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Repurposing Oxfendazole for Onchocerciasis: Population Pharmacokinetics of a Tablet Formulation in Healthy African Adults
Get PDFGlobal efforts to eliminate onchocerciasis are hampered by the lack of a macrofilaricidal drug capable of killing adult parasites. Oxfendazole, a veterinary anthelminthic, exhibits macrofilaricidal activity and holds promise to shorten treatment durations. Phase 1 studies in healthy Caucasian adults demonstrated favorable pharmacokinetics and safety using a veterinary oral liquid formulation. More recently, a Phase 1 bioavailability trial (NCT04920292) evaluated a field‐applicable tablet formulation in healthy African adults. This study presents a secondary analysis to (i) characterize the population pharmacokinetics of oxfendazole and its major metabolites in healthy African adults receiving the tablet formulation and (ii) propose a dosing regimen for Phase 2 evaluation in patients with onchocerciasis. Thirty healthy African adults were enrolled, and plasma concentration–time profiles of oxfendazole, fenbendazole, and oxfendazole sulfone were obtained from 24 participants who received oxfendazole (8 per dose group: 100 mg single dose, 400 mg single dose, 400 mg once daily for 5 days). All cohorts were pooled and analyzed using nonlinear mixed effects modeling. Oxfendazole absorption was best described by first‐order kinetics with first‐pass metabolism. Dose‐limited bioavailability was evident. Disposition was best described by one‐compartment models with linear elimination. Simulations suggested that 400 mg once daily (or 50 mg twice daily) for 5 days is required to achieve putative exposure targets (> 200 ng/mL for 5 days), with low risk of safety concerns. The population pharmacokinetic model adequately described oxfendazole pharmacokinetics in healthy African adults and supports dosing selection for future clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT0492029
Straightforward routes to hexagonal boron nitride nanomaterials
Get PDFAdvanced fibres such as carbon, ceramic, and polymer fibres enable the fabrication of structures and composites for applications reliant on lightweight, oxidation resistant, mechanically strong, and electrically insulating materials, e.g. in all forms of land, air and space transportation and in applications within extreme environments. Hexagonal-boron nitride fibres (BNF) harness these advantages, and in addition, offer ultra-high-strength-to-weight ratio and low density. Yet, existing precursors for polymer-derived BNF are limited to insoluble and highly air/moisture sensitive polyborazylenes, hindering fibre production at scale. The future exploitation of BNF depends on the development of economically accessible and safe production methods. These should also present a scope for BNF microstructural and compositional tunability and output a high purity/crystallinity of BNF. In this thesis, two novel synthesis pathways are proposed that are primarily motivated by the demand to address the scalability challenges of BNF. Both pathways rely on the polymer-derived ceramic route based on the recently developed robust synthesis of the pre-ceramic precursor: N-methyl poly(aminoborane) [(H2B·NHCH3)n, denoted as PMeAB]. The reliable synthesis of PMeAB, when combined with its non-volatility, highly solubility, and high B- N-content, makes it a promising single-source precursor for BN materials. First, I demonstrate a straightforward synthesis of BNF through solution electrospinning process. Examination of PMeAB solution properties, electro-spinnability, and thermal behaviours, determine, for the first time, the optimal parameters for electrospinning PMeAB solutions into fibres. Subsequent curing and high temperature annealing using ammonolysis demonstrated the formation of cross-linked PMeAB fibres and its gradual transition toward BNF with ~97 wt.% purity and turbostratic/hexagonal ordering. To my knowledge, the method presented here represents the first instance of using additive-free solution electrospinning process to produce BNF. Secondly, two template-free synthesis approaches for high-purity, porous, three-dimensional solids constructed from low-dimensional hexagonal-BN (h-BN) nanostructures, including nanosheets (BNNS), nanofibers (BNNF), and/or nanotubes (BNNT) were proposed. The first structure is synthesized via a one-step, template-free, and substrate-free reaction of PMeAB with ammonia gas, resulting in a porous and mechanically stable interconnected BNNS/BNNF hierarchical structure, where the thermal dehydrogenation process, known as "chemical blowing", plays a pivotal role. The second structure utilises the eee-isomer of N,N,N-trimethylcyclotriborazane [(H2BNMeH)3, denoted as MeCTB], repurposing a main-group polymer as a precursor for 3D porous BN, constructed from fibrous BN (BNNT/BNNF). Comprehensive microscopic and spectroscopic analyses confirm the high purity and crystallinity of the resulting hexagonal-phase porous BN, marking the first reliable, controllable, and scalable synthesis of BNNS/BNNF and BNNT/BNNF porous structures via PMeAB-based chemistry. Finally, a theoretical model is proposed for the PMeAB-to-h-BN conversion route, based on a combination of density functional theory (DFT) calculations and reactive force field (ReaxFF) molecular dynamics (MD) simulations. The thermal decomposition pathways of PMeAB, its monomer unit MeIB, and its cyclic derivative MeCTB were first systematically investigated through potential energy surface (PES) mapping using DFT. Subsequently, existing ReaxFF parameter sets were evaluated and validated against DFT-derived data for key PMeAB-related chemistries. Large-scale MD simulations were conducted using the validated ReaxFF, coupled with ChemTraYzer2 (CTY2), to enable detailed reaction pathway analysis. The integrated framework of PES mapping and ReaxFF MD provides comprehensive insights into the fundamental reaction pathways involved in the molecule evolution from precursors to h-BN, i.e. (i) bond dissociation, (ii) dehydrogenation, (iii) cyclisation, (iv) carbon removal, and (v) network formation. This thesis describes the development of new polymer-derived ceramic routes to BN nanomaterials based on PMeAB, a B–N polymer derived from commercially available starting materials. It also provides fundamental, underpinning experimental and theoretical observations that serve as a basis for the further design of other h-BN nanostructures
Model selection in preclinical nucleic acid therapeutics research
Get PDFNucleic acid therapeutics (NATs) are a maturing drug class with many active clinical trials and a growing number of approvals. For NATs such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), a major hurdle during the research and development phase lies in selecting preclinical model systems with meaningful readouts on molecular and phenotypic efficacy. Key questions include: Which in vitro models are best positioned to quantify NAT activity and identify hits? In advancing a NAT from in vitro to in vivo studies, when is it appropriate to employ a surrogate or humanize a target locus; conversely, when is it appropriate to rely solely on human-derived cells? In this review, we will introduce and critique current approaches to ASO and siRNA preclinical efficacy studies and consider future advances in this fast-moving therapeutic area
Generation of human monoclonal autoantibodies from rare myelin oligodendrocyte glycoprotein-specific patient-derived B cells using an optofluidic-based platform
No full textBackground: Monoclonal antibodies (mAbs) are powerful tools for elucidating disease mechanisms. Capturing heterogeneity of patient responses—including clonality, somatic mutations, isotypes, and pathogenic potential—requires building large libraries of mAbs using high-throughput approaches. However, current techniques for identifying and isolating patient-derived mAbs targeting conformational epitopes on membrane proteins remain labor-intensive and inefficient.
Objective: Evaluate a high-throughput antibody discovery pipeline to generate patient B cell-derived mAbs against myelin oligodendrocyte glycoprotein (MOG), a transmembrane autoantigen targeted in MOG antibody-associated disease (MOGAD).
Methods: An optofluidic-based workflow incorporated mammalian display of human MOG (hMOG) in a live cell-based assay (CBA) format. B-cell receptor sequences from individual hMOG-binding B cells were cloned and expressed to generate mAbs from three patients. The hMOG binding specificity of these mAbs was validated in off-platform hMOG-CBAs.
Results: Validated hMOG-specific antibody-secreting cells in one patient represented 0.02% of all single B cells screened. From these low-frequency populations, one patient-B-cell-derived IgG mAb was successfully generated and validated. This human IgG mAb, characterized by a high frequency of Vregion somatic mutations (5-12.2%), bound hMOG at concentrations as low as 1 ng/mL.
Discussion: This workflow enables rapid discovery of rare, patient-derived mAbs targeting conformational epitopes on membrane antigens, offering a scalable approach for dissecting autoantibody repertoires
Longitudinal associations between play experiences and trajectories of preschoolers' mental health from April–July, 2020
Get PDFBackground: Play provides an important foundation for a healthy childhood but longitudinal data exploring how play experiences relate to children's mental health over time is scarce. In this study, data on preschool‐aged children's activities and mental health during Covid‐19 related restrictions was used to explore how where (inside/outside) and with whom children played related to internalising and externalising problems over time. Methods: UK based parents/carers (n = 1028) of preschool‐aged children (2–5 years) completed an online survey at four time points between April and July 2020. The survey asked how much time in the previous week their child had spent: Playing inside; Playing outside; Playing alone; Playing with a parent; Playing with another child in their household; and their child's mental health (Strengths and Difficulties Questionnaire internalising and externalising scales). Four hierarchical linear regression analyses were conducted to examine associations between where children play (inside/outside) and (1) internalising and (2) externalising symptoms, and with whom children play (with parent, other child, alone) and (3) internalising and (4) externalising symptoms. Effects of linear and quadratic time, and interactions between play and time were examined. Parent mental health, parent education, contact with nature and physical activity were included as covariates. Results: Both inside and outside play was associated with less severe internalising problems (beta = −0.23 [SE = 0.10]; beta −0.54 [SE = 0.19]) and, in statistical interaction with time, less time playing inside was associated with a stronger improvement in externalising problems over time (beta = 0.77 [SE = 0.23]). Further, more time playing with other children was associated with less severe internalising problems (beta = −0.50 [SE = 0.13]) whereas playing alone was associated with more severe internalising problems (beta = 0.28 [SE = 0.10]). Conclusion: Varied play opportunities are related to young children's mental health. Even during a pandemic response, children should be given opportunity to play with other children and play outdoors wherever possible
14 C-labelled nanoplastics reveal size-dependent bioaccumulation in juvenile rainbow trout ( Oncorhynchus mykiss )
Get PDFConcerns have been raised about the occurrence of nanoplastics (NP) in the environment. Herein we investigated size-dependent uptake, biodistribution, and egestion of 20 and 250 nm [14C]nanopolystyrene in juvenile rainbow trout (Oncorhynchus mykiss) at environmentally relevant concentrations: a single-day “high-dose” (250 ng gw.w.−1 (∼ppb) fed once) and a 5 day “low-dose” (8 ng gw.w.−1). Following single-day ‘high’ dose exposure, 20 nm particles – but not 250 nm – were detected in internal tissues, indicating translocation across gut endothelia. Rapid depuration returned NP concentrations to control levels within 10 days, with no evidence of accumulation in organs. The presence of 20 nm NPs in circulation suggests temporary vascular transport without parenchymal retention. Translocation of 20 nm NPs across the gut endothelia and association with blood cells should be investigated to determine the cell types involved and the outcome of these associations. These results indicate that uptake-depuration kinetics for [14C]nanopolystyrene in rainbow trout differ from those of other chemical substances (e.g., metals, persistent organic pollutants) and likely have different implications on organism health. The results of this study and the methods developed provide a means of studying and comparing the fate of NPs in organisms such as bivalves and fish
Experiences of people from minoritised groups who report healthcare-related harm in the UK: a qualitative socioecological study exploring factors contributing to unsafe care
Get PDFObjectives: To capture the experiences of people from minoritised groups who self-report healthcare-related harm and their views on contributory factors to the harm. Design: In-depth one-to-one qualitative interviews, analysed using inductive and deductive methods to explore and then organise factors participants associated with healthcare-related harm and map these factors onto a socioecological framework (SEF). Setting: People from minoritised groups in the United Kingdom (UK) self-reporting harm arising from the National Health Service (NHS), recruited from community groups, social media and a survey of the general public. Participants: 48 participants currently minoritised in the UK based on one or more of faith, ethnicity, disability, sexual orientation or gender modality who have experienced harm in the NHS. Results: Heterogeneous and interacting factors contribute to healthcare-related harms, spanning all five levels of the SEF: individual, interpersonal, community, organisational and societal. Multiple factors from powerlessness and low trust to unwelcoming NHS environments reinforce each other to increase risk of harm in minoritised populations. The SEF helped draw out less visible factors associated with the experience of unsafe care, including a health service designed around the needs of the majority population and societal attitudes to minoritised groups. Conclusions: Multiple individual factors are already known drivers of disparities in safety among minoritised groups such as language barriers and cultural differences in beliefs. The SEF enabled an expanded view of contributory factors to harm in these groups, thereby providing a wider set of potential interventions to address safety inequities. A narrow focus on improving the quality of interpersonal, relational care is unlikely to have a significant impact on safety improvement in minoritised groups without addressing structural and institutionalised processes that drive discrimination and exclusion
Frequent co-occurrence of AChR-positive myasthenia gravis in facioscapulohumeral muscular dystrophy suggests a novel disease association
Get PDFEleanor Coade & fired artificial stone 1650-1851
No full textFired artificial stone (stoneware used in statuary and architecture) was a key enabler of sculptural display and external ornamentation in the long eighteenth century. From the 1720s, its production enabled the commodification of fine art, expressions of self-fashioning, and the dissemination and homogenization of architectural taste. For contemporaries, fired artificial stone became associated exclusively with Eleanor Coade (1733-1821) and her Lambeth manufactory. Coade was an exceptional entrepreneur and brand pioneer, her eponymous stone achieving international renown for its durability, which allowed it to be positioned as superior to natural stone. Although intrinsically astylar, Coade stone was especially associated with neoclassicism, bringing the style out from aristocratic settings into everyday townscapes. This study dispels various myths that have accrued to Eleanor Coade and her formulation. It will be demonstrated that she benefited from a century of prior artisanal development. Her predecessors are examined in detail: John Dwight, Aaron Mutchell, Richard Holt, Batty Langley, George Davy and Daniel Pincot. Evidence of Davy’s and Pincot’s supply to customers like the Duke of Northumberland, the 2nd Marquess of Rockingham, Henry Hoare of Stourhead and Horace Walpole indicate the sophistication the sector had reached before Coade’s involvement. New collaborative molecular spectroscopy analyses prompted by this research reveal that it was Daniel Pincot, not Coade, who perfected the formulation. Coade’s triumph was to make it a commercial success when she took over Pincot’s manufactory c.1770. Notwithstanding Alison Kelly’s self-published book 'Mrs Coade’s stone' (1990), Eleanor Coade has been largely ignored by mainstream scholarship, despite her value as a case study of exceptional entrepreneurship, made more remarkable by her gender. This study seeks to correct this bias, by placing Coade for the first time in her full historical context, both geographically and socially. Doing so provides some important correctives, and does not diminish her achievements
