Numerous studies have shown that the hippocampus is critical for spatial memory. Within nonhuman research, a task often used to assess spatial memory is the radial arm maze. Because of the spatial nature of this task, this maze is often used to assess the function of the hippocampus. Our goal was to extrapolate this task to humans and examine whether healthy undergraduates utilize their hippocampus while performing a virtual reality version of the radial arm maze task. Thirteen undergraduates performed a virtual radial arm maze during functional magnetic resonance imaging. The brain maps of activity reveal bilateral hippocampal BOLD signal changes during the performance of this task. However, paradoxically, this BOLD signal change decreases during the spatial memory component of the task. Additionally, we note frontal cortex activity reflective of working memory circuits. These data reveal that, as predicted by the rodent literature, the hippocampus is involved in performing the virtual radial arm maze in humans. Hence, this virtual reality version may be used to assess the integrity of hippocampus so as to predict risk or severity in a variety of psychiatric disorders.

Performance on a novel, virtual reality (VR) assessment of medication management skills, the Virtual Reality Apartment Medication Management Assessment (VRAMMA), was investigated in 25 patients with schizophrenia and 18 matched healthy controls. The VRAMMA is a virtual 4-room apartment consisting of a living room with an interactive clock and TV, a bedroom, a kitchen, and a bathroom with an interactive medicine cabinet. After an exploratory phase, participants were given a mock prescription regimen to be taken 15 minutes later from pill bottles located in the medicine cabinet in the bathroom of the virtual environment. The VRAMMA was administered with a validated measure of medication management skills, several neurocognitive tests, and a symptom scale. Results revealed that (1) schizophrenic patients made significantly more quantitative errors in the number of pills taken, were less accurate at taking the prescribed medications at the designated time, and checked the interactive clock less frequently than healthy controls; (2) in patients with schizophrenia, there was significant agreement in classification of adherence vs nonadherence between a validated measure of medication management skills and the VRAMMA; and (3) in patients with schizophrenia, years of education and a measure of verbal learning and memory were linked to quantitative errors on the VRAMMA, while positive symptoms, specifically delusional symptoms, were inversely linked to distance traveled within the VRAMMA. This is the first study, to our knowledge, to provide evidence for the utility of VR technology in the assessment of instrumental role functioning in patients with schizophrenia.

IntroductionBronchopulmonary dysplasia (BPD), an important sequela of preterm birth, is associated with long-term abnormalities of lung function and adverse neurodevelopmental outcomes. Inflammation, inhibition of secondary septation and vascular maldevelopment play key roles in the pathogenesis of BPD. Human amnion epithelial cells (hAECs), stem-like cells, derived from placental tissues are able to modulate the inflammatory milieu and, in preclinical studies of BPD-like injury, restore lung architecture and function. Allogeneic hAECs may present a new preventative and reparative therapy for BPD.Methods and analysisIn this two centre, phase I cell dose escalation study we will evaluate the safety of intravenous hAEC infusions in preterm infants at high risk of severe BPD. Twenty-four infants born at less than 29 weeks’ gestation will each receive intravenous hAECs beginning day 14 of life. We will escalate the dose of cells contained in a single intravenous hAEC infusion in increments from 2 million cells/kg to 10 million cells/kg. Further dose escalation will be achieved with repeat infusions given at 5 day intervals to a maximum total dose of 30 million cells/kg (three infusions). Safety is the primary outcome. Infants will be followed-up until 2 years corrected age. Additional outcome measures include a description of infants’ cytokine profile following hAEC infusion, respiratory outcomes including BPD and pulmonary hypertension and other neonatal morbidities including neurodevelopmental assessment at 2 years.Ethics and disseminationThis study was approved on the June12th, 2018 by the Human Research Ethics Committee of Monash Health and Monash University. Recruitment commenced in August 2018 and is expected to take 18 months. Accordingly, follow-up will be completed mid-2022. The findings of this study will be disseminated via peer-reviewed journals and at conferences.Protocol version5, 21 May 2018.Trial registration numberACTRN12618000920291; Pre-results.

Recent decades have seen the rapid progress of neonatal intensive care, and the survival rates of the most preterm infants are improving. This improvement is associated with changing patterns of morbidity and new phenotypes of bronchopulmonary dysplasia and preterm brain injury are recognised. Inflammation and immaturity are known contributors to their pathogenesis. However, a new phenomenon, the exhaustion of progenitor cells is emerging as an important factor. Current therapeutic approaches do not adequately address these new mechanisms of injury. Cell therapy, that is the use of stem and stem-like cells, with its potential to both repair and prevent injury, offers a new approach to these challenging conditions. This review will examine the rationale for cell therapy in the extremely preterm infant, the preclinical and early clinical evidence to support its use in bronchopulmonary dysplasia and preterm brain injury. Finally, it will address the challenges in translating cell therapy from the laboratory to early clinical trials.

Predicting an infant's risk of bronchopulmonary dysplasia (BPD) is challenging, particularly during the first weeks after birth. However, strategies to prevent BPD may have most benefit if delivered during this period. A tool assessing BPD risk would prove valuable to clinicians and researchers-aiding clinical decisions and developing eligibility criteria to evaluate preventative BPD therapies. The NICHD 'BPD Outcome Estimator' (BPD estimator) uses clinical and demographic data to estimate, on postnatal days 1, 3, 7, 14, 21 and 28, an infant's risk of mild, moderate and severe BPD, and the Fellowship No. 1157782 to PGD).

The muscarinic receptor agonist xanomeline improved cognition in phase 2 trials in Alzheimer’s disease and schizophrenia. We present data on the effect of KarXT (xanomeline–trospium) on cognition in schizophrenia from the 5-week, randomised, double-blind, placebo-controlled EMERGENT-1 trial (NCT03697252). Analyses included 125 patients with computerised Cogstate Brief Battery (CBB) subtest scores at baseline and endpoint. A post hoc subgroup analysis evaluated the effects of KarXT on cognitive performance in patients with or without clinically meaningful cognitive impairment at baseline, and a separate outlier analysis excluded patients with excessive intraindividual variability (IIV) across cognitive subdomains. ANCOVA models assessed treatment effects for completers and impairment subgroups, with or without removal of outliers. Sample-wide, cognitive improvement was numerically but not statistically greater with KarXT (n = 60) than placebo (n = 65), p = 0.16. However, post hoc analyses showed 65 patients did not exhibit clinically meaningful cognitive impairment at baseline, while eight patients had implausibly high IIV at one or both timepoints. Significant treatment effects were observed after removing outliers (KarXT n = 54, placebo n = 63; p = 0.04). Despite the small sample size, a robust (d = 0.50) and significant effect was observed among patients with cognitive impairment (KarXT n = 23, placebo n = 37; p = 0.03). These effects did not appear to be related to improvement in PANSS total scores (linear regression, R2 = 0.03). Collectively, these findings suggest that KarXT may have a separable and meaningful impact on cognition, particularly among patients with cognitive impairment.

Medication compliance is essential to treating the symptoms of schizophrenia effectively. This study utilized a virtual reality (VR) apartment paradigm to assess medication compliance behaviors in 25 patients with schizophrenia and in 16 healthy control subjects. Participants were assigned a prescription consisting of three medications and were asked to self-administer this regimen in 15 min. Results demonstrate that patients had considerably more difficulty in complying with the medication regimen than did controls. They manifested significantly more quantitative errors, and were much less accurate in consuming the medications at the assigned time. Significant differences in performance between these groups were also evidenced by a variety of validated neuropsychological measures. Correlations between the data may suggest a convergent validity for this new VR task. Future research will investigate the validity of this task in predicting additional measures of psychosocial functioning.

Cell therapies for neonatal morbidities are progressing to early phase clinical trials. However, protocols for intravenous (IV) delivery of cell therapies to infants have not been evaluated. It has been assumed the cell dose prescribed is the dose delivered. Early in our clinical trial of human amnion epithelial cells (hAECs), we observed cells settling in the syringe and IV tubing used to deliver the suspension. The effect on dose delivery was unknown. We aimed to quantify this observation and determine an optimal protocol for IV delivery of hAECs to extremely preterm infants. A standard pediatric infusion protocol was modeled in the laboratory. A syringe pump delivered the hAEC suspension over 60 minutes via a pediatric blood transfusion set (200‐μm filter and 2.2 mL IV line). The infusion protocol was varied by agitation methods, IV‐line volumes (0.2‐2.2 mL), albumin concentrations (2% vs 4%), and syringe orientations (horizontal vs vertical) to assess whether these variables influenced the dose delivered. The influence of flow rate (3‐15 mL/h) was assessed after other variables were optimized. The standard infusion protocol delivered 17.6% ± 9% of the intended hAEC dose. Increasing albumin concentration to 4%, positioning the syringe and IV line vertically, and decreasing IV‐line volume to 0.6 mL delivered 99.7% ± 13% of the intended hAEC dose. Flow rate did not affect dose delivery. Cell therapy infusion protocols must be considered. We describe the refinement of a cell infusion protocol that delivers intended cell doses and could form the basis of future neonatal cell delivery protocols.