Similarly Efficacious Anti-Malarial Drugs SJ733 and Pyronaridine Differ in Their Ability to Remove Circulating Parasites in Mice

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the parasite clearance curve , has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation. METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound\u27s capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication. RESULTS: These three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal. CONCLUSIONS: Anti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites

Sex differences in the adult human brain:Evidence from 5216 UK Biobank participants

Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44–77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

Patient and provider perspectives on the development and resolution of prescribing cascades: a qualitative study

Abstract Background Prescribing cascades occur when the side effect of a medication is treated with a second medication. The aim of the study was to understand how prescribing cascades develop and persist and to identify strategies for their identification, prevention and management. Method This qualitative study employed semi-structured interviews to explore the existence of prescribing cascades and to gather patients', caregivers' and clinicians’ perspectives about how prescribing cascades start, persist and how they might be resolved. Participants were older adults (over age 65) at an outpatient Geriatric Day Hospital (GDH) with possible prescribing cascades (identified by a GDH team member), their caregivers, and healthcare providers. Data were analyzed using an inductive content analysis approach. Results Fourteen participants were interviewed (eight patients, one family caregiver, one GDH pharmacist, three GDH physicians and one family physician) providing a total of 22 interviews about patient-specific cases. The complexity and contextually situated nature of prescribing cascades created challenges for all of those involved with their identification. Three themes impacted how prescribing cascades developed and persisted: varying awareness of medications and cascades; varying feelings of accountability for making decisions about medication-related care; and accessibility to an ideal environment and relevant information. Actions to prevent, identify or resolve cascades were suggested. Conclusion Patients and healthcare providers struggled to recognize prescribing cascades and identify when they had occurred; knowledge gaps contributed to this challenge and led to inaction. Strategies that equip patients and clinicians with resources to recognize prescribing cascades and environmental and social supports that would help with their identification are needed. Current conceptualizations of cascades warrant additional refinement by considering the nuances our work raises regarding their appropriateness and directionality. </jats:sec

Patient and provider perspectives on the development and resolution of prescribing cascades: a qualitative study

Abstract Background Prescribing cascades occur when the side effect of a medication is treated with a second medication. The aim of the study was to understand how prescribing cascades develop and persist and to identify strategies for their identification, prevention and management. Method This qualitative study employed semi-structured interviews to explore the existence of prescribing cascades and to gather patients', caregivers' and clinicians’ perspectives about how prescribing cascades start, persist and how they might be resolved. Participants were older adults (over age 65) at an outpatient Geriatric Day Hospital (GDH) with possible prescribing cascades (identified by a GDH team member), their caregivers, and healthcare providers. Data were analyzed using an inductive content analysis approach. Results Fourteen participants were interviewed (eight patients, one family caregiver, one GDH pharmacist, three GDH physicians and one family physician) providing a total of 22 interviews about patient-specific cases. The complexity and contextually situated nature of prescribing cascades created challenges for all of those involved with their identification. Three themes impacted how prescribing cascades developed and persisted: varying awareness of medications and cascades; varying feelings of accountability for making decisions about medication-related care; and accessibility to an ideal environment and relevant information. Actions to prevent, identify or resolve cascades were suggested. Conclusion Patients and healthcare providers struggled to recognize prescribing cascades and identify when they had occurred; knowledge gaps contributed to this challenge and led to inaction. Strategies that equip patients and clinicians with resources to recognize prescribing cascades and environmental and social supports that would help with their identification are needed. Current conceptualizations of cascades warrant additional refinement by considering the nuances our work raises regarding their appropriateness and directionality

Exported code book.

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Case summaries of prescribing cascade experiences.

Case summaries of prescribing cascade experiences.</p