Search

Spacecraft data reveals a nonuniform ambipolar electric field transverse to the magnetic field in a thin magnetotail current sheet that leads to intense ExB velocity shear and non-gyrotropic particle distributions. The ExB drift far exceeds the diamagnetic drift and drives lower hybrid waves localized to the magnetic field reversal region, which is ideally suited for the anomalous dissipation necessary for reconnection. It also reveals substructures embedded in the current density, indicating the formation of a non-ideal current sheet., Comment: 6 pages, 4 figures

Context Originally developed for treatment of human immunodeficiency virus (HIV), the antiviral combination lopinavir/ritonavir (LPV/r) is being repurposed for treating the novel coronavirus disease (COVID-19) despite minimal experience in this markedly different population and an in-vitro derived EC50 against SARS-CoV-2 several hundred-fold greater than for HIV. We present a case series including a case of severe hyponatremia and a 32-fold overdose raising safety and effectiveness concerns in COVID-19 patients. Methods We measured LPV trough concentrations in 12 patients and reviewed their clinical charts for side effects known to occur in HIV patients. Findings Compared to established LPV trough concentrations in HIV patients, concentrations in COVID-19 patients were 3-fold greater (19.37 ± 10.12 mcg/mL versus 6.25 mcg/mL). In addition, cholestasis and dyslipidemia toxicity thresholds were exceeded in 12/12 and 11/12 patients respectively. No patients achieved the presumed therapeutic concentration. Side effects included gastrointestinal symptoms (5/12), electrolyte imbalances (4/12), liver enzyme disturbances (5/12) and triglyceride elevations (2/12). Conclusion No patients reached presumed therapeutic LPV concentrations despite experiencing side effects and exceeding cholestasis and dyslipidemia toxicity thresholds. This raises concerns for the safety and effectiveness of LPV/r. Clinicians should consider closely monitoring for side effects and not necessarily attribute them to COVID-19.

Objective Adult polyglucosan body disease (APBD) is an adult‐onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods We characterized the effects of knocking out two pro‐glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro‐ and micro‐gliosis in the brains of GYS1‐ and PPP1R3C‐deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

Summary: Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a−/− and Epm2b−/−) and one of APBD (Gbe1ys/ys), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms. : EPM2A, EPM2B, or GBE1 deficiency causes insoluble glycogen accumulation and neurodegenerative diseases. Sullivan et al. show that these defects do not impair the construction of WT-like soluble glycogen. Demonstrating varying chain length distributions and correlating precipitation propensity among WT-glycogen molecules, a mechanistic explanation emerges for the structural characteristics of insoluble glycogen. Keywords: Lafora disease, laforin, malin, APBD, glycogen branching enzyme, glycogen synthase, glycogen storage disease, polyglucosan bodies, phosphorylation, glycogen chain length distribution

BackgroundOlder adults are more vulnerable to severe infection and mortality due to COVID-19. They often have atypical presentations of the disease without respiratory symptoms, which makes early diagnosis clinically challenging. We aimed to compare the baseline characteristics, presentation, and disease course of older and younger patients hospitalized with COVID-19.MethodsThe charts of 429 consecutive patients hospitalized in Montreal, Canada, with PCR-confirmed COVID-19 were retrospectively reviewed. Baseline health, presentation, in-hospital complications, and outcomes were recorded. Desegregation by age was performed to compare older (≥70) versus younger (ResultsOlder patients presented with more comorbidities compared to younger patients as captured by the Charlson Comorbidity Index (mean 6 vs 2), including higher rates of cardiovascular, cerebrovascular, chronic obstructive pulmonary, and chronic kidney disease. Older patients were less likely than younger patients to present with cough (27% vs 47%) or dyspnea (33% vs 48%). Fifty-two (52%) had no respiratory symptoms on presentation compared to 32% in the younger group (pDiscussionOlder adults presenting to hospital with COVID-19 commonly have no respiratory symptoms and can present with only a geriatric syndrome. A new geriatric syndrome in an older person should trigger isolation and evaluation for COVID-19. Furthermore, older adults are particularly vulnerable to complications related to dehydration, warranting early initiation of multidisciplinary care.

Objectives: To quantify the impact of IV pump relocation for COVID-19 patients from the bedside to outside the patient room on nurse exposure to COVID-19 and conservation of PPE. Design: Original Article Setting: Intensive care units at a single-center teaching hospital. Patients: Critically ill COVID-19 patients under contact and special droplet precautions. Interventions: Relocation of intravenous pumps for COVID-19 patients from bedside to outside the patient room using extension tubing. Measurements and Main Results: The primary objective of the study was to measure the impact of this strategy on COVID-19 exposure, utilizing the number of nurse entries into the patient room as a surrogate endpoint, and extrapolation of this data to determine the reduction or PPE usage. Secondary endpoints included incidence of extravasation, hyperglycemia, hypotension, and diagnosis of CLABSI/bacteremia. A statistically significant reduction in the primary endpoint of the study was observed as room entries prior to pump relocation averaged 15.36 (± 4.10) as opposed to an average of 7.92 (± 2.19) following pump relocation (p < 0.0001). In both pre- and post-pump relocation groups, there was no incidence of extravasation or CLABSI. No significant differences were noted in number of patients experiencing hyperglycemia, hypotensive episodes, or bacteremia. Conclusions: There was a significant decrease in COVID-19 exposure based on the number of nurse entries following the relocation of intravenous pumps from inside to outside of the patient room. These results may be cautiously extrapolated to suggest a decrease in personal protective equipment utilization. Future prospective, randomized controlled trials investigating the impact of this strategy are required.

This paper presents an elegant yet straightforward design procedure for a compact rat-race coupler (RRC) with an extended harmonic suppression. The coupler's conventional \lambda /4 transmission lines (TLs) are replaced by a specialized TL that offers significant size reduction and harmonic elimination capabilities in the proposed approach. The design procedure is verified through the theoretical, circuit, and electromagnetic (EM) analyses, showing excellent agreement among different analyses and the measured results. The circuit and EM results show that the proposed TL replicates the same frequency behaviour of the conventional one at the design frequency of 1.8 GHz while enables harmonic suppression up to the 7 {\mathrm {th}} harmonic and a size reduction of 74%. According to the measured results, the RRC has a fractional bandwidth of 20%, with input insertion losses of around 0.2 dB and isolation level better than 35 dB. Furthermore, the total footprint of the proposed RRC is only 31.7 mm \times15.9 mm, corresponding to 0.28\,\,\lambda \times 0.14\,\,\lambda , where \lambda is the guided wavelength at 1.8 GHz.

Mammalian glycogen chain lengths are subject to complex regulation, including by seven proteins (protein phosphatase-1 regulatory subunit 3, PPP1R3A through PPP1R3G) that target protein phosphatase-1 (PP1) to glycogen to activate the glycogen chain-elongating enzyme glycogen synthase and inactivate the chain-shortening glycogen phosphorylase. Lafora disease is a fatal neurodegenerative epilepsy caused by aggregates of long-chained, and as a result insoluble, glycogen, termed Lafora bodies (LBs). We previously eliminated PPP1R3C from a Lafora disease mouse model and studied the effect on LB formation. In the present work, we eliminate and study the effect of absent PPP1R3D. In the interim, brain cell type levels of all PPP1R3 genes have been published, and brain cell type localization of LBs clarified. Integrating these data we find that PPP1R3C is the major isoform in most tissues including brain. In the brain, PPP1R3C is expressed at 15-fold higher levels than PPP1R3D in astrocytes, the cell type where most LBs form. PPP1R3C deficiency eliminates ~90% of brain LBs. PPP1R3D is quantitatively a minor isoform, but possesses unique MAPK, CaMK2 and 14-3-3 binding domains and appears to have an important functional niche in murine neurons and cardiomyocytes. In neurons, it is expressed equally to PPP1R3C, and its deficiency eliminates ~50% of neuronal LBs. In heart, it is expressed at 25% of PPP1R3C where its deficiency eliminates ~90% of LBs. This work studies the role of a second (PPP1R3D) of seven PP1 subunits that regulate the structure of glycogen, toward better understanding of brain glycogen metabolism generally, and in Lafora disease.

ContextOriginally developed for the treatment of human immunodeficiency virus (HIV), the antiviral combination lopinavir/ritonavir (LPV/r) is being investigated for use against coronavirus disease (COVID-19). We present a case series raising safety and efficacy concerns in COVID-19 affected patients.MethodsWe measured LPV trough concentrations in 12 patients treated at our center and reviewed their clinical charts for side effects known to occur in HIV patients.ResultsCompared to established LPV trough concentrations in HIV treated patients, concentrations in COVID-19 affected patients were 3-fold greater (20.64 +/- 10.14 mcg/mL versus 6.25 mcg/mL). In addition, cholestasis and dyslipidemia toxicity thresholds were exceeded in 12/12 and 11/12 patients respectively. No patients achieved the presumed therapeutic concentration. The side effects noted were mainly gastrointestinal symptoms (5/12, 42%), electrolytes imbalances (4/12, 33%), liver enzyme disturbances (5/12, 42%), and triglyceride elevations (2/12, 17%).ConclusionNone of our patients reached presumed therapeutic LPV concentrations despite experiencing side effects and exceeding cholestasis and dyslipidemia toxicity thresholds. This raises concerns for the safety and efficacy of LPV/r. Clinicians should consider closely monitoring for side effects and not necessarily attribute them to COVID-19 itself.

Background Human adenoviruses are common causes of community-acquired respiratory tract and enteric infections. Severe disseminated infections with high mortality rates may be seen in immunocompromised individuals. An accurate and cost-effective quantitative assay is essential not only for laboratory diagnosis of adenoviral infections, but also for monitoring of response to antiviral treatment. The diagnostic performance of an in-house quantitative polymerase chain reaction assay was compared to a commercial system. Methods The analytical sensitivity, specificity, linearity, precision and accuracy of an in-house adenovirus quantitative polymerase chain reaction assay were evaluated against the RealStar® Adenovirus PCR Kit (Altona Diagnostics GmbH, Hamburg, Germany), using 122 clinical specimens and 18 proficiency testing samples. Results Linear regression analysis of the quantitative results by the in-house assay showed the dynamic range from 2.60 to 9 log10 (plasma) and 2.94 to 9 log10 (viral transport medium) copies/mL, with the coefficient of determination (R2) of 0.996 and 0.998, respectively. A dilution series demonstrated the limits of detection and lower limits of quantification for plasma were 2.06 log10 and 2.60 log10 copies/mL and those for viral transport medium were 2.31 log10 and 2.94 log10 copies/mL respectively. The precision of the in-house assay was highly reproducible among runs with coefficients of variance ranging from 0.07 to 3.21% for plasma and 0.17% to 2.11% for viral transport medium. A comparison of 52 matched samples showed an excellent correlation between the quantitative viral loads measured by the in-house assay and the RealStar® Adenovirus PCR Kit (R2 = 0.984), with an average bias of − 0.16 log10 copies/mL. Conclusions The in-house adenovirus assay is a sensitive and reliable assay with lower cost for the detection and quantification of adenoviral DNA when compared to the RealStar® Adenovirus PCR Kit. Electronic supplementary material The online version of this article (10.1186/s12985-018-1059-7) contains supplementary material, which is available to authorized users.