Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period.Supplementary Fig. 1. Mean 6-min walk test distance versus age in Morquio A Clinical Assessment Program subjects aged ≤20 years. Reproduced with permission from P.R. Harmatz, K.E. Mengel, R. Giugliani, V. Valayannopoulos, S.P. Lin, R. Parini, N. Guffon, B.K. Burton, C.J. Hendriksz, J.J. Mitchell, A.M. Martins, S.A. Jones, N. Guelbert, A. Vellodi, F.A. Wijburg, K. Yang, P. Slasor, C. Decker. Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome, Mol. Genet. Metab. 114 (2015) 186–194. http://dx.doi.org/10.1016/j.ymgme.2014.10.015. MorCAP, Morquio A Clinical Assessment Program.Supplementary Fig. 2. Log10 mean TAb titer by study week in MOR-002 and MOR-100.Supplementary Fig. 3. (A) uKS versus TAb titer; (B) uKS versus NAb positivity; (C) 6MWT versus TAb titer; (D) 6MWT versus NAb positivity (E) 3MSCT versus TAb titer; (F) 3MSCT versus Nab positivity.Supplementary Table 1. Study drug-related adverse events and serious adverse events in MOR-002 and MOR-100.Supplementary Table 2. Hypersensitivity AEs in MOR-002 and MOR-100 using MedDRA SMQs.Supplementary Table 3. Patients who developed elosulfase alfa TAb, NAb, and IgE during MOR-002 and MOR-100.Supplementary Table 4. Mean TAb titer and NAb responses by hypersensitivity AE severity in IgE-negative patients (safety population).Supplementary Table 5. Incidence of hypersensitivity AEs in IgE-negative patients (safety population) by TAb response group using MedDRA SMQs by preferred term.BioMarin Pharmaceutical Inc.http://www.elsevier.com/locate/ymgmePaediatrics and Child Healt

Tooth loss and the risk of cognitive decline and dementia: A meta-analysis of cohort studies

IntroductionEpidemiological studies have shown that tooth loss may be associated with an increased risk of cognitive decline and dementia. However, some results do not show a significant association. Therefore, we performed a meta-analysis to evaluate this association.MethodsRelevant cohort studies were searched in PubMed, Embase, Web of Science (up to May 2022), and the reference lists of retrieved articles. The pooled relative risk (RR) and 95% confidence intervals were computed using a random-effects model (CI). Heterogeneity was evaluated using the I2 statistic. Publication bias was evaluated using the Begg's and Egger's tests.ResultsEighteen cohort studies met the inclusion criteria. Original studies with 356,297 participants with an average follow-up of 8.6 years (ranging from 2 to 20 years) were included in this study. The pooled RRs of tooth loss on dementia and cognitive decline were 1.15 (95% CI: 1.10–1.20; P < 0.01, I2 = 67.4%) and 1.20 (95% CI: 1.14–1.26; P = 0.04, I2 = 42.3%), respectively. The results of the subgroup analysis showed an increased association between tooth loss and Alzheimer's disease (AD) (RR = 1.12, 95% CI: 1.02–1.23) and vascular dementia (VaD) (RR = 1.25, 95% CI: 1.06–1.47). The results of the subgroup analysis also showed that pooled RRs varied by geographic location, sex, use of dentures, number of teeth or edentulous status, dental assessment, and follow-up duration. None of the Begg's and Egger's tests or funnel plots showed evidence of publication bias.DiscussionTooth loss is associated with a significantly increased risk of cognitive decline and dementia, suggesting that adequate natural teeth are important for cognitive function in older adults. The likely mechanisms mostly suggested include nutrition, inflammation, and neural feedback, especially deficiency of several nutrients like vitamin D

Impacts of Size on Pharmacokinetics and Biodistributions of Mebendazole Nanoformulations in Mice and Rats

Mebendazole (Mbz), a poorly water-soluble anthelminthic drug, possesses siginificant antineoplastic effects in both in vitro and in vivo studies. Microemulsions (PM1 37nm and PM2 478 nm) and nanosuspensions (NS-167nm, NS-400nm, NS-700nm and NS-1700nm) of various sizes, and a cosolvent formulation have been developed for the potential parenteral delivery of Mbz. The purpose of the study was to investigate the role of physical nature and particle size of the nanoformulations on Mbz dispositions by comparatively establishing their pharmacokinetics and biodistribution profiles in athymic nude mouse and rat models. In vitro release studies of Mbz from the cosolvent and nanosuspensions was slower in rat plasma than in PBS, and the initial rates and extent of release from NS-167nm in PBS and rat plasma were significantly greater than those of NS-700nm and NS-1700nm in PBS, and that of NS-1700nm in rat plasma. Mbz from cosolvent and nanoformulations followed a two-compartment model after administration. PM1 and PM2 exhibited similar plasma pharmacokinetics of cosolvent in mice, with only Cmax/dose, k10 and k21 different from those of cosolvent. However, the tissue distribution patterns of PM1 and PM2 were distinct from that of cosolvent. PM1 and PM2 displayed very high AUCs/dose in lung, 6 to 7 times of that of cosolvent. The t1/2 of Mbz in lung from PM1 was longer than those of cosolvent and PM2. Different from the cosolvent, Mbz nanosuspensions exhibited very high and prolonged drug concentrations in liver and spleen due to the reticuloendothelial system (RES) uptake. The large-sized NS-1700nm displayed larger Vss and V2 (1.45 and 1.35 L) than NS-167nm (0.85 and 0.79 L) in mice. Biodistributions of Mbz from cosolvent, NS-167nm, NS-400nm, NS-700nm, and NS-1700nm in rats were comparatively established. The patterns of nanosuspensions in rats were similar to those in mice. The half-life of total Mbz in liver for NS-700nm was longer than those for NS-167nm and NS-400nm. The half-life of total Mbz in spleen for NS-400nm was longer than that for NS-167nm. The elimination half-lives of parent Mbz in liver and spleen of rats increased as particle size increased. Three-compartment pharmacokinetic models described the relationship between plasma and lung concentrations of Mbz after i.v. administration of PM1 and PM2 was successfully developed and validated, enabling the prediction of lung concentration profiles based on measured plasma concentrations. Human plasma pharmacokinetic parameters (CL, Vss, t1/2, α, and t1/2, β) for Mbz cosolvent, PM1 and PM2, as well as NS-167nm and NS-1700nm were predicted by allometric scaling. The PK parameters predicted for human from Mbz microemulsions of various sizes between PM1 and PM2 were similar, while distinct between NS-167nm and NS-1700nm. Our results demonstrated that the droplet/particle size of the nanoformulations had profound effects on Mbz dispositions in mice and rats, that might be critical in optimizing cancer therapy.Pharmacological and Pharmaceutical Sciences, Department o

CONVOLUTION ON FUNCTIONALS OF DISCRETE-TIME NORMAL MARTINGALE

Let $M=(M)_{n\in \mathbb{N}}$ be a discrete-time normal martingale satisfying some mild requirements. In this paper we show that through the full Wiener integral introduced by Wang \textit{et al.} (C.S. Wang, Y.C. Lu and H. F. Chai, An alternative approach to Privault's discrete-time chaotic calculus, J. Math. Anal. Appl. 373 (2011), 643--654.), one can define a multiplication-type operation on square integrable functionals of $M$, which we call the convolution. We examine algebraic and analytical properties of the convolution and in particular we prove an interesting result, which shows that the convolution can be used to represent a certain family of conditional expectation operators associated with $M$. We also present an example of discrete-time normal martingale to show DOI: 10.1017/S000497271100309

Understanding choline bioavailability and utilization: first step toward personalizing choline nutrition

Choline is an essential macronutrient involved in neurotransmitter synthesis, cell-membrane signaling, lipid transport, and methyl-group metabolism. Nevertheless, the vast majority are not meeting the recommended intake requirement. Choline deficiency is linked to nonalcoholic fatty liver disease, skeletal muscle atrophy, and neurodegenerative diseases. The conversion of dietary choline to trimethylamine by gut microbiota is known for its association with atherosclerosis and may contribute to choline deficiency. Choline-utilizing bacteria constitutes less than 1% of the gut community and is modulated by lifestyle interventions such as dietary patterns, antibiotics, and probiotics. In addition, choline utilization is also affected by genetic factors, further complicating the impact of choline on health. This review overviews the complex interplay between dietary intakes of choline, gut microbiota and genetic factors, and the subsequent impact on health. Understanding of gut microbiota metabolism of choline substrates and interindividual variability is warranted in the development of personalized choline nutrition.Startup funding from Lee Kong Chian School of Medicine is acknowledged

Dim Blue Light at Night Induces Spatial Memory Impairment in Mice by Hippocampal Neuroinflammation and Oxidative Stress

Light pollution is one of the most serious public problems, especially the night light. However, the effect of dim blue light at night (dLAN-BL) on cognitive function is unclear. In this study, we evaluated the effects of exposure to dLAN-BL in C57BL/6J mice for 4 consecutive weeks. Our results showed dLAN-BL significantly impaired spatial learning and memory and increased plasma corticosterone level in mice. Consistent with these changes, we observed dLAN-BL significantly increased the numbers and activation of microglia and the levels of oxidative stress product MDA in the hippocampus, decreased the levels of antioxidant enzymes Glutathione peroxidase (GSH-Px), Superoxide dismutase (SOD), Gluathione reductase (Gsr), total antioxidants (T-AOC) and the number of neurons in the hippocampus, up-regulated the mRNA expression levels of IL6, TNF-α and the protein expression levels of iNOS, COX2, TLR4, p-p65, Cleaved-Caspase3 and BAX, and down-regulated the mRNA expression levels of IL4, IL10, Psd95, Snap25, Sirt1, Dcx and the protein expression level of BCL2. In vitro results further showed corticosterone (10uM)-induced BV2 cell activation and up-regulated content of IL6, TNF-α in the cell supernatant and the protein expression levels of iNOS, COX2, p-p65 in BV2 cells. Our findings suggested dLAN-BL up-regulated plasma corticosterone level and hippocampal microglia activation, which in turn caused oxidative stress and neuroinflammation, leading to neuronal loss and synaptic dysfunction, ultimately leading to spatial learning and memory dysfunction in mice