Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Japanese Yew (Taxus) poisoning of wild ungulates in Utah during the winter of 2022-2023.

Taxus is a genus of coniferous shrubs and trees, commonly known as the yews, in the family Taxaceae. All species of yew contain taxine alkaloids, which are ascribed as the toxic principles. Anecdotally, free ranging ruminants such as antelope, deer, elk, and moose have been regarded as tolerant to yew. Herein several cases of intoxication of deer, elk, and moose by yew from the state of Utah in the winter of 2022-2023 are documented. Ingestion of yew was documented by three means among the poisoned cervids; plant fragments consistent with yew were visually observed in the rumen contents, chemical analysis and subsequent detection of the taxines from rumen and liver contents, and identification of operational taxonomic units identified as Taxus species from DNA metabarcoding. Undoubtedly, the record snowfall in Utah during the winter of 2022-2023 contributed to these poisonings.

QSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency.

O6-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine O6-alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using [3H]-methylated-DNA-based MGMT inactivation assays and calculated the IC50 values. Using the results of 370 compounds, we performed quantitative structure-activity relationship (QSAR) modeling to identify the correlation between the chemical structure and MGMT-inactivating ability. Modeling was based on subdividing the sorted pIC50 values or on chemical structures or was random. A total of nine molecular descriptors were presented in the model equation, in which the mechanistic interpretation indicated that the status of nitrogen atoms, aliphatic primary amino groups, the presence of O-S at topological distance 3, the presence of Al-O-Ar/Ar-O-Ar/R..O..R/R-O-C=X, the ionization potential and hydrogen bond donors are the main factors responsible for inactivation ability. The final model was of high internal robustness, goodness of fit and prediction ability (R2pr = 0.7474, Q2Fn = 0.7375-0.7437, CCCpr = 0.8530). After the best splitting model was decided, we established the full model based on the entire set of compounds using the same descriptor combination. We also used a similarity-based read-across technique to further improve the external predictive ability of the model (R2pr = 0.7528, Q2Fn = 0.7387-0.7449, CCCpr = 0.8560). The prediction quality of 66 true external compounds was checked using the "Prediction Reliability Indicator" tool. In summary, we defined key structural features associated with MGMT inactivation, thus allowing for the design of MGMT inactivators that might improve clinical outcomes in cancer treatment.

Improving educational and reproductive outcomes for adolescent mothers in South Africa: A cross-sectional analysis towards realising policy goals.

Adolescent mothers face numerous challenges. This study aimed to address the operationalisation of the new South African national policy for young mothers by testing the associations of potential protective provisions with three policy goals: School return, grade promotion, and pregnancy/HIV prevention. Adolescent mothers aged 12-24 from rural and urban communities of South Africa's Eastern Cape completed study questionnaires between 2017-2019. Using multivariate multi-level analysis, we simultaneously estimated associations between hypothesized provisions and protective variables and all policy-aligned goals. School return was associated with using formal childcare services, higher confidence and self-efficacy scores, and remaining in school throughout pregnancy. Grade promotion was associated with greater exposure to friendly and respectful health staff, using formal childcare services, higher confidence and self-efficacy scores, and remaining in school throughout pregnancy. Pregnancy/HIV prevention (condom use) was moderately associated with greater exposure to friendly and respectful health staff. There was evidence of synergies of provisions whereby a combination of protective characteristics showed larger positive effects than receipt of any single factor alone. This study provides essential evidence for operationalising South Africa's new policy on the Prevention and Management of Learner Pregnancy in Schools, and points to implementation strategies that provide low-cost opportunities to promote educational and health outcomes for adolescent mothers.

Health and development-related priorities and challenges of adolescents and young people: findings from South Africa and Kenya prior to and during COVID-19 pandemic.

Growing evidence documents the effects of the COVID-19 pandemic on adolescents in East and Southern Africa. We present and explore the longitudinal health and development-related priorities and challenges of adolescent advisors in South Africa and Kenya, including prior to, and during the COVID-19 pandemic. Findings were co-generated with adolescent advisors in the Eastern Cape Province of South Africa (n=15, ages 18-22 in 2019) and Kisumu, Kenya (n=16, ages 10-14 in 2020). Prior to COVID-19, adolescent advisors engaged in a participatory exercise to share and explore their health and development-related priorities and challenges in 2019 and 2020. During the COVID-19 pandemic in 2020 and 2021, members of the same groups shared their experiences, challenges and coping strategies in semi-structured telephone interviews (Eastern Cape: n=14, aged 19-23; Kisumu n=12, aged 11-16) and group-based remote participatory social media activities (n=27 activities with n=12 advisors, Eastern Cape). We thematically analysed COVID-19 activities, considering them alongside pre-pandemic priorities and challenges. Many of the health and development-related priorities and challenges identified prior to COVID-19 remained issues of concern during COVID-19. These included education; victimization and violence; teenage pregnancy; substance use; household tension, conflict and inadequate family and caregiver support; health and medication concerns (South Africa) and water and food shortages (Kenya). Other issues such as financial insecurity, mental health, and crime were strong themes that emerged during COVID-19, which were not directly reported as priorities prior. Although almost all of adolescent advisors' most pressing pandemic-related challenges were also priorities for them prior to COVID-19, these issues were often discussed as new, and caused by the onset of COVID-19. While demonstrating how COVID-19 has exacerbated pre-existing vulnerabilities, we also suggest that the pandemic may have brought about a new way for adolescents to make sense of, and articulate pre-existing challenges.

Perspectivas sobre a educação de alunos com deficiência na África do Sul: desafiando a cultura do silêncio

A África do Sul estabeleceu um sistema de Educação Inclusiva que mantém escolas especiais para atender estudantes que demandam grandes necessidades de apoio e centros de apoio vizinhos às escolas comuns. Embora haja discussão sobre o que agregam ou não as escolas especiais, existem relativamente poucos estudos que se propõem a compartilhar as perspectivas de estudantes dessas escolas. Este estudo baseia-se em entrevistas com 39 estudantes de seis escolas especiais e dois de centros educacionais de apoio. As entrevistas foram transcritas e submetidas à análise temática de conteúdo, o que revelou que os estudantes se sentem desapontados, pois suas deficiências não são compreendidas pelos professores. Eles expressam a necessidade de maior apoio social e psicológico relativo às suas experiências escolares, à deficiência e aos problemas sociais. Eles também apontam a necessidade de os professores serem mais pacientes e comprometidos. Os estudantes que vivem em instituições de acolhimento destacam as condições precárias de vida e a ausência de apoio dos cuidadores dessas instituições, o que impacta sua possibilidade de aprendizagem. As necessidades que foram identificadas pelos estudantes podem subsidiar professores que se interessam em melhorar a qualidade da educação ofertada.

HIV and SRH healthcare delivery experiences of South African healthcare workers and adolescents and young people during COVID-19.

While substantial research has emerged from the frontlines of the COVID-19 pandemic, as well as from studies with adolescent populations, there has been a dearth of research focused in South Africa on the context-specific experiences of healthcare workers (HCWs) and the adolescents and young people (AYP) to whom they provide services. This article documents the experiences of provision and receipt of HIV and sexual and reproductive health (SRH) services during the COVID-19 pandemic from the perspective of South African HCWs (n = 13) and AYP (n = 41, ages 17-29). Findings highlight several barriers to accessing comprehensive HIV and SRH services during the pandemic including lockdown-related mobility restrictions (reported by HCWs), prioritisation of COVID-19 above other healthcare needs, longer health facility waiting times, poor treatment by HCWs (reported by AYP), discomfort and perceived stigma from having to queue outside health facilities, and fear of contracting COVID-19 (reported by both groups). While HCWs reported that HIV and SRH services continued to be available during the pandemic, AYP described seeking these services - such as long-acting reversible contraception, check-ups for their babies and medical refills - and being told that because they were not considered emergency cases, they should return on a different date. By capturing diverse experiences and perspectives from both groups, our findings reiterate the growing call for health system investments to strengthen the delivery of adolescent services, including investing in appropriate channels of communication between young people and their healthcare providers (for example, through adolescent peer supporters or community healthcare workers) and differentiated models of service delivery (for example, multi-month ART refills and community pick-ups). Closing the gap between the experiences and needs of adolescents and the healthcare workers who serve them may support young people and HCWs in buffering against changes brought about by the COVID-19 pandemic.

Development and Refinement of the American Occupational Therapy Association's Knowledge Translation Toolkit.

IMPORTANCE: Occupational therapy practitioners are expected to translate promising discoveries from empirical research into routine practice with their clients. However, complex barriers can influence practitioners' knowledge translation (KT) efforts, leading the American Occupational Therapy Association's Evidence-Based Practice (EBP) group to develop the KT Toolkit tailored to the perceived needs of occupational therapists and occupational therapy assistants. OBJECTIVE: To identify common barriers to implementing EBPs and potential strategies to support EBP uptake. DESIGN: Cross-sectional survey. SETTING: United States. PARTICIPANTS: Occupational therapy practitioners. OUTCOMES AND MEASURES: Data underwent descriptive and directed content analysis, the latter of which was guided by the Consolidated Framework for Implementation Research. RESULTS: Occupational therapy survey respondents (N = 818) identified common EBP implementation barriers (e.g., lack of time and resources, difficulty understanding research findings). Initial KT Toolkit content was developed to address these barriers and included resources for searching for, analyzing, and applying evidence in practice. CONCLUSIONS AND RELEVANCE: Survey findings have informed the development of the KT Toolkit, which includes resources designed to support occupational therapy practitioners' EBP implementation efforts. This KT Toolkit is available at AOTA.org and will be continuously revised and updated on an ongoing basis. What This Article Adds: Several barriers limit the extent to which occupational therapy practitioners can implement evidence with their client populations. The KT Toolkit is directly informed by practitioner input and provides resources to support practitioners in their efforts to translate knowledge into real-world practice.

Total Synthesis and Antimalarial Activity of 2-(p-Hydroxybenzyl)-prodigiosins, Isoheptylprodigiosin, and Geometric Isomers of Tambjamine MYP1 Isolated from Marine Bacteria.

Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(p-hydroxybenzyl)-prodigiosins (2-5), isoheptylprodigiosin (6), and geometric isomers of tambjamine MYP1 ((E/Z)-7) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines 24-27 in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel of Plasmodium falciparum parasites, with a great therapeutic index. Notably, prodiginines 6 and 24-27 provided curative in vivo efficacy against erythrocytic Plasmodium yoelii at 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines.

Feasibility pilot of an adapted parenting program embedded within the Thai public health system.

BACKGROUND: This feasibility pilot of the Parenting for Lifelong Health for Young Children program in Thailand aimed to: 1) explore the feasibility of study evaluation approaches; 2) assess the feasibility of delivering an adapted program; 3) report indicative effects on child maltreatment and related outcomes; and 4) examine intervention content associated with key mechanisms of change perceived by caregivers and facilitators. METHOD: Sixty primary caregivers of children aged 2-9 years were recruited for an 8-week parenting program embedded within the local health system. Mixed-methods approaches included quantitative caregiver-report and observational data from standardized instruments, and qualitative data from individual and group interviews with caregivers and program facilitators. Analyses involved Wilcoxon signed-rank tests, paired t-tests, Friedman's ANOVA, and thematic analysis. RESULTS: Participants reported that most (65%) were grandparents or great-grandparents. Study retention and response rates were high, and enrolled caregivers attended an average of 93% of sessions. Primary outcomes showed caregiver-reported pre-post reductions in overall child maltreatment (d = - 0.58, p < 0.001), as well as reductions in physical (d = - 0.58, p < 0.001) and emotional abuse (d = - 0.40, p < 0.001). Combined caregiver report and observational assessments using the HOME Inventory showed reductions in abusive and harsh parenting (d = - 0.52, p < 0.001). Secondary outcomes demonstrated decreases in child neglect; dysfunctional parenting; poor child monitoring and supervision; parental sense of inefficacy; child behavior problems; daily report on child problem behavior; parent overall depression, anxiety, and stress; and attitudes supporting physical punishment and harsh discipline. There were increases in overall positive parenting, daily positive parenting behavior, as well as HOME Inventory assessments on parent-child relationships. Thematic analyses from interviews and focus group data identified six key program themes associated with strengthened parent-child relationships, reduced child behavior problems, improved attitudes and strategies toward discipline, and improved management of parental stress. CONCLUSIONS: This study represents one of few evaluations to test the feasibility of an evidence-based parenting program embedded within routine public health service delivery in a low- or middle-income country. Findings show preliminary effectiveness in reducing child maltreatment, improvements on 22 of 24 secondary outcomes, and perceived mechanisms of change that support quantitative findings. Prospects are promising for program scalability, pending randomized controlled trial results. TRIAL REGISTRATION: 11/01/2019, ClinicalTrials.gov, ID# NCT03539341 .

Acridones Are Highly Potent Inhibitors of Toxoplasma gondii Tachyzoites.

Acridone derivatives, which have been shown to have in vitro and in vivo activity against Plasmodium spp, inhibit Toxoplasma gondii proliferation at picomolar concentrations. Using enzymatic assays, we show that acridones inhibit both T. gondii cytochrome bc1 and dihydroorotate dehydrogenase and identify acridones that bind preferentially to the Qi site of cytochrome bc1. We identify acridones that have efficacy in a murine model of systemic toxoplasmosis. Acridones have potent activity against T. gondii and represent a promising new class of preclinical compounds.

Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum.

Robenidine is a veterinary drug used in the poultry industry to treat coccidiosis caused by parasites in the Eimeria genus. Though this compound and related aminoguanidines have recently been studied in other pathogens, the chemotype has not been systematically explored to optimize antimalarial activity despite the close genetic relationship between Eimeria and Plasmodium (both are members of the Apicomplexa phylum of unicellular, spore-forming parasites). In this study, a series of aminoguanidine robenidine analogues was prepared and tested in vitro against Plasmodium falciparum, including multidrug-resistant strains. Selected compounds were further evaluated in vivo against murine Plasmodium yoelii in mice. Iterative structure-activity relationship studies led to the discovery of 1, an aminoguanidine with excellent activity against drug-resistant malaria in vitro and impressive in vivo efficacy with an ED50 value of 0.25 mg/kg/day in a standard 4-day test.

Mental health interventions for adolescents living with HIV or affected by HIV in low- and middle-income countries: systematic review.

BACKGROUND: Mental health difficulties and mental disorders are common in adolescents living with HIV or who are affected by HIV because of living in HIV-affected households in low- and middle-income (LMICs) countries, but little is known about the interventions that target these individuals and whether they are effective. AIMS: This systematic review aims to address these gaps by examining what has worked and what has not worked to support the mental health of adolescents living with HIV or affected by HIV in low- and middle-income contexts (PROSPERO Number: CRD42018103269). METHOD: A systematic literature review of online databases from the year 2000 to 2018, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, included English-language publications of quantitative evaluations of psychosocial interventions aiming to improve mental health among adolescents living with HIV and adolescents from HIV-affected households (aged 10-24 years) in LMICs. RESULTS: Out of 2956 articles, 16 studies from 8 LMICs met the inclusion criteria. Thirteen studies focused on adolescents affected by HIV and only three studies on adolescents living with HIV. Only five studies included were from Sub-Saharan Africa. Interventions most often used a family-strengthening approach strengthening caregiver-adolescent relationships and communication and some problem-solving in groups or individually. Five studies reported statistically significant changes in adolescent and caregiver mental health or mental well-being, five among adolescents only and two among caregivers only. CONCLUSIONS: Research on what works to improve mental health in adolescents living with HIV in LMIC is in its nascent stages. Family-based interventions and economic strengthening show promise.

Unsymmetrical Bisquinolines with High Potency against P. falciparum Malaria.

Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered. We report here the results of a structure-activity relationship (SAR) study assessing potential unsymmetrical bisquinoline antiplasmodial drug candidates using in vitro activity against intact parasites in cell culture. Many unsymmetrical bisquinolines were found to be highly potent against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Further work to develop such compounds could focus on minimizing toxicities in order to find suitable candidates for clinical evaluation.

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

A systematic review of the South African work on the well-being of young people (2000-2016).

Burgeoning research on the well-being of young people in recent years has made it difficult to identify conceptual gaps in the literature. We conducted a review of South African research in this area to better understand the use and measurement of the construct, as well as factors associated with it. The search of multiple databases identified 28 studies published in academic journals between 2000 and 2016. Within this period, studies that referred to well-being and its related subjective components varied significantly in terms of how they defined and operationalised these constructs, resulting in a fragmented body of work. The review highlights the need for a coherent research agenda in this area given the centrality of well-being research in promoting optimal outcomes in young people. Recommendations for strengthening South African research in this area are provided.

ELQ-331 as a prototype for extremely durable chemoprotection against malaria.

BACKGROUND: The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. METHODS: Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection. RESULTS: A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM). CONCLUSIONS: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.