Protocol for a randomised, multicentre, four-arm, double-blinded, placebo-controlled trial to assess the benefits and safety of iron supplementation with malaria chemoprevention to children in Malawi: IRMA trial.

INTRODUCTION: Approximately 40% of children aged 6-59 months worldwide are anaemic. Iron-containing multiple micronutrient powders (MNPs) and iron supplements (syrup/drops) are used to combat anaemia in children in different parts of the world. However, evidence for functional benefits of iron supplementation in children is scarce, and potential risks remain poorly defined, particularly concerning diarrhoea and malaria. This trial aims to determine if: (1) the efficacy of iron supplements or MNPs (containing iron) given with malaria chemoprevention is superior to malaria chemoprevention alone, or (2) if the efficacy of malaria chemoprevention alone is superior to placebo on child cognitive development. METHODS AND ANALYSIS: IRMA is a four-arm, parallel-group, double-blinded, placebo-controlled, triple-dummy, randomised trial in Southern Malawi. The study recruits 2168 infants aged 6 months, with an intervention period of 6 months and a post-intervention period of a further 6 months. Children are randomised into four arms: (1) No intervention (placebo); (2) malaria chemoprevention only; (3) MNPs and malaria chemoprevention; and (4) iron syrup and malaria chemoprevention. The primary outcome, cognitive development (Cognitive Composite Score (CogCS)), is measured at the end of the 6 months intervention. Secondary outcomes include CogCS at a further 6 months post-intervention, motor, language and behavioural development, physical growth and prevalence of anaemia and iron deficiency. Safety outcomes include incidence of malaria and other infections, and prevalence of malaria parasitaemia during and post-intervention period. ETHICS AND DISSEMINATION: The trial is approved by the National Health Sciences Research Committee (#19/01/2213) (Malawi) and the Human Research Ethics Committee (WEHI: 19/012) (Australia). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders. TRIAL REGISTRATION NUMBER: ACTRN12620000386932.

Neuroimaging in psychedelic drug development: past, present, and future.

Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating psychiatric disorders, including depression, addiction, post-traumatic stress disorder, and potentially others. 'Classic' serotonergic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), which have a key locus of action at the 5-HT2A receptor, form the main focus of this movement, but substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The modern phase of development of these treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This can potentially enable assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline the major trends in existing data and suggest the modern development of PT has benefitted greatly from the use of neuroimaging. Important gaps in existing knowledge are identified, namely: the relationship between acute drug effects and longer-term (clinically-relevant) effects, the precise characterisation of effects at the 5-HT2A receptor and relationships with functional/clinical effects, and the possible impact of these compounds on neuroplasticity. A road-map for future research is laid out, outlining clinical studies which will directly address these three questions, principally using combined Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) methods, plus other adjunct techniques. Multimodal (PET/MRI) studies using modern PET techniques such as the 5-HT2A-selective ligand [11 C]Cimbi-36 (and other ligands sensitive to neuroplasticity changes) alongside MRI measures of brain function would provide a 'molecular-functional-clinical bridge' in understanding. Such results would help to resolve some of these questions and provide a firmer foundation for the ongoing development of PT.

Psychedelic therapy in the treatment of addiction: the past, present and future.

Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific and medical communities with evidence now building for its safety and efficacy in treating a range of psychiatric disorders including addiction. In this review we will chart the research investigating the role of these interventions in individuals with addiction beginning with an overview of the current socioeconomic impact of addiction, treatment options, and outcomes. We will start by examining historical studies from the first psychedelic research era of the mid-late 1900s, followed by an overview of the available real-world evidence gathered from naturalistic, observational, and survey-based studies. We will then cover modern-day clinical trials of psychedelic therapies in addiction from first-in-human to phase II clinical trials. Finally, we will provide an overview of the different translational human neuropsychopharmacology techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), that can be applied to foster a mechanistic understanding of therapeutic mechanisms. A more granular understanding of the treatment effects of psychedelics will facilitate the optimisation of the psychedelic therapy drug development landscape, and ultimately improve patient outcomes.

Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model.

BACKGROUND: There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin-assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT. METHODS: A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates. RESULTS: The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective. CONCLUSIONS: Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base.

Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial.

BACKGROUND: Anaemia affects 46% of pregnancies in Africa; oral iron is recommended by WHO but uptake and adherence are suboptimal. We tested a single dose of a modern intravenous iron formulation, ferric carboxymaltose, for anaemia treatment in Malawian pregnant women. METHODS: In this open-label, individually randomised controlled trial, we enrolled women with a singleton pregnancy of 13-26 weeks' gestation in primary care and outpatient settings across two regions in southern Malawi. Women were eligible if they had capillary haemoglobin of less than 10·0 g/dL and negative malaria rapid diagnostic test. Participants were randomised by sealed envelope 1:1. Assessors for efficacy outcomes (laboratory parameters and birthweight) were masked to intervention; participants and study nurses were not masked. Participants were given ferric carboxymaltose up to 1000 mg (given once at enrolment in an outpatient primary care setting), or standard of care (60 mg elemental iron twice daily for 90 days), along with intermittent preventive malaria treatment. The primary maternal outcome was anaemia at 36 weeks' gestation. The primary neonatal outcome was birthweight. Analyses were performed in the intention-to-treat population for mothers and liveborn neonates, according to their randomisation group. Safety outcomes included incidence of adverse events during infusion and all adverse events from randomisation to 4 weeks' post partum. The trial is registered with ANZCTR, ACTRN12618001268235. The trial has completed follow-up. FINDINGS: Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 randomly assigned to ferric carboxymaltose (n=430) or standard of care (n=432). Ferric carboxymaltose did not reduce anaemia prevalence at 36 weeks' gestation compared with standard of care (179 [52%] of 341 in the ferric carboxymaltose group vs 189 [57%] of 333 in the standard of care group; prevalence ratio [PR] 0·92, 95% CI 0·81 to 1·06; p=0·27). Anaemia prevalence was numerically lower in mothers randomly assigned to ferric carboxymaltose compared with standard of care at all timepoints, although significance was only observed at 4 weeks' post-treatment (PR 0·91 [0·85 to 0·97]). Birthweight did not differ between groups (mean difference -3·1 g [-75·0 to 68·9, p=0·93). There were no infusion-related serious adverse events or differences in adverse events by any organ class (including malaria; ≥1 adverse event: ferric carboxymaltose 183 [43%] of 430 vs standard of care 170 [39%] of 432; risk ratio 1·08 [0·92 to 1·27]; p=0·34). INTERPRETATION: In this malaria-endemic sub-Saharan African setting, treatment of anaemic pregnant women with ferric carboxymaltose was safe but did not reduce anaemia prevalence at 36 weeks' gestation or increase birthweight. FUNDING: Bill & Melinda Gates Foundation (INV-010612).

Protocol and statistical analysis plan for a randomized controlled trial of the effect of intravenous iron on anemia in Malawian pregnant women in their third trimester (REVAMP - TT).

Background: Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over 40% of anemia cases in Africa. Oral iron supplementation is insufficient for Low-and-Middle-Income-Countries (LMICs) to meet current WHO targets. We hypothesized that a single intravenous dose of Ferric Carboxymaltose (FCM) may be more effective than oral iron treatment for anemia recovery, particularly in these settings where women present late for antenatal care. Methods: This is a two-arm parallel open-label individual-randomized controlled trial in third trimester, in malaria Rapid Diagnostic Test-negative pregnant women with moderate or severe anemia - capillary hemoglobin <10 g/dL - who are randomized to receive either parenteral iron - with FCM - or standard-of-care oral iron for the remainder of pregnancy. This is the sister trial to the second-trimester REVAMP trial, funded by the Bill and Melinda Gates Foundation (trial registration ACTRN12618001268235, Gates Grant number INV-010612). In REVAMP-TT, recruitment and treatment are performed within primary health centers. The trial will recruit 590 women across Zomba district, Malawi. The primary outcome is the proportion of anemic women - venous hemoglobin <11 g/dL - at 36 weeks' gestation or delivery (whichever occurs first). Other pre-specified key secondary clinical and safety outcomes include maternal iron-status and hypophosphatemia, neonate birth weight, infant growth and infant iron and hematological parameters. Discussion: This study will determine whether FCM, delivered within primary health centers, is effective, safe and feasible for treating moderate to severe anemia in third-trimester pregnant Malawian women. This intervention could have long-term benefits for maternal and child health, resulting in improved survival and child development.

Protocol for a multicentre, parallel-group, open-label randomised controlled trial comparing ferric carboxymaltose with the standard of care in anaemic Malawian pregnant women: the REVAMP trial.

INTRODUCTION: Anaemia in pregnancy remains a critical global health problem, affecting 46% of pregnant women in Africa and 49% in Asia. Oral iron therapy requires extended adherence to achieve correction of anaemia and replenishment of iron stores. Ferric carboxymaltose (FCM) is a recently established intravenous iron formulation associated with substantial advantages in safety, speed of delivery and total dose deliverable in a single infusion. We aim to determine whether FCM given once during the second trimester of pregnancy compared with standard oral iron distributed through routine antenatal services is effective and safe for treatment of moderate to severe maternal anaemia in sub-Saharan Africa. METHODS AND ANALYSIS: The randomized controlled trial of the effect of intravenous iron on anaemia in Malawian pregnant women (REVAMP) is a two-arm confirmatory individually randomised trial set in Blantyre and Zomba districts in Malawi. The trial will randomise 862 women in the second trimester of pregnancy with a capillary haemoglobin concentration below 100.0 g/L. The study comprises two arms: (a) intravenous FCM (20 mg/kg up to 1000 mg) given once at randomisation, and (b) standard of care oral iron (65 mg elemental iron two times per day) for 90 days (or the duration of pregnancy, whichever is shorter) provided according to local healthcare practices. Both arms receive sulfadoxine-pyrimethamine as intermittent preventive treatment in pregnancy. The primary outcome is the prevalence of anaemia (Hb <110.0 g/L) at 36 weeks' gestation. Secondary outcomes include birth weight, gestation duration and safety outcomes, including clinical malaria, serious perinatal events and postpartum haematologic and health-related outcomes in the mother and child. ETHICS AND DISSEMINATION: Ethical approval was granted by the Research Ethics Committee (COMREC P.02/18/2357) in Malawi and the Human Research Ethics Committee (WEHI: 18/02), Melbourne, Australia. The protocol is registered with the Australian and New Zealand Clinical Trials Registry. The results will be shared with the local community that enabled the research, and also to the international fora. TRIAL REGISTRATION NUMBER: ACTRN12618001268235; Pre-results.

Sleep-Related Breathing Problem Trajectories Across Early Childhood and Academic Achievement-Related Performance at Age Eight.

Background: Childhood sleep disordered breathing (SDB) has been linked to poorer academic performance; however, research has not investigated the extent improvement in SDB may alter outcomes across key academic skills. This study aimed to investigate if children's early SDB status could predict later academic outcomes, and if an improvement in SDB status across the early childhood years would coincide with better, later performance in key academic skills related to reading, numeracy, and listening comprehension. Methods: Eighty five case children with an SDB symptom score >25 (maximum 77) were matched to 85 control children (score <12) at recruitment (age 3). SDB severity (symptom history and clinical assessment) was evaluated at ages 3, 4, 6, and 8 years and performance on individually-administered academic skills assessed at age 8 (91% retention from age 3). Case children were categorized into "improved" or "not-improved" groups based on SDB trajectories over the 5 years. Contributions of SDB status and trajectory group to academic performance were determined using regression analysis adjusted for demographic variables. Results: History of SDB from age 3 predicted significantly poorer performance on some key academic skills (oral reading and listening skills) at age 8. Children whose SDB improved (45%) performed better in oral reading fluency than those whose SDB did not improve, but difficulties with specific tasks involving oral language (listening retell) remained when compared to controls. Conclusion: Findings support links between early SDB and worse academic outcomes and suggest key academic areas of concern around oral language. Findings highlight the need for child mental health professionals to be aware of children's sleep problems, particularly SDB (past and present), when assessing potential barriers to children's achievement, to assist with appropriate and timely referrals for evaluation of children's sleep difficulties and collaborative evaluation of response to intervention for sleep difficulties.

Sluggish Cognitive Tempo and Daytime Sleepiness Mediate Relationships Between Sleep and Academic Performance.

OBJECTIVE: Sleep difficulties, daytime sleepiness, and sluggish cognitive tempo (SCT) are associated with impairments in academic performance. SCT refers to symptoms of sluggishness, tiredness/lethargy, and slowed thinking/processing, but despite symptom overlap with sleepiness, research examining interrelations of SCT with sleep and daytime sleepiness is limited. The aims of this study were to evaluate the relationship between SCT and daytime sleepiness and to examine pathways between sleep, daytime sleepiness, SCT, and academic performance. METHOD: Participants were a community sample of 1628 parents/caregivers of children aged between 6 and 10 years who completed questionnaires about their child's behavior, sleep, and academic performance. Confirmatory factor analysis was used to examine whether SCT was distinct from daytime sleepiness. Then, structural equation modeling was used to examine direct and indirect pathways between sleep (sleep-disordered breathing [SDB] symptoms, sleep duration, and latency), daytime sleepiness, SCT, and academic performance in reading, writing, and math. RESULTS: SCT and daytime sleepiness were distinct but moderately correlated (r = 0.33, p ≤ 0.001). Sleep, in particular SDB symptoms, predicted increased SCT and daytime sleepiness. SCT was directly and negatively associated with all domains of academic performance, daytime sleepiness was associated with poorer reading performance, and longer sleep duration was directly associated with poorer math performance. SCT and, to a lesser extent, daytime sleepiness mediated effects of sleep on academic performance. CONCLUSION: SCT symptoms are important for understanding how sleep difficulties affect academic performance in children. Sleep, daytime sleepiness, and SCT are interrelated but distinct factors that affect children's academic performance.

Investigating the brain structural connectome following working memory training in children born extremely preterm or extremely low birth weight.

Children born extremely preterm (EP, <28 weeks' gestation) or extremely low birth weight (ELBW, <1,000 g) are a vulnerable population at high risk of working memory impairments. We aimed to examine changes in the brain structural connectivity networks thought to underlie working memory performance, after completion of a working memory training program (Cogmed) compared with a placebo program in EP/ELBW children. This was a double-blind, placebo-controlled randomized trial (the Improving Memory in a Preterm Randomised Intervention Trial). Children born EP/ELBW received either the Cogmed or placebo program at 7 years of age (n = 91). A subset of children had magnetic resonance imaging of the brain immediately pre- and 2 weeks post-training (Cogmed n = 28; placebo n = 27). T1 -weighted and diffusion-weighted images were used to perform graph theoretical analysis of structural connectivity networks. Changes from pre-training to post-training in structural connectivity metrics were generally similar between randomized groups. There was little evidence that changes in structural connectivity metrics were related to changes in working memory performance from pre- to post-training. Overall, our results provide little evidence that the Cogmed working memory training program has training-specific effects on structural connectivity networks in EP/ELBW children.

A Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP): Statistical analysis plan.

Background: Anaemia affects more than half of Africa's pregnancies. Standard care, with oral iron tablets, often fails to achieve results, with compliance and gastrointestinal side-effects being a significant issue. In recent years, intravenous iron formulations have become safe, effective, and quick to administer, allowing the complete iron requirements of pregnancy to be provided in one 15-minute infusion. The Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP) will evaluate whether a modern intravenous iron formulation, ferric carboxymaltose (FCM), given once during the second trimester is effective and safe in improving maternal and neonatal outcomes for treatment of moderate to severe anaemia in sub-Saharan Africa.   The objective was to publish the detailed statistical analysis plan for the REVAMP trial prior to unblinding the allocated treatments and performing the analysis.   Methods: REVAMP is a multicentre, two-arm, open-label, parallel-group randomized control trial (RCT) in 862 pregnant women in their second trimester. The trial statistician developed the statistical analysis plan in consultation with the trial management team based on the protocol, data collection forms, and study outcomes available in the blinded study database.   Results: The detailed statistical analysis plan will support the statistical analyses and reporting of the REVAMP trial after unblinding the treatment allocations.   Conclusions: A statistical analysis plan allows for transparency as well as reproducibility of reporting and statistical analyses.

Parent report of children's sleep disordered breathing symptoms and limited academic progress in reading, writing, and math.

OBJECTIVES: To estimate via questionnaire within a population sample of New Zealand (NZ) children aged 6-to-10 years, the prevalence of sleep disordered breathing (SDB) and those struggling academically, and to identify individual and shared risk factors (health and demographic) for parent-reported SDB symptoms and academic difficulties. METHODS: In this cross-sectional study, parents/caregivers of children were recruited through schools and social media to complete an online questionnaire covering health and demographic factors, their children's SDB symptoms (Pediatric Sleep Questionnaire; PSQ) and parental ratings of academic performance based on teacher feedback relative to expected progress in the national curriculum (well below/below/at/above) in reading, writing, and math. RESULTS: A total of 1205 children (53% male) aged (mean) eight years two months were included, comprising 79.4% NZ European/other and 15.0% Maori. The survey-weighted prevalence of SDB (based on the PSQ) was 17.5%. This was higher amongst those with academic difficulties rated 'below/well below' expected progress for reading, writing and math (estimated at 24.0%, 31.0% and 27.5% respectively), with increased odds (adjusted odds ratios) for poor progress of 1.9 (95% CI: 1.2, 3.0), 1.8 (95% CI: 1.2, 2.7) and 2.4 (95% CI: 1.6, 3.7) respectively. There were no shared risk factors common to both SDB and academic difficulties identified from multivariate analyses. CONCLUSIONS: The findings suggest that children with parent-reported SDB symptoms may be at high risk for poor progress in reading, writing, and math. Future research could examine whether treatment of SDB reduces barriers to learning and offsets educational risk.

Animals can assign novel odours to a known category.

The ability to identify a novel stimulus as a member of a known category allows an organism to respond appropriately towards it. Categorisation is thus a fundamental component of cognition and an essential tool for processing and responding to unknown stimuli. Therefore, one might expect to observe it throughout the animal kingdom and across sensory domains. There is much evidence of visual categorisation in non-human animals, but we currently know little about this process in other modalities. In this experiment, we investigated categorisation in the olfactory domain. Dogs were trained to discriminate between 40 odours; the presence or absence of accelerants formed the categorical rule. Those in the experimental group were rewarded for responding to substrates with accelerants (either burnt or un-burnt) and inhibit responses to the same substrates (either burnt or un-burnt) without accelerants (S+ counterbalanced). The pseudocategory control group was trained on the same stimuli without the categorical rule. The experimental group learned the discrimination and animals were able to generalise to novel stimuli from the same category. None of the control animals were able to learn the discrimination within the maximum number of trials. This study provides the first evidence that non-human animals can learn to categorise non-biologically relevant odour information.

Educating staff working in long-term care about delirium: the Trojan horse for improving quality of care?

OBJECTIVE: This study aimed to design a multicomponent intervention to improve delirium care in long-term care facilities for older people in the UK and to identify the levers and barriers to its implementation in practice. METHODS: The research incorporated the theoretical phase and Phase 1 of the Medical Research Council's framework. We designed a multicomponent intervention based on the evidence for effective interventions for delirium and for changing practice. We refined the intervention with input from care home staff and field visits to homes. Our intervention incorporated the following features: targeting risk factors for delirium, a 'delirium practitioner' functioning as a facilitator, an education package for care home staff, staff working groups at each home to identify barriers to improving delirium care and to produce tailored solutions, a local champion identified from the working groups, consultation, liaison with other professionals, and audit or feedback. The delirium practitioner recorded her experiences of delivering the intervention in a contemporaneous log. This was analysed using framework analysis to determine the levers and barriers to implementation. RESULTS: We introduced a multicomponent intervention for delirium in six care homes in Leeds. Levers to implementation included flexibility, tailoring training to staff needs, engendering pride and ownership amongst staff, and minimising extra work. Barriers included time constraints, poor organization, and communication problems. CONCLUSION: We were able to design and deliver an evidence-based multicomponent intervention for delirium that was acceptable to staff. The next steps are to establish its feasibility and effectiveness in modifying outcomes for residents of care homes.