bluuebunny/crossref_metadata_2025_split huggingface dataset:
QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin
Authors: Chorin Ehud , Wadhwani Lalit , Magnani Silvia , Dai Matthew , Shulman Eric , Nadeau-Routhier Charles , Knotts Robert , Bar-Cohen Roi , Kogan Edward , Barbhaiya Chirag , Aizer Anthony , Holmes Douglas , Bernstein Scott , Spinelli Michael , Park David , Stefano Carugo , Chinitz Larry , Jankelson Lior 
Published: May 2020

AbstractBackgroundThe emergence of the COVID-19 pandemic has resulted in over two million affected and over 150 thousand deaths to date. There is no known effective therapy for the disease. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP).MethodsThis is a multicenter retrospective study of 251 patients with COVID-19 treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality.ResultsQTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 15.9% of patients. One patient developed TdP requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting QTc prolongation of > 60 ms was normal.ConclusionThe combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.
A fundamental model and predictions for the spread of the COVID-19 epidemic
Authors: Cheng Baolian , Wang Yi-Ming 
Published: May 2020

The spread of the novel coronavirus is characterized by two phases: (I) a natural exponential growth phase that occurs in the absence of intervention and (II) a regulated growth phase that is affected by enforcing social distancing and isolation. We have developed a fundamental spreading model for the COVID-19 epidemic that has two parameters: the community transmission rate and a metric describing the degree of isolation and social distancing in a given community or region (country, state, county, or city). These two parameters are calibrated to data from the community, so the model uncertainty depends on the quality of the data and ability to test for COVID-19. The model shows that social distancing significantly reduces the epidemic spread and flattens the curve. The model predicts well the spreading trajectory and peak time of new infections for a community of any size and provides an upper estimate for the total number of infections and daily new infection rate for weeks into the future, providing the vital information and lead time needed to prepare for and mitigate the epidemic. The theory has immediate and far-reaching applications for ongoing outbreaks or similar future outbreaks of other emergent infectious diseases (LA-UR-20–22877).DisclaimerThis material is not final and is subject to be updated any time. Contact information:bcheng@lanl.gov.
ACE inhibitors, AT1 receptor blockers and COVID-19: clinical epidemiology evidences for a continuation of treatments. The ACER-COVID study
Authors: Dauchet Luc , Lambert Marc , Gauthier Victoria , Poissy Julien , Faure Karine , Facon Alain , Yelnik Cécile , Panaget Sophie , Plagnieux Thierry , Verfaillie Florent , Mathieu Daniel , Goldstein Patrick , Meirhaeghe Aline , Amouyel Philippe 
Published: May 2020

AbstractAimsThe question of interactions between the renin angiotensin aldosterone system drugs and the incidence and prognosis of COVID-19 infection has been raised by the medical community. We hypothesised that if patients treated with ACE inhibitors (ACEI) or AT1 receptor blockers (ARB) were more prone to SARS-CoV2 infection and had a worse prognosis than untreated patients, the prevalence of consumption of these drugs would be higher in patients with COVID-19 compared to the general population.Methods and resultsWe used a clinical epidemiology approach based on the estimation of standardised prevalence ratio (SPR) of consumption of ACEI and ARB in four groups of patients (including 187 COVID-19 positive) with increasing severity referred to the University hospital of Lille and in three French reference samples (the exhaustive North population (n=1,569,968), a representative sample of the French population (n=414,046), a random sample of Lille area (n=1,584)).The SPRs of ACEI and ARB did not differ as the severity of the COVID-19 patients increased, being similar to the regular consumption of these drugs in the North of France population with the same non-significant increase for both treatment (1.17 [0.83–1.67]). A statistically significant increase in the SPR of ARB (1.56 [1.02–2.39]) was observed in intensive care unit patients only. After stratification on obesity, this increase was limited to the high risk subgroup of obese patients.ConclusionsOur results strongly support the recommendation that ACEI and ARB should be continued in the population and in COVID-19 positive patients, reinforcing the position of several scientific societies.
Health and economic outcomes of newborn screening for infantile-onset Pompe disease
Authors: Richardson John S. , Kemper Alex R. , Grosse Scott D. , Lam Wendy K.K. , Rose Angela M. , Ahmad Ayesha , Gebremariam Achamyeleh , Prosser Lisa A. 
Published: May 2020

AbstractPurposeTo estimate health and economic outcomes associated with NBS for infantile-onset Pompe disease in the United States.MethodsA decision analytic microsimulation model simulated health and economic outcomes of a birth cohort of 4 million children in the United States. Universal NBS and treatment was compared to clinical identification and treatment of infantile-onset Pompe disease. Main outcomes were projected cases identified, costs, quality adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) over the life course.ResultsUniversal NBS for Pompe disease and confirmatory testing was estimated to cost an additional $26 million annually. Additional medication costs associated with earlier treatment initiation were $181 million; however, $8 million in medical care costs for other services were averted due to delayed disease progression. Infants with screened and treated infantile-onset Pompe disease experienced an average lifetime increase of 11.66 QALYs compared to clinical detection. The ICER was $408,000/QALY from the health care perspective and $379,000/QALY from a societal perspective. Results were sensitive to the cost of enzyme replacement therapy.ConclusionsNewborn screening for Pompe disease results in substantial health gains for individuals with infantile-onset Pompe disease, but with additional costs.
A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis
Authors: Deguise Marc-Olivier , Pileggi Chantal , Beauvais Ariane , Tierney Alexandra , Chehade Lucia , De Repentigny Yves , Michaud Jean , Llavero-Hurtado Maica , Lamont Douglas , Atrih Abdelmadjid , Wishart Thomas M. , Gillingwater Thomas H. , Schneider Bernard L. , Harper Mary-Ellen , Parson Simon H. , Kothary Rashmi 
Published: May 2020

AbstractBackground & aimsSpinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and death in children. SMA patients are more susceptible to dyslipidemia as well as liver steatosis, features reproduced in SMA mouse models. As current pre-clinical models of NAFLD are invariably imperfect and generally take a long time to develop, the rapid development of liver steatosis in SMA mice provides a means to identify molecular markers of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whetherSmn2B/-mice, a model of severe SMA, display typical features of NAFLD/non-alcoholic steatohepatitis (NASH).MethodsBiochemical, histological, electron microscopy, proteomic, and high-resolution respirometry were used.ResultsTheSmn2B/-mice develop steatohepatitis early in life. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in impaired hepatic function including alterations in protein output, complement, coagulation, iron homeostasis, and IGF-1 metabolism. The steatohepatitis is reversible by AAV9-SMN gene therapy. The NAFLD phenotype is likely due to non-esterified fatty acid (NEFA) overload from peripheral lipolysis, subsequent to hyperglucagonemia compounded by reduced muscle use. Mitochondrial β-oxidation contributed to hepatic damage as we observed enhanced hepatic mitochondrial β-oxidation and reactive oxygen species production. Hepatic mitochondrial content, however, was decreased. In contrast to typical NAFLD/NASH, theSmn2B/-mice lose weight due to their neurological condition, develop hypoglycemia and do not develop hepatic fibrosis.ConclusionTheSmn2B/-mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.
Post-mitotic expansion of cell nuclei requires ACTN4-mediated nuclear actin filament bundling
Authors: Krippner Sylvia , Winkelmeier Jannik , Schwan Carsten , Knerr Julian , Virant David , Endesfelder Ulrike , Grosse Robert 
Published: May 2020

AbstractThe actin cytoskeleton operates in a multitude of cellular processes including cell shape and migration, mechanoregulation, as well as membrane or organelle dynamics. However, its filamentous properties and functions inside the mammalian cell nucleus are less well explored. We previously described transient actin assembly at mitotic exit that promotes nuclear expansion during chromatin decondensation. Here, we identify non-muscle ACTN4 as a critical regulator to facilitate F-actin formation, reorganization and bundling during postmitotic nuclear expansion. ACTN4 binds to nuclear actin filaments and ACTN4 clusters associate with nuclear F-actin in a highly dynamic fashion. ACTN4 but not ACTN1 is required for proper postmitotic nuclear volume expansion, mediated by its actin binding domain. Using super-resolution imaging to quantify actin filament numbers and widths in individual nuclei we find that ACTN4 is necessary for postmitotic nuclear actin assembly and actin filament bundling. Our findings uncover a nuclear cytoskeletal function for ACTN4 to control nuclear size during mitotic cell division.
A human single-cell atlas of the Substantia nigra reveals novel cell-specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders
Authors: Agarwal Devika , Sandor Cynthia , Volpato Viola , Caffrey Tara , Monzon-Sandoval Jimena , Bowden Rory , Alegre-Abarrategui Javier , Wade-Martins Richard , Webber Caleb 
Published: May 2020

AbstractWe describe a human single-nuclei transcriptomic atlas for theSubstantia nigra(SN), generated by sequencing ~ 17,000 nuclei from matched cortical and SN samples. We show that the common genetic riskfor Parkinson’s disease(PD) is associated withdopaminergic neuron(DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. UnlikeAlzheimer’s disease(AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression patterns with multiple neuropsychiatric disorders. Nevertheless, we find that each neuropsychiatric disorder is associated with a distinct set of genes within that neuron type. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.
Low-pass sequencing increases the power of GWAS and decreases measurement error of polygenic risk scores compared to genotyping arrays
Authors: Li Jeremiah H. , Mazur Chase A. , Berisa Tomaz , Pickrell Joseph K. 
Published: May 2020

AbstractLow-pass sequencing (sequencing a genome to an average depth less than 1 coverage) combined with genotype imputation has been proposed as an alternative to genotyping arrays for trait mapping and calculation of polygenic scores. To empirically assess the relative performance of these technologies for different applications, we performed low-pass sequencing (targeting coverage levels of 0.5× and 1×) and array genotyping (using the Illumina Global Screening Array (GSA)) on 120 DNA samples derived from African and European-ancestry individuals that are part of the 1000 Genomes Project. We then imputed both the sequencing data and the genotyping array data to the 1000 Genomes Phase 3 haplotype reference panel using a leave-one-out design. We evaluated overall imputation accuracy from these different assays as well as overall power for GWAS from imputed data, and computed polygenic risk scores for coronary artery disease and breast cancer using previously derived weights. We conclude that low-pass sequencing plus imputation, in addition to providing a substantial increase in statistical power for genome wide association studies, provides increased accuracy for polygenic risk prediction at effective coverages of ~ 0.5× and higher compared to the Illumina GSA.
Interaction of levothyroxine with bovine serum albumin: a spectroscopic assay
Authors: Sandu Nicoleta , Chilom Claudia G. , David Melinda , Florescu Monica 
Published: May 2020

ABSTRACTBovine serum albumin (BSA) acts as a carrier for many endogenous and exogenous compounds, such as thyroid hormones or corresponding drugs. Binding of the hydrophilic compound levothyroxine (LT4) to BSA can significantly alter the pharmacological properties of the compound. Therefore, studying its interaction with BSA could be a difficult issue. In this work, the binding mechanism and affinity of the interaction between LT4 and BSA were investigated, both in solution using UV-Vis, Fourier-transform infrared spectroscopy (FT-IR), fluorescence and fluorescence resonance energy transfer (FRET), as well as by Surface Plasmon Resonance (SPR) with BSA confined to a gold-coated chips, as far as we know for the first time used to study the interactions between LT4 and proteins. Quenching of BSA fluorescence by LT4 combined with UV-Vis spectroscopy shows a ground-state complex formation that may be accompanied by a nonradiative energy transfer process. FT-IR revealed the changes induced by LT4 in the secondary structure of BSA molecules, due to the partial unfolding of BSA native structure upon LT4 binding. Scatchard approach allowed the determination of the binding constant and the thermodynamic parameters, which correspond to an enthalpic process, driven mainly by hydrogen bonds and van der Waals forces. Using SPR, the adsorbed amount of biomolecules was calculated and the binding affinity of LT4 with confined-BSA was characterized using the Hill-Langmuir equation, indicating that the BSA immobilization plays an important role in LT4 binding. As preliminary results, both fluorescence quenching and SPR can be used as a stepping stone for the development of a spectroscopic biosensor for LT4 detection, with a limit of detection as low as 0.23 × 10−6M.
Effects of agricultural systems on the anuran diversity in the Colombian amazon
Authors: Diaz-Ricaurte Juan C. , Arriaga-Villegas Nayra Camila , López-Coronado Juan David , Macias-Garzón Gina Ximena , Fiorillo Bruno F. 
Published: May 2020

AbstractWe provide information on the diversity of anurans from agroforestry systems in the Colombian Amazon. This area is inserted at the tropical rainforest ecosystem and consists mainly of secondary forest remnants surrounded by crops, grasslands, and agroforestry systems. From February to May 2015, we sampled anurans mainly with visual and auditory surveys. We recorded a total of 1096 individuals of 20 species of anurans from six families at the study area. The relictual forest was the richest environment, followed by Achapo and Cacao agroforestry systems. The Achapo system showed great similarity in species composition with relictual forest, however, the latter presented the highest number of exclusive species, whereas the first presented only two and Cacao system didn’t have any exclusive species. Our results show that the richness can vary between the different types of agroforestry systems and highlight their importance as management tool for anurans conservation in the Colombian Amazon.
Fractional re-distribution among cell motility states during ageing
Authors: Phillip Jude M. , Zamponi Nahuel , Phillip Madonna P. , Daya Jena , McGovern Shaun , Williams Wadsworth , Tschudi Katherine , Jayatilaka Hasini , Wu Pei-Hsun , Walston Jeremy , Wirtz Denis 
Published: May 2020

ABSTRACTAgeing in humans is associated with a decreased capacity to regulate cell physiology. Cellular properties, such as cell morphology and cell mechanics, encode ageing information and as a result can be used as robust ageing biomarkers. Using a panel of dermal fibroblasts derived from healthy donors spanning a wide age range, we observe an age-related reduction in average cell motility, which we show is not due to the decreased motility of all cells, but results from fractional re-distribution among motility states. By taking advantage of the single-cell nature of our motility data, we show that cells can be classified based on spatial and activity patterns that define age-dependent motility states. These findings highlight an important feature of ageing cells shown by the decrease in the heterogeneity of cell movement in older adults, that potentially offer new mechanistic insights into the ageing process and avenues for novel biomarker development.
A Rapid COVID-19 RT-PCR Detection Assay for Low Resource Settings
Authors: Arumugam Arunkumar , Faron Matthew L. , Yu Peter , Markham Cole , Wong Season 
Published: May 2020

ABSTRACTQuantitative reverse transcription polymerase chain reaction (RT-qPCR) assay is the gold standard recommended to test for acute SARS-CoV-2 infection. It has been used by the Centers for Disease Control and Prevention (CDC) and several other companies in their Emergency Use Authorization (EUA) assays. RT-qPCR requires expensive equipment such as RNA isolation instruments and real-time PCR thermal cyclers, which are not available in many low resource settings and developing countries. As a pandemic, COVID-19 has quickly spread to the rest of the world. Many underdeveloped and developing counties do not have the means for fast and accurate COVID-19 detection to control this outbreak. Using COVID-19 positive clinical specimens, we demonstrated that RT-PCR assays can be performed in as little as 12 minutes using untreated samples, heat-inactivated samples, or extracted RNA templates. Rapid RT-PCR was achieved using thin-walled PCR tubes and a setup including sous vide immersion heaters/circulators. Our data suggest that rapid RT-PCR can be implemented for sensitive and specific molecular diagnosis of COVID-19 in situations where sophisticated laboratory instruments are not available.
Ndel1 promotes keratin assembly and desmosome stability
Authors: Kim Yong-Bae , Hlavaty Daniel , Maycock Jeff , Lechler Terry 
Published: May 2020

ABSTRACTKeratin intermediate filaments form dynamic polymer networks that organize in specific ways dependent on the cell type, the stage of the cell cycle, and the state of the cell. In differentiated cells of the epidermis, they are organized by desmosomes, cell-cell adhesion complexes which provide essential mechanical integrity to this tissue. Despite this, we know little about how keratin organization is controlled and whether desmosomes actively promote keratin assembly in addition to binding pre-assembled filaments. We recently discovered that Ndel1 is a desmosome-associated protein in differentiated epidermis. Here, we show that Ndel1 binds directly to keratin subunits through a motif conserved in all intermediate filament proteins. Further, Ndel1 is necessary for robust desmosome-keratin association and sufficient to reorganize keratins to distinct cellular sites. Lis1, a Ndel1 binding protein, is required for desmosomal localization of Ndel1, but not for its effects on keratin filaments. Finally, we use mouse genetics to demonstrate that loss of Ndel1 results in desmosome defects in the epidermis. Our data thus identify Ndel1 as a desmosome-associated protein which promotes local assembly/organization of keratin filaments and is essential for both robust cell adhesion and epidermal barrier function.
Molecular epidemiology of mumps viruses detected in the Netherlands, 2017-2019
Authors: Bodewes Rogier , Reijnen Linda , Kerkhof Jeroen , Cremer Jeroen , Schmitz Dennis , van Binnendijk Rob , Veldhuijzen Irene K. 
Published: May 2020

AbstractMumps cases continue to occur, also in countries with a relatively high vaccination rate. The last major outbreaks of mumps in the Netherlands were from 2009-2012 and thereafter, only small clusters and single cases were reported. Molecular epidemiology can provide insights in the circulation of mumps viruses. The aims of the present study were to analyze the molecular epidemiology of mumps viruses in the Netherlands in 2017-2019 and to elucidate whether complete genome sequencing adds to the molecular resolution of mumps viruses when compared to sequencing of the mumps SH gene and non-coding regions (SH+NCRs). To this end, Sanger sequence data from the SH+NCRs were analyzed from 82 mumps genotype G viruses. In addition, the complete genomes were obtained from 10 mumps virus isolates using next-generation sequencing. Analysis of SH+NCRs of mumps viruses revealed the presence of two major lineages in the Netherlands, which was confirmed by analysis of complete genomes. Comparison of molecular resolution obtained with SH+NCRs and complete genomes clearly indicated that additional molecular resolution can be obtained by analyzing complete genomes. In conclusion, analysis of SH + NCRs sequence data from recent mumps genotype G viruses indicate that mumps viruses continue to circulate in the Netherlands and surrounding countries. However, to understand exact transmission trees and to compare mumps viruses on a large geographic scale, analysis of complete genomes is a very useful approach.