Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes

Photon CT Scanning of Advanced Ceramic Materials

Advanced ceramic materials (e. g. Si3N4, ZrO2, SiC, A12O3) are being developed for high temperature applications in advanced heat engines and high temperature heat recovery systems [1]. Although fracture toughness has been a constant problem, advanced ceramics are now being developed with fracture toughnesses close to those of metals [2]. Small size flaws (10–200 μm), small non-uniformities in density distributions (0.1–2%) present as long-range density gradients, and porous regions which can be seen as localized areas of slightly lower density, are critical in most ceramics. The need to detect these small flaws is causing a significant effort to be devoted towards nondestructive evaluation. Detection of “defects” such as those noted in engineering ceramics has presented problems for conventional non-destructive evaluation methods [3]

Genetic differentiation and admixture between sibling allopolyploids in the Dactylorhiza majalis complex

Allopolyploidization often happens recurrently, but the evolutionary significance of its iterative nature is not yet fully understood. Of particular interest are the gene flow dynamics and the mechanisms that allow young sibling polyploids to remain distinct while sharing the same ploidy, heritage and overlapping distribution areas. By using eight highly variable nuclear microsatellites, newly reported here, we investigate the patterns of divergence and gene flow between 386 polyploid and 42 diploid individuals, representing the sibling allopolyploids Dactylorhiza majalis s.s. and D. traunsteineri s.l. and their parents at localities across Europe. We make use in our inference of the distinct distribution ranges of the polyploids, including areas in which they are sympatric (that is, the Alps) or allopatric (for example, Pyrenees with D. majalis only and Britain with D. traunsteineri only). Our results show a phylogeographic signal, but no clear genetic differentiation between the allopolyploids, despite the visible phenotypic divergence between them. The results indicate that gene flow between sibling Dactylorhiza allopolyploids is frequent in sympatry, with potential implications for the genetic patterns across their entire distribution range. Limited interploidal introgression is also evidenced, in particular between D. incarnata and D. traunsteineri. Altogether the allopolyploid genomes appear to be porous for introgression from related diploids and polyploids. We conclude that the observed phenotypic divergence between D. majalis and D. traunsteineri is maintained by strong divergent selection on specific genomic areas with strong penetrance, but which are short enough to remain undetected by genotyping dispersed neutral markers.UE FWF; P22260UE: Y66

Using a simple expert system to assist a powered wheelchair user

A simple expert system is described that helps wheelchair users to drive their wheelchairs. The expert system takes data in from sensors and a joystick, identifies obstacles and then recommends a safe route. Wheelchair users were timed while driving around a variety of routes and using a joystick controlling their wheelchair via the simple expert system. Ultrasonic sensors are used to detect the obstacles. The simple expert system performed better than other recently published systems. In more difficult situations, wheelchair drivers did better when there was help from a sensor system. Wheelchair users completed routes with the sensors and expert system and results are compared with the same users driving without any assistance. The new systems show a significant improvement

The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII

Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy (ERT) for Mucopolysaccharidosis (MPS) VII, a highly heterogeneous, ultra-rare disease. Twelve subjects, ages 8-25 years, completed a Phase 3, randomized, placebo-controlled, blind-start, single crossover study (UX003-CL301; NCT02377921), receiving 24-48 weeks of vestronidase alfa 4 mg/kg IV. All 12 subjects completed the blind-start study, which showed significantly reduced urinary glycosaminoglycans (GAG) and clinical improvement in a multi-domain responder index, and enrolled in a long-term, open-label, extension study (UX003-CL202; NCT02432144). Here, we report the final results of the extension study, up to an additional 144 weeks after completion of the blind-start study. Three subjects (25%) completed all 144 weeks of study, eight subjects (67%) ended study participation before Week 144 to switch to commercially available vestronidase alfa, and one subject discontinued due to non-compliance after receiving one infusion of vestronidase alfa in the extension study. The safety profile of vestronidase alfa in the extension study was consistent with observations in the preceding blind-start study, with most adverse events mild to moderate in severity. There were no treatment or study discontinuations due to AEs and no noteworthy changes in a standard safety chemistry panel. Out of the eleven subjects who tested positive for anti-drug antibodies at any time during the blind-start or extension study, including the baseline assessment in the blind-start study, seven subjects tested positive for neutralizing antibodies and all seven continued to demonstrate a reduction in urinary GAG levels. There was no association between antibody formation and infusion associated reactions. Subjects receiving continuous vestronidase alfa treatment showed a sustained urinary GAG reduction and clinical response evaluated using a multi-domain responder index that includes assessments in pulmonary function, motor function, range of motion, mobility, and visual acuity. Reduction in fatigue was also maintained in the overall population. As ERT is not expected to cross the blood brain barrier, limiting the impact on neurological signs of disease, and not all subjects presented with neurological symptoms, outcomes related to central nervous system pathology are not focused on in this report. Results from this study show the long-term safety and durability of clinical efficacy in subjects with MPS VII with long-term vestronidase alfa treatment.This work was supported by Ultragenyx Pharmaceutical Inc. LZ, TC, DM, and AJ, authors of this manuscript, are employees of Ultragenyx Pharmaceutical and contributed to the conduct of the research; the study design; data collection, analysis and interpretation; development of this manuscript; and the decision to submit this article.info:eu-repo/semantics/publishedVersio

The validity of an updated metabolic power algorithm based upon Di Prampero’s theoretical model in Elite soccer players

The aim of this study was to update the metabolic power (MP) algorithm (P.VO2, W·kg−1) related to the kinematics data (PGPS, W·kg−1) in a soccer-specific performance model. For this aim, seventeen professional (Serie A) male soccer players (.VO2max 55.7 ± 3.4 mL·min−1·kg−1) performed a 6 min run at 10.29 km·h−1 to determine linear-running energy cost (Cr). On a separate day, thirteen also performed an 8 min soccer-specific intermittent exercise protocol. For both procedures, a portable Cosmed K4b2 gas-analyzer and GPS (10 Hz) was used to assess the energy cost above resting (C). From this aim, the MP was estimated through a newly derived C equation (PGPSn) and compared with both the commonly used (PGPSo) equation and direct measurement (P.VO2). Both PGPSn and PGPSo correlated with P.VO2 (r = 0.66, p < 0.05). Estimates of fixed bias were negligible (PGPSn = −0.80 W·kg−1 and PGPSo = −1.59 W·kg−1), and the bounds of the 95% CIs show that they were not statistically significant from 0. Proportional bias estimates were negligible (absolute differences from one being 0.03 W·kg−1 for PGPSn and 0.01 W·kg−1 for PGPSo) and not statistically significant as both 95% CIs span 1. All variables were distributed around the line of unity and resulted in an under-or overestimation of PGPSn, while PGPSo routinely underestimated MP across ranges. Repeated-measures ANOVA showed differences over MP conditions (F1,38 = 16.929 and p < 0.001). Following Bonferroni post hoc test significant differences regarding the MP between PGPSo and P.VO2 /PGPSn (p < 0.001) were established, while no differences were found between P.VO2 and PGPSn (p = 0.853). The new approach showed it can help the coaches and the soccer trainers to better monitor external training load during the training seasons.© 2020 by the authors. Licensee MDPI, Basel, Switzerland

CYP2D6 Allele Frequency in Five Malaria Vivax Endemic Areas From Brazilian Amazon Region

Funding Information: We acknowledge the participants in the study, without whom this research could not have been done. For laboratorial support the authors wish to show their appreciation to Gabriel Barbosa de Abreu (in memorian). To Norman Ratcliffe for the English revision of this manuscript. Part of this work is described in a Master?s Dissertation by PS, conducted at the Applied Microbiology and Parasitology Post-graduation Program, Federal Fluminense University. Publisher Copyright: © Copyright © 2021 Salles, Perce-da-Silva, Rossi, Raposo, Ramirez Ramirez, Pereira Bastos, Pratt-Riccio, Cassiano, Baptista, Cardoso, Banic and Machado.Genetic variability was linked with individual responses to treatment and susceptibility to malaria by Plasmodium vivax. Polymorphisms in the CYP2D6 gene may modulate enzyme level and activity, thereby affecting individual responses to pharmacological treatment. The aim of the study was to investigate whether or not CYP2D6 single nucleotide polymorphisms rs1065852, rs38920-97, rs16947 and rs28371725 are unequally distributed in malaria by Plasmodium vivax individuals from the Brazilian Amazon region. The blood samples were collected from 220 unrelated Plasmodium vivax patients from five different endemic areas. Genotyping was performed using SNaPshot® and real-time polymerase chain reaction methods. In all five areas, the rs1065852 (CYP2D6*10, C.100C > T), rs3892097 (CYP2D6*4, 1846C > T) and rs16947 (CYP2D6*2, C.2850G > A), as a homozygous genotype, showed the lowest frequencies. The rs28371725 (CYP2D6*41, 2988G > A) homozygous genotype was not detected, while the allele A was found in a single patient from Macapá region. No deviations from Hardy-Weinberg equilibrium were found, although a borderline p-value was observed (p = 0.048) for the SNP rs3892097 in Goianésia do Pará, Pará state. No significant associations were detected in these frequencies among the five studied areas. For the SNP rs3892097, a higher frequency was observed for the C/T heterozygous genotype in the Plácido de Castro and Macapá, Acre and Amapá states, respectively. The distribution of the CYP2D6 alleles investigated in the different areas of the Brazilian Amazon is not homogeneous. Further investigations are necessary in order to determine which alleles might be informative to assure optimal drug dosing recommendations based on experimental pharmacogenetics.publishersversionpublishe