. PRACTITIONER POINTS: Effective interventions for the social cognitive deficits of schizophrenia spectrum disorders are still being refined. Social Cognition Interaction Training is a promising therapy but requires further modifications to improve its effectiveness.

Lumbar Spine Trabecular Bone Score (TBS) Reflects Diminished Bone Quality in Patients With Diabetes Mellitus and Oral Glucocorticoid Therapy.

Trabecular bone score (TBS) is a texture parameter that measures the grayscale variation within dual-energy X-ray absorptiometry (DXA) images, and has been shown to significantly correlate with the 3-dimensional bone microarchitecture. The objective of this study was to determine whether TBS is a better clinical tool than traditionally used bone mineral density (BMD) to detect the skeletal deterioration seen in patients with diabetes (DM), patients undergoing oral glucocorticoid (GC) therapy, and patients who are both diabetic and taking steroids (GC + DM). We performed retrospective, cross-sectional study using DXA images of patients who visited UTHealth Department of Internal Medicine DXA clinic in Houston, TX, from May 30, 2014 to May 30, 2016. A total of 477 men and women, who were 55 years or older, were included in the study. Lumbar spine (LS) BMD and TBS were collected. Electronic medical records were reviewed to collect clinical information for each patient. When both men and women were analyzed as a single group, LS-BMD was significantly higher in the diabetic group than in the control group (1.14 vs 1.10, p = 0.038), whereas mean TBS of L1-L4 was significantly lower in the diabetic group (1.21 vs 1.26, p = 0.004). LS-TBS was also significantly lower in diabetic women than in nondiabetic women (1.20 vs 1.26, p = 0.002). Receiver operating characteristic curves and areas under the curve indicated that LS-TBS provided better ability than LS-BMD to discriminate between control subjects and those in the DM, GC, or GC + DM groups (areas under the curve between 0.645 and 0.697, p < 0.010 for all). LS-TBS is a BMD-independent parameter that is capable of capturing a larger portion of bone quality deterioration undetected by BMD alone in patients with DM and undergoing oral GC therapy.

Associations of the Gut Microbiome With Treatment Resistance in Schizophrenia.

Importance: There is growing interest in the role of gut microbiome composition in schizophrenia. However, lifestyle factors are often neglected, and few studies have investigated microbiome composition in treatment-resistant schizophrenia. Objective: To explore associations between the gut microbiome and schizophrenia diagnosis, treatment resistance, clozapine response, and treatment-related adverse effects while adjusting for demographic and lifestyle factors. Design, Setting, and Participants: In this case-control study of adults aged 20 to 63 years, stool samples and data on demographic characteristics, lifestyle, and medication use were collected and gut microbiome measures obtained using shotgun metagenomics. Participants with a schizophrenia diagnosis were referred through psychiatric inpatient units and outpatient clinics. Data were collected for 4 distinct groups: control individuals without a psychiatric diagnosis (past or present), individuals with treatment-responsive schizophrenia taking nonclozapine antipsychotic medications, clozapine-responsive individuals with treatment-resistant schizophrenia, and clozapine-nonresponsive individuals with treatment-resistant schizophrenia. Participants were recruited between November 2020 and November 2021. Control individuals were recruited in parallel through posters and online advertisements and matched for age, sex, and body mass index (BMI) to the individuals with schizophrenia. Participants were excluded if taking antibiotics in the past 2 months, if unable to communicate in English or otherwise follow study instructions, were pregnant or planning to become pregnant, or had any concomitant disease or condition making them unsuited to the study per investigator assessment. Data were analyzed from January 2022 to March 2023. Main Outcomes and Measures: Omics relationship matrices, α and ß diversity, and relative abundance of microbiome features. Results: Data were collected for 97 individuals (71 [74%] male; mean [SD] age, 40.4 [10.3] years; mean [SD] BMI, 32.8 [7.4], calculated as weight in kilograms divided by height in meters squared). Significant microbiome associations with schizophrenia were observed at multiple taxonomic and functional levels (eg, common species: b2, 30%; SE, 13%; adjusted P = .002) and treatment resistance (eg, common species: b2, 27%; SE, 16%; adjusted P = .03). In contrast, limited evidence was found for microbiome associations with clozapine response, constipation, or metabolic syndrome. Significantly decreased microbial richness was found in individuals with schizophrenia compared to control individuals (t95 = 4.25; P < .001; mean [SD] for control individuals, 151.8 [32.31]; mean [SD] for individuals with schizophrenia, 117.00 [36.2]; 95% CI, 18.6-51.0), which remained significant after a covariate and multiple comparison correction. However, limited evidence was found for differences in ß diversity (weighted UniFrac) for schizophrenia diagnosis (permutational multivariate analysis of variance [PERMANOVA]: R2, 0.03; P = .02), treatment resistance (R2, 0.02; P = .18), or clozapine response (R2, 0.04; P = .08). Multiple differentially abundant bacterial species (19) and metabolic pathways (162) were found in individuals with schizophrenia, which were primarily associated with treatment resistance and clozapine exposure. Conclusions and Relevance: The findings in this study are consistent with the idea that clozapine induces alterations to gut microbiome composition, although the possibility that preexisting microbiome differences contribute to treatment resistance cannot be ruled out. These findings suggest that prior reports of microbiome alterations in individuals with chronic schizophrenia may be due to medication or lifestyle factors and that future studies should incorporate these variables in their design and interpretation.

Comprehensive Geriatric Assessment for younger outpatients with severe mental illness: protocol for a feasibility study.

INTRODUCTION: Individuals with severe mental illness are at risk of becoming prematurely frail. There is a critical unmet need for an intervention that reduces the risk of frailty and minimises the associated negative outcomes in this population. This study aims to provide novel evidence on the feasibility, acceptability and preliminary effectiveness of Comprehensive Geriatric Assessment (CGA) to improve health outcomes among people with co-occurring frailty and severe mental illness. METHODS AND ANALYSIS: Twenty-five participants with frailty and severe mental illness, aged 18-64 years, will be recruited from Metro South Addiction and Mental Health Service outpatient clinics and provided with the CGA. Primary outcome measures will include the feasibility and acceptability of the CGA embedded in routine healthcare. Other variables of interest will include frailty status, quality of life, polypharmacy, and a range of mental and physical health factors. ETHICS AND DISSEMINATION: All procedures involving human subjects/patients were approved by Metro South Human Research Ethics Committee (HREC/2022/QMS/82272). Study findings will be disseminated through peer-reviewed publications and conference presentations.

Clinical findings predictive of maternal adverse outcomes with pyelonephritis.

BACKGROUND: Pyelonephritis, a leading cause of infection during pregnancy, is associated with increased maternal adverse outcomes. Therefore, early recognition and intervention of pyelonephritis are important. Early recognition of pyelonephritis has historically been dependent on fever and costovertebral angle tenderness. However, the reliability of these findings to distinguish women who will develop maternal adverse outcomes is limited. OBJECTIVE: This study aimed to identify clinical variables on presentation that are predictive of maternal adverse outcomes associated with pyelonephritis during pregnancy. STUDY DESIGN: A retrospective cohort study of pregnant women admitted with pyelonephritis at a single hospital from October 1, 2015, to July 31, 2021, was conducted. The primary outcome was a composite maternal adverse outcome consisting of any of the following: maternal intensive care unit admission, surgical intervention, hypotension requiring vasopressors, acute respiratory distress syndrome, pulmonary edema, mechanical ventilation, high-flow nasal cannula, disseminated intravascular coagulation, altered mental status, dialysis, organ failure, venous thromboembolism, or maternal death. Differences in maternal characteristics and clinical signs and symptoms on admission were stratified by the presence or absence of a maternal adverse outcome. Categorical variables were analyzed using the Fisher exact test. Continuous data were analyzed with Wilcoxon rank-sum test. Sensitivity and specificity and likelihood ratios with 95% confidence intervals were calculated for the detection of maternal adverse outcomes by specified admission physical examination and laboratory findings. RESULTS: Of 97 women that met the inclusion criteria, 28 (28.9%) had maternal adverse outcomes. Moreover, 50 of 97 women (51.5%) had fever on presentation, with no difference between cohorts recognized. Admission vital signs were not significantly different between cohorts. Costovertebral angle tenderness was present in 78 of 97 women (80.4%) on presentation, with no difference between cohorts. Compared with women without a maternal adverse outcome, women with maternal adverse outcomes were more likely to have leukocytosis (18/28 [64.3%] vs 20/69 [29.0%]), thrombocytosis (3/28 [10.7%] vs 5/69 [7.2%]), bandemia (8/28 [28.6%] vs 7/69 [10.1%]), and an abnormal serum potassium (20/28 [71.4%] vs 32/63 [50.8%]). CONCLUSION: Admission vital signs may not reliably identify women with pyelonephritis at risk of maternal adverse outcomes. Laboratory studies, particularly a complete blood count and electrolytes, may provide a means of distinguishing those at risk of maternal adverse outcomes.

Cannabidiol for at risk for psychosis youth: A randomized controlled trial.

BACKGROUND: No biological treatment has been firmly established for the at-risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra-high risk (UHR) for psychosis group. METHODS: Three-arm randomized controlled trial of 405 patients (135 per arm) aged 12-25 years who meet UHR for psychosis criteria. The study includes a 6-week lead-in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At-Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. CONCLUSION: This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.

Metformin reduces 12-month change in body weight among people newly commenced on clozapine: a retrospective naturalistic cohort study.

BACKGROUND: People with schizophrenia have a 15-20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap. METHODS: We retrospectively analysed digital health records of patients with TRS aged 18-65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio. RESULTS: Among 90 patients initiated on clozapine, metformin use (n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight. CONCLUSION: In this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.

CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine.

BACKGROUND: There is limited evidence on interventions to minimise weight gain at clozapine commencement. We compared the effect of adjunctive metformin versus placebo at clozapine initiation. METHODS: People with schizophrenia commencing on clozapine were randomised to either metformin or placebo for 24 weeks. The primary outcome was difference in the change of body weight. Secondary outcomes included comparative rates of weight gain of more than 5%, overall weight gain/loss, and differences in metabolic and psychosis outcomes. RESULTS: The study was closed prematurely in March 2020 due to COVID-19 restrictions. Ten participants were randomised to each of the metformin and placebo groups. Eight metformin group and five placebo group participants completed the trial and were included in the analysis. The study was insufficiently powered to detect difference between the metformin and placebo groups for the primary outcome of change in weight (0.09 kg vs 2.88 kg, p = 0.231). In terms of secondary outcomes, people in the metformin group were significantly less likely to gain >5% of their body weight (12.5% vs 80%, p = 0.015) and were more likely to lose weight (37.5% vs 0% p = 0.024) compared to placebo. There was no difference between the groups in terms of adverse drug reactions (ADRs). CONCLUSION: While limited by the forced premature closure of the trial due to COVID19, the findings from this randomised controlled trial are promising. Clozapine and metformin co-commencement may be a promising treatment to prevent clozapine-associated weight gain, especially given the low rates of ADRs associated with metformin. This supports the consideration of use of metformin to prevent weight gain in people initiated on clozapine; however, further studies are needed to confirm this finding. TRIAL REGISTRATION: ACTRN12617001547336.

Cadence discovery: study protocol for a dose-finding and mechanism of action clinical trial of sodium benzoate in people with treatment-refractory schizophrenia.

BACKGROUND: Schizophrenia is a persistent psychotic disorder often accompanied by severe disability and premature mortality. New pharmacological treatments are urgently needed. Sodium benzoate, a common food preservative holds potential to be an effective, accessible treatment for schizophrenia, though the optimal dosing and mechanism of action of the compound requires further investigation. METHODS: Individuals with persistent treatment-refractory schizophrenia (n=52) will be recruited. Patients will be randomised in a 1:1:1:1 ratio to receive treatment of one of three active doses (1000, 2000 or 4000 mg daily) of sodium benzoate or placebo for 6 weeks duration. The primary outcome measurement is change in the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measurements are PANSS subscales, Global Assessment of Function (GAF), Clinical Global Impression (CGI) and Patient Global Impression (PGI-I). Change in concentrations of peripheral amino acids (D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate), plasma sodium benzoate, plasma catalase, 3-nitrotyrosine, malondialdehyde and high-sensitivity C-reactive protein (hs-CRP) will be determined as tertiary measures. DISCUSSION: This trial seeks to build upon previous research indicating potential efficacy of sodium benzoate for reduction of symptoms in individuals with treatment-refractory schizophrenia. The trial aims to improve the understanding of the mechanism of action of the compound. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621000327886 . Registered on 23 March 2021.

The Effect of Adjunctive Mangosteen Pericarp on Cognition in People With Schizophrenia: Secondary Analysis of a Randomized Controlled Trial.

Background: Cognitive impairment is prevalent and often highly burdensome in people with schizophrenia. The aim of this study was to investigate if mangosteen (Garcinia mangostana Linn.) pericarp extract may be an effective intervention to improve cognitive performance in this population. Methods: This was a secondary analysis of a larger randomized placebo-controlled trial that investigated a 24-weeks intervention of mangosteen pericarp extract supplementation in people diagnosed with schizophrenia. A subset of n = 114 participants with completed cognitive outcomes at follow up were included in this analysis. Using the Cogstate Brief Battery, the following cognitive outcomes were assessed: psychomotor function, attention, visual learning and memory (visual and working). Subgroup analyses investigated whether baseline clinical parameters (baseline cognitive functioning, illness severity and duration, depressive symptoms) moderated the relationship between mangosteen pericarp extract intervention and change in cognitive outcomes. Results: There were no significant between-group changes in any cognitive outcomes assessed. Subgroup analysis based on baseline cognition and clinical characteristics did not reveal any significant between-group difference in change. Conclusions: Mangosteen pericarp extract did not affect cognitive outcomes in people with schizophrenia. Further investigation regarding optimal dosing strategies for mangosteen interventions and the testing of additional cognitive domains may be warranted. Trial Registration: ANZCTR.org.au identifier: ACTRN12616000859482, registered 30 June 3 2016.

Effects of Sterilization Techniques on Bioactivity of Polymethyl Methacrylate Antibiotic Beads Containing Vancomycin and Tobramycin.

OBJECTIVES: Prefabrication and storage of antibiotic beads may decrease surgical time and allow for use in other settings. This study investigated the effects of sterilization technique and storage time on the bioactivity of antibiotic polymethyl methacrylate (PMMA) beads. METHODS: Uniform beads of PMMA containing 1 g each of tobramycin and vancomycin were sterilized using autoclave, ethylene oxide (ETO), or ultraviolet (UV) light. Beads were made in a sterile fashion as a control. Disks containing eluted antibiotics from each of the 4 groups were placed onto agar plates inoculated with Staphylococcus aureus. Zones of inhibition, a measure of bioactivity for antibiotic eluted, were determined for the experimental groups and control. Repeat testing was performed for beads stored for 1 week, 1, 3, and 6 months. RESULTS: Beads sterilized using autoclave, ETO, and UV light showed similar ZOIs after 24 hours of and 1 week of elution compared with the control group. Beads stored for up to 6 months demonstrated similar bioactivity to beads made sterile and tested immediately. CONCLUSION: PMMA beads containing vancomycin and tobramycin made in a sterile fashion and stored for up to 6 months have the same efficacy as the current standard of beads made sterile and used immediately. The elution and bioactivity of vancomycin-tobramycin antibiotic beads are not negatively impacted by the sterilization methods of autoclaving, ETO gas, or UV light. Furthermore, nonsterile beads can be sterilized and stored up to 6 months with an expected efficacy comparable with beads made in a standard sterile fashion.

Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis: A Randomized Clinical Trial.

Importance: There is evidence that sodium benzoate (BZ) may be an effective adjunctive treatment for schizophrenia. The clinical efficacy of BZ has been investigated in chronic schizophrenia; however, the efficacy of this agent has not been studied in individuals with early psychosis. Objective: To examine the clinical efficacy of the adjunctive use of BZ for symptoms in people with early psychosis. Design, Setting, and Participants: Using a placebo-controlled double-masked parallel-group design, this randomized clinical trial was conducted from August 2015 to July 2018. Participants aged between 15 and 45 years experiencing early psychosis were enrolled from 5 major clinical sites in Queensland, Australia. Data analysis was conducted from October 2018 to February 2020. Interventions: Participants were randomized 1:1 (50 participants in each group) to receive 500 mg of sodium benzoate twice daily or placebo for 12 weeks. Main Outcomes and Measures: The primary efficacy outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks. The key secondary efficacy measures were (1) the Clinical Global Impression score, (2) the Hamilton Depression Rating Scale for depression, (3) functioning as assessed by the clinician-rated Global Assessment of Function, and (4) the Assessment of Quality of Life Scale. The PANSS subscale scores and impact on selected amino acid concentrations were also assessed. Results: The study comprised 100 participants with a mean (SD) age of 21.4 (4.1) years, of whom 73 (73%) were male individuals. The mean (SD) baseline PANSS score was 75.3 (15.4). We found no improvement in total PANSS score in the BZ group compared with the placebo group. The end result of least-squares mean difference (SE) for total PANSS was -1.2 (2.4) (P = .63). There were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. The dose of BZ was well tolerated without any clinically significant treatment-emergent adverse event differences between BZ and placebo groups. Conclusions and Relevance: In this randomized clinical trial, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis. Trial Registration: anzctr.org.au Identifier: ACTRN12615000187549.

Students' Perceptions on a Business Plan Assignment for an Ambulatory Care Pharmacy Elective.

Objective. To evaluate a business-centered assignment implemented in a pharmacy elective course at two different institutions and analyze student perceptions of the delivery platforms used and the value and utility of the assignment. Methods. The ambulatory care electives at Butler University and Samford University introduce students to the expanding role of the ambulatory care pharmacist, emphasizing business plan development for new ambulatory care pharmacy services. As part of the elective, students are asked to work in groups to complete a business plan for a new ambulatory care service of their choosing. A survey was conducted to assess student perceptions on the assignment. Results. Of the 58 students who completed the business plan assignment, 49 completed the survey and were included in the data analysis. Overall, 100% of Samford students and 97% of Butler students either strongly agreed or agreed that the business plan was an innovative assignment unlike others completed in the curriculum. Samford students strongly agreed (100%) that if asked by a future employer to develop a new pharmacy service, concepts learned from this assignment would be useful, compared to 59% of Butler students who felt this way. While both the web and written delivery platforms had identical learning outcomes, the written business plan was the approach that the majority of students were more comfortable using. Conclusion. The business plan assignment was used as a method to familiarize students with the process of developing new ambulatory care pharmacy services. Based on survey results, the students perceived this to be an innovative assignment that allowed them to feel confident in developing and communicating ambulatory care business plans. As the practice of ambulatory care pharmacy expands, assignments such as this can be included in the pharmacy curriculum to meet the need for teaching effective business strategies to future pharmacists.

Protocol and Rationale: A 24-week Double-blind, Randomized, Placebo Controlled Trial of the Efficacy of Adjunctive Garcinia mangostanaLinn. (Mangosteen) Pericarp for Schizophrenia.

OBJECTIVE: : Garcinia mangostana Linn., commonly known as mangosteen, is a tropical fruit with a thick pericarp rind containing bioactive compounds that may be beneficial as an adjunctive treatment for schizophrenia. The biological underpinnings of schizophrenia are believed to involve altered neurotransmission, inflammation, redox systems, mitochondrial dysfunction, and neurogenesis. Mangosteen pericarp contains xanthones which may target these biological pathways and improve symptoms; this is supported by preclinical evidence. Here we outline the protocol for a double- blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp (1,000 mg/day), compared to placebo, in the treatment of schizophrenia. METHODS: : We aim to recruit 150 participants across two sites (Geelong and Brisbane). Participants diagnosed with schizophrenia or schizoaffective disorder will be randomized to receive 24 weeks of either adjunctive 1,000 mg/day of mangosteen pericarp or matched placebo, in addition to their usual treatment. The primary outcome measure is mean change in the Positive and Negative Symptom Scale (total score) over the 24 weeks. Secondary outcomes include positive and negative symptoms, general psychopathology, clinical global severity and improvement, depressive symptoms, life satisfaction, functioning, participants reported overall improvement, substance use, cognition, safety and biological data. A 4-week post treatment interview at week 28 will explore post-discontinuations effects. RESULTS: : Ethical and governance approvals were gained and the trial commenced. CONCLUSION: : A positive finding in this study has the potential to provide a new adjunctive treatment option for people with schizophrenia and schizoaffective disorder. It may also lead to a greater understanding of the pathophysiology of the disorder.