Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase.Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6 months.Results: A total of n = 8/15 patients received alglucosidase for more than 3 years prior to switching, and n = 7/15 received it for more than 5 years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of −104.8 U/L, −3.0 mmol/molCr, and −14.7 U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch.Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD

Vertical Current Density Structure of Saturn's Equatorial Current Sheet

Routine spacecraft encounters with the Saturn current sheet due to the passage of aperiodic waves provide the opportunity to analyze the current sheet structure. The current density is expected to peak where the field strength reaches a minimum if approximated as a Harris current sheet. However, in Earth's magnetotail this is not always the case as the sheet is sometimes bifurcated (having two or more maxima in the current density). We utilize measurements of Saturn's magnetic field to estimate the current density during crossings of the current sheet by time differentiating the B a component of the field in a current sheet coordinate system, where B a is perpendicular to both the current and current sheet normal. This is then averaged and organized by the magnitude of B a. Using this method, we can identify a classical Harris-style or bifurcated current sheet as a peak at the center or two distinct maxima on either side of B a=0, respectively. We find that around 10% of current sheet profiles exhibit a bifurcated current sheet signature, which is substantially lower than an ∼25% occurrence rate at Earth

Remote environmental monitoring units : An autonomous vehicle for characterizing coastal environments

Author Posting. © American Meteorological Society 2005. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Atmospheric and Oceanic Technology 22 (2005): 1797–1808, doi:10.1175/JTECH1809.1.In oceanography, there has been a growing emphasis on coastal regions, partially because of their inherent complexity, as well as the increasing acknowledgment of anthropogenic impacts. To improve understanding and characterization of coastal dynamics, there has been significant effort devoted to the development of autonomous systems that sample the ocean on relevant scales. Autonomous underwater vehicles (AUVs) are especially well suited for studies of the coastal ocean because they are able to provide near-synoptic spatial observations. These sampling platforms are beginning to transition from the engineering groups that developed and continue to improve them to the science user. With this transition comes novel applications of these vehicles to address new questions in coastal oceanography. Here, the relatively mature Remote Environmental Monitoring Units (REMUS) AUV system is described and assessed. Analysis of data, based on 37 missions and nearly 800 km of in-water operation, shows that the vehicle’s navigational error estimates were consistently less than 10 m, and error estimates of mission duration, distance, velocity, and power usage, once the vehicle was properly ballasted, were below 10%. An example of the transition to science is demonstrated in an experiment conducted in 2002 in Monterey Bay, California, where the vehicle was used to quantify critical horizontal length scales of variability. Length scales on the order of tens to hundreds of meters were found for the region within 25 km of the coastline, which has significant implications for designing proper sampling approaches and parameterizing model domains. Results also demonstrate the overall utility of the REMUS vehicle for use by coastal oceanographers.This work was supported by the Office of Naval Research (N00014-00-1- 0570 and N00014-03-1-0341 to M. Moline)

Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM

New drugs are needed for relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown excellent activity in those with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (CI <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over single drug alone. Dosing of dexamethasone and selumetinib singly, and in combination in mice engrafted with primary derived RAS pathway mutated leukemia cells, resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukaemia burden showed a significant reduction in drug treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway mutated acute lymphoblastic leukemia and an international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway for children with multiple relapsed/refractory disease

Measuring single cell divisions in human tissues from multi-region sequencing data

Both normal tissue development and cancer growth are driven by a branching process of cell division and mutation accumulation that leads to intra-tissue genetic heterogeneity. However, quantifying somatic evolution in humans remains challenging. Here, we show that multi-sample genomic data from a single time point of normal and cancer tissues contains information on single-cell divisions. We present a new theoretical framework that, applied to whole-genome sequencing data of healthy tissue and cancer, allows inferring the mutation rate and the cell survival/death rate per division. On average, we found that cells accumulate 1.14 mutations per cell division in healthy haematopoiesis and 1.37 mutations per division in brain development. In both tissues, cell survival was maximal during early development. Analysis of 131 biopsies from 16 tumours showed 4 to 100 times increased mutation rates compared to healthy development and substantial inter-patient variation of cell survival/death rates

Mechanical activation of β-catenin regulates phenotype in adult murine marrow-derived mesenchymal stem cells

Regulation of skeletal remodeling appears to influence the differentiation of multipotent mesenchymal stem cells (MSC) resident in the bone marrow. As murine marrow cultures are contaminated with hematopoietic cells, they are problematic for studying direct effects of mechanical input. Here we use a modified technique to isolate marrow-derived MSC (mdMSC) from adult mice, yielding a population able to differentiate into adipogenic and osteogenic phenotypes that is devoid of hematopoietic cells. In pure mdMSC populations, a daily strain regimen inhibited adipogenic differentiation, suppressing expression of PPARγ and adiponectin. Strain increased β-catenin and inhibition of adipogenesis required this effect. Under osteogenic conditions, strain activated β-catenin signaling and increased expression of WISP1 and COX2. mdMSC were also generated from mice lacking caveolin-1, a protein known to sequester β-catenin: caveolin-1(−/−) mdMSC exhibited retarded differentiation along both adipogenic and osteogenic lineages, but retained mechanical responses that involved β-catenin activation. Interestingly, caveolin-1(−/−) mdMSC failed to express bone sialoprotein and did not form mineralized nodules. In summary, mdMSC from adult mice respond to both soluble factors and mechanical input, with mechanical activation of β-catenin influencing phenotype. As such, these cells offer a useful model for studies of direct mechanical regulation of MSC differentiation and function

An integrated approach to identify new anti-filarial leads to treat river blindness, a neglected tropical disease

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adul

JEPEGMIX2: improved gene-level joint analysis of eQTLs in cosmopolitan cohorts.

Motivation: To increase detection power, researchers use gene level analysis methods to aggregate weak marker signals. Due to gene expression controlling biological processes, researchers proposed aggregating signals for expression Quantitative Trait Loci (eQTL). Most gene-level eQTL methods make statistical inferences based on i) summary statistics from genome-wide association studies (GWAS) and ii) linkage disequilibrium (LD) patterns from a relevant reference panel. While most such tools assume homogeneous cohorts, our Gene-level Joint Analysis of functional SNPs in Cosmopolitan Cohorts (JEPEGMIX) method accommodates cosmopolitan cohorts by using heterogeneous panels. However, JEPGMIX relies on brain eQTLs from older gene expression studies and does not adjust for background enrichment in GWAS signals. Results: We propose JEPEGMIX2, an extension of JEPEGMIX. When compared to JPEGMIX, it uses i) cis-eQTL SNPs from the latest expression studies and ii) brains specific (sub)tissues and tissues other than brain. JEPEGMIX2 also i) avoids accumulating averagely enriched polygenic information by adjusting for background enrichment and ii), to avoid an increase in false positive rates for studies with numerous highly enriched (above the background) genes, it outputs gene q-values based on Holm adjustment of p-values. Supplementary information: Supplementary material is available at Bioinformatics online. Bioinformatics 2018; 34(2):286-28

Understanding Judicial Hierarchy, Reversals and the Behavior of Intermediate Appellate

One of the central controversies in the judicial behavior literature is the extent to which judges' ability to act according to their ideological preferences is affected by their location in the judicial hierarchy. Judges on intermediate appellate courts have different decisionmaking environments than high court judges. As a result, the goals of lower appellate court judges may differ from those of their superiors: the quest for legal accuracy may compete with the desire to pursue policy preferences. Analysis of the reversal rate of the U.S. circuit courts of appeals offers insight into the extent to which these judges balance the pressures of their own policy preferences with the desire to achieve the legally accurate result in cases they decide. Int eraction between first-level and second-level appellate courts is a subject that has garnered increasing attention over the past several years, but an opportunity to bridge disciplinary divides by integrating recent scholarly work by political scientists and legal academics has largely been missed in the process. Disagreements between the two levels of courts produce reversals of the lower court by the higher court, but the process that drives such reversal is not well-understood given its importance in maintenance of judicial organization. Particularly in systems where review by the second-level appellate court is discretionary, higher courts reverse lower courts in pursuit of making broader policy statements, so the process takes on added importance. Work that assesses decisions by high courts to grant leave to appea

Prospectus, September 10, 1980

ARE YOU A \u27REAL STUDENT\u27?; Parkland People; Gamut challenges you; Emergency course offered; Oops!; Stugo hopefuls list qualifications; Kinks wow U of I fans; Coates announces student audtions; Country music is moving up; Women\u27s Program offers self-series; Classifieds; Students are....well, just students; Student disappointed; Correction; Science You Can See: Ask not what Cable T.V. can do for you, ask what you can do for Cable T.V.; B-ball deadline is Sept. 22; Football and tennis are IM openers; PC Datebook; Golfers begin season with win over Danville; After some surprises last week, Fast Freddy is ready; LaBadie confident of his runners; Fast Freddy Contest; Bench Warmer: Cobras show talenthttps://spark.parkland.edu/prospectus_1980/1022/thumbnail.jp