bluuebunny/crossref_metadata_2025 huggingface dataset:
Orbital and superorbital periods in ULX pulsars, disc-fed HMXBs, Be/X-ray binaries, and double-periodic variables
Authors: Townsend L J , Charles P A
Published: May 2020

We present evidence for a simple linear relationship between the orbital period and superorbital period in ultra-luminous X-ray (ULX) pulsars, akin to what is seen in the population of disc-fed neutron star supergiant X-ray binary and Be/X-ray binary systems. We argue that the most likely cause of this relationship is the modulation of precessing hotspots or density waves in an accretion or circumstellar disc by the binary motion of the system, implying a physical link between ULX pulsars and high-mass X-ray binary (HMXB) pulsars. This hypothesis is supported by recent studies of Galactic and Magellanic Cloud HMXBs accreting at super-Eddington rates, and the position of ULX pulsars on the spin period–orbital period diagram of HMXBs. An interesting secondary relationship discovered in this work is the apparent connection between disc-fed HMXBs, ULXs, and a seemingly unrelated group of early-type binaries showing so-called double-periodic variability. We suggest that these systems are good candidates to be the direct progenitors of Be/X-ray binaries.
Phylogenetic Reconstruction Based on Synteny Block and Gene Adjacencies
Authors: Drillon Guénola , Champeimont Raphaël , Oteri Francesco , Fischer Gilles , Carbone Alessandra
Published: May 2020

Gene order can be used as an informative character to reconstruct phylogenetic relationships between species independently from the local information present in gene/protein sequences. PhyChro is a reconstruction method based on chromosomal rearrangements, applicable to a wide range of eukaryotic genomes with different gene contents and levels of synteny conservation. For each synteny breakpoint issued from pairwise genome comparisons, the algorithm defines two disjoint sets of genomes, named partial splits, respectively, supporting the two block adjacencies defining the breakpoint. Considering all partial splits issued from all pairwise comparisons, a distance between two genomes is computed from the number of partial splits separating them. Tree reconstruction is achieved through a bottom-up approach by iteratively grouping sister genomes minimizing genome distances. PhyChro estimates branch lengths based on the number of synteny breakpoints and provides confidence scores for the branches. PhyChro performance is evaluated on two data sets of 13 vertebrates and 21 yeast genomes by using up to 130,000 and 179,000 breakpoints, respectively, a scale of genomic markers that has been out of reach until now. PhyChro reconstructs very accurate tree topologies even at known problematic branching positions. Its robustness has been benchmarked for different synteny block reconstruction methods. On simulated data PhyChro reconstructs phylogenies perfectly in almost all cases, and shows the highest accuracy compared with other existing tools. PhyChro is very fast, reconstructing the vertebrate and yeast phylogenies in <15 min.
Iron deficiency after kidney transplantation
Authors: Vinke Joanna Sophia J , Francke Marith I , Eisenga Michele F , Hesselink Dennis A , de Borst Martin H
Published: May 2020

Iron deficiency (ID) is highly prevalent in kidney transplant recipients (KTRs) and has been independently associated with an excess mortality risk in this population. Several causes lead to ID in KTRs, including inflammation, medication and an increased iron need after transplantation. Although many studies in other populations indicate a pivotal role for iron as a regulator of the immune system, little is known about the impact of ID on the immune system in KTRs. Moreover, clinical trials in patients with chronic kidney disease or heart failure have shown that correction of ID, with or without anaemia, improves exercise capacity and quality of life, and may improve survival. ID could therefore be a modifiable risk factor to improve graft and patient outcomes in KTRs; prospective studies are warranted to substantiate this hypothesis.
Surgical Management of the Trigeminocerebellar Artery in Microvascular Decompression for Trigeminal Neuralgia
Authors: Goto Yukihiro , Inoue Takuro
Published: May 2020

BACKGROUND

The trigeminocerebellar artery (TCA) is a variant branch of the basilar artery supplying the trigeminal nerve root and cerebellar hemisphere, which may contribute to trigeminal neuralgia (TGN). Despite its unique anatomic description, information regarding the preoperative diagnosis and surgical management of TCA is lacking.

OBJECTIVE

To evaluate our preoperative diagnosis of TCA using 3-dimensional (3D) images and surgical management of TGN cases with TCA involvement.

METHODS

We reviewed our 15 patients with TCA involvement (3.3%) among 460 consecutive patients undergoing microvascular decompression for TGN. In this study, all patients were examined using 3D images using GammaPlan (Elekta, Stockholm, Sweden). TCAs were divided into 2 groups based on surgical findings: encircling type and intraneural type. Biographical data, radiological findings, and operative video recordings were reviewed retrospectively. Surgical outcomes and follow-up were assessed and compared between the 2 groups.

RESULTS

TCA involvement was confirmed preoperatively in 14 of the 15 patients using 3D images. All patients were operated with our unique transposition technique and became pain free immediately after the surgery. Pain-free status was maintained during the follow-up period (3.5 ± 2.6 yr) in all patients but one in whom pain recurred 4 yr after the initial surgery. Re-exploration revealed an adhesion between the Teflon felt and the nerve root.

CONCLUSION

Although TCA involvement is rare, an accurate preoperative diagnosis is essential because the decompression technique may differ from those used for other common cases. Scrutinizing anatomically rare variation with 3D images is recommended for predicting TCA involvement.
The Conserved and Particular Roles of the R2R3-MYB Regulator FhPAP1 from Freesia hybrida in Flower Anthocyanin Biosynthesis
Authors: Li Yueqing , Shan Xiaotong , Tong Linna , Wei Chao , Lu Keyu , Li Shuying , Kimani Shadrack , Wang Shucai , Wang Li , Gao Xiang
Published: May 2020

Anthocyanin biosynthesis is mainly controlled by MYB–bHLH–WD40 (MBW) complexes that modulate the expression of anthocyanin biosynthetic genes (ABGs). The MYB regulators involved in anthocyanin biosynthesis arose early during plant evolution and thus might function divergently in different evolutionary lineages. Although the anthocyanin-promoting R2R3-MYB regulators in eudicots have been comprehensively explored, little consensus has been reached about functional discrepancies versus conservation among MYB regulators from different plant lineages. Here, we integrated transcriptome analysis, gene expression profiles, gain-of-function experiments and transient protoplast transfection assays to functionally characterize the monocot Freesia hybrida anthocyanin MYB regulator gene FhPAP1, which showed correlations with late ABGs. FhPAP1 could activate ABGs as well as TT8-clade genes FhTT8L, AtTT8 and NtAN1 when overexpressed in Freesia, Arabidopsis and tobacco, respectively. Consistently, FhPAP1 could interact with FhTT8L and FhTTG1 to form the conserved MBW complex and shared similar target genes with its orthologs from Arabidopsis. Most prominently, FhPAP1 displayed higher transactivation capacity than its homologs in Arabidopsis and tobacco, which was instantiated in its powerful regulation on ABGs. Moreover, we found that FhPAP1 might be the selected gene during the domestication and rapid evolution of the wild Freesia species to generate intensive flower pigmentation. These results showed that while the MBW complex was highly evolutionarily conserved between tested monocot and core eudicot plants, participating MYB regulators showed functional differences in transactivation capacity according to their activation domain and played important roles in the flower coloration domestication and evolution of angiosperms.
Maintaining High-Quality Multidisciplinary Pain Medicine Fellowship Programs: Part II: Innovations in Clinical Care Workflow, Clinical Supervision, Job Satisfaction, and Postgraduation Mentorship for Pain Fellows During the COVID-19 Pandemic
Authors: Kohan Lynn , Sobey Christopher , Wahezi Sayed , Brancolini Scott , Przkora Rene , Shaparin Naum , Spektor Boris , Moeschler Susan , Anitescu Magdalena
Published: May 2020

Background

Pain fellowship programs are facing unique challenges during the COVID-19 pandemic. Restrictions by state governments and the Centers for Disease Control and Prevention have resulted in a rapidly changing and evolving learning environment for today’s fellows. Innovative solutions must be sought to maintain proper education and ensure the well-being of our trainees.

Methods

We assembled a panel of pain program directors who serve as officers/board members of the Association of Pain Program Directors, offering guidance and recommendations to pain fellowship directors nationwide. Panel members evaluate the best available evidence and expert opinion on use of remote and virtual platforms in clinical care, adaptability to alterations in clinic and referral management, and provide guidance on postgraduate impact.

Conclusions

The country is in the midst of an unprecedented pandemic. The impact on pain management fellowships has been significant and will likely last for months, resulting in extraordinary challenges to the administration of pain fellowship programs and the education of our fellows. Several strategies will help address these challenges, including employing telehealth capabilities to continue clinical experiences and providing trainees with opportunities to continue their professional growth beyond fellowship completion. Together, we can implement innovative solutions to overcome these challenges.
Striving to Rollback or Protect Roe: State Legislation and the Trump-Era Politics of Abortion
Authors: Wilson Joshua C
Published: May 2020

Abortion’s centrality to the Christian Right, together with that movement’s importance to Republican Party politics, as well as the policy realities of abortion, have all combined to make regulating abortion a fixture within U.S. state politics for decades. While the levels and forms of state activity have varied since the 1980s, the Trump presidency has produced strategic changes in the content and perceived importance of abortion policy. Notably, recent changes in the state politics of abortion have not just been on the side of Republican states restricting abortion access, the most traditional and highest profile form of policy activity in this area, but have also taken the form of Democratic states actively defending abortion access. This article provides an overview of the interrelated changes in party politics, perceptions of political opportunities, and the content of state abortion regulations. It concludes that the frequency of state abortion laws has increased modestly during the Trump presidency, but substantive shifts in recent policies create the potential to fundamentally reorganize state and national abortion politics.
Paracingulate Sulcus Length Is Shorter in Voice-Hearers Regardless of Need for Care
Authors: Powers Albert R , van Dyck Laura I , Garrison Jane R , Corlett Philip R
Published: May 2020

Hallucinations—while often considered an indication of mental illness—are commonly experienced by those without a need for clinical care. These nonclinical voice-hearers offer an opportunity to investigate hallucinations in the absence of confounds inherent to the clinical state. Recent work demonstrates an association between auditory verbal hallucinations (AVH) and structural variability in paracingulate sulcus (PCS) of medial prefrontal cortex in a clinical population. However, before PCS length may be considered a biomarker for clinical hallucination risk, it is necessary to investigate PCS structure in a nonclinical population of voice-hearers with AVH phenomenology similar to those of their clinical counterparts. In the current study, PCS length was measured from T1-weighted structural MRI scans of four groups of participants: (1) voice-hearers with a psychotic disorder (n = 15); (2) voice-hearers without a psychotic disorder (n = 15); (3) nonvoice-hearers with a psychotic disorder (n = 14); and (4) nonvoice-hearers without a psychotic disorder (n = 15). There was a main effect of AVH status—but not psychosis—on right PCS length, with no interaction of AVH and psychosis. Participants with AVH exhibited reduced right PCS length compared to participants without AVH (mean reduction = 8.8 mm, P < 0.05). While past studies have demonstrated decreased PCS length in clinical voice-hearers, ours is the first demonstration that shorter right PCS extends to nonclinical voice-hearers. Our findings support the hypothesis that differences in PCS length are related to the propensity to hear voices and not to illness, consistent with a continuum model of voice-hearing.
Privacy protection in Hungary
Authors: Menyhei Ákos , Zsoldos János
Published: May 2020

The EU beneficial ownership register leaves very little room for maneuver for those who prefer to maintain their privacy in present times. This article discusses the privacy element of the Hungarian Asset Management Foundation (AMF), analyzes the impact of the AMF law on the privacy of the participants in an AMF, and gives an insight into the workings of a hybrid structure when an AMF acts as trustee.
Tracing Back the Temporal Change of SARS-CoV-2 with Genomic Signatures
Authors: Biswas Sourav , Saha Suparna , Bandyopadhyay Sanghamitra , Bhattacharyya Malay
Published: May 2020

The coronavirus disease (COVID-19) outbreak starting from China at the end of 2019 and its subsequent spread in many countries have given rise to thousands of coronavirus samples being collected and sequenced till date. To trace back the initial temporal change of SARS-CoV-2, the coronavirus implicated in COVID-19, we study the limited genomic sequences that were available within the first couple of months of its spread. These samples were collected under varying circumstances and highlight wide variations in their genomic compositions. In this paper, we explore whether these variations characterize the initial temporal change of SARS-CoV-2 sequences. We observe thatn-mer distributions in the SARS-CoV-2 samples, which were collected at an earlier period of time, predict its collection timeline with approximately 78% accuracy. However, such a distinctive pattern disappears with the inclusion of samples collected at a later time. We further observe that isolation sources (e.g., oronasopharynx, saliva, feces, etc.) could not be predicted by then-mer patterns in these sequences. Finally, the phylogenetic and protein-alignment analyses highlight interesting associations between SARS-CoV-2 and other coronaviruses.
Performance & Quality Evaluation of Marketed COVID-19 RNA Detection Kits
Authors: Kapitula David Surace , Jiang Zhuopu , Jiang Jianhao , Zhu Jing , Chen Xiangyong , Lin Claudia Qiao
Published: May 2020

Compared to other coronaviruses, COVID-19 has a longer incubation period and features asymptomatic infection at a high rate (>25%)1,2. Therefore, early detection of infection is the key to early isolation and treatment. Direct detection of the virus itself has advantages over indirect detection. Currently, the most sensitive and commercially validated method for COVID-19 testing is RT-qPCR, designed to detect amplified virus-specific RNA. Reliable testing has proven to be a bottleneck in early diagnosis of virus infection in all countries dealing with the pandemic. Significant performance and quality issues with available testing kits have caused confusion and serious health risks. In order to provide better understanding of the Quality and performance of COVID-19 RNA detection kits on the market, we designed a system to evaluate the specificity (quantitation), sensitivity (LOD) and robustness of the kits using positive RNA and pseudovirus controls based on COVID-19 genomic sequence3,4. We evaluated 8 Nucleic Acid qPCR Kits approved in China, some of which are also approved in the US and EU. Our study showed that half of these 8 kits lack 1:1 linear relationship for virus RNA copy: qPCR signal. Of the 4 with linear response, 2 demonstrated sensitivity at 1 Copy viral RNA/Reaction, suitable for early detection of virus infection. Furthermore, we established the best RNA extraction, handling and qPCR procedures allowing highly sensitive and consistent performance using BGI qPCR kits. Our study provides an effective method to assess and compare performance quality of all COVID-19 nucleic acid testing kits, globally.

Significance Statement

Testing for COVID-19 has been a critical topic in the pandemic management since the first outbreak reported in China, and now globally. Despite of focused efforts from global biomedical industries and regulatory authorities, testing tools currently available on the market are not satisfying the huge and most important needs for virus control, which is specific, sensitive, affordable, and commercially viable early diagnosis of infected populations. We have designed an experimental system to assess and compare all nucleic acid-based COVID-19 testing kits from quality control perspectives. The results reported here demonstrate the suitability of using our system as an objective QC system for all commercial kits, including any future kits. We also identified the best testing method using commercially available reagents.
High frequency of SARS-CoV-2 RNAemia and association with severe disease
Authors: Hogan Catherine A. , Stevens Bryan , Sahoo Malaya K. , Huang ChunHong , Garamani Natasha , Gombar Saurabh , Yamamoto Fiona , Murugesan Kanagavel , Kurzer Jason , Zehnder James , Pinsky Benjamin A.
Published: May 2020

Background

Detection of SARS-CoV-2 RNA in the blood, also known as RNAemia, has been reported, but its prognostic implications are not well understood. This study aimed to determine the frequency of SARS-CoV-2 RNA in plasma and its association with the clinical severity of COVID-19.

Methods

An analytical cross-sectional study was performed in a single-center tertiary care institution in northern California and included consecutive inpatients and outpatients with COVID-19 confirmed by detection of SARS-CoV-2 RNA in nasopharyngeal swab specimens. The prevalence of SARS CoV-2 RNAemia and the strength of its association with clinical severity variables were examined and included the need for transfer to an intensive care unit (ICU), mechanical ventilation and 30-day all-cause mortality.

Results

Paired nasopharyngeal and plasma samples were included from 85 patients. The overall median age was 55 years, and individuals with RNAemia were older than those with undetectable SARS-CoV-2 RNA in plasma (63 vs 50 years; p=0.001). Comorbidities were frequent including obesity (37.7%), hypertension (30.6%) and diabetes mellitus (22.4%). RNAemia was detected in a total of 28/85 (32.9%) individual patients, including 22/28 (78.6%) who required hospital admission. RNAemia was detected more frequently in individuals who developed severe disease including the need for ICU transfer (32.1% vs 14.0%; p=0.05), mechanical ventilation (21.4% vs 3.5%; p=0.01) and 30-day all-cause mortality (14.3% vs 0%; p=0.01). No association was detected between RNAemia and estimated levels of viral RNA in the nasopharynx. An additional 121 plasma samples from 28 individuals with RNAemia were assessed longitudinally, and RNA was detected for a maximum duration of 10 days.

Conclusion

This study demonstrated a high proportion of SARS-CoV-2 RNAemia, and an association between RNAemia and clinical severity suggesting the potential utility of plasma viral testing as a prognostic indicator for COVID-19.
Clinical presentation and evolution of COVID-19 in immunosuppressed patients. Preliminary evaluation in a North Italian cohort on calcineurin-inhibitors based therapy
Authors: Cavagna Lorenzo , Bruno Raffaele , Zanframundo Giovanni , Gregorini Marilena , Seminari Elena , Di Matteo Angela , Rampino Teresa , Montecucco Carlomaurizio , Pelenghi Stefano , Cattadori Barbara , Pattonieri Eleonora Francesca , Vitulo Patrizio , Bertani Alessandro , Sambataro Gianluca , Vancheri Carlo , Bonetto Valentina , Monti Maria Cristina , Ticozzelli Elena , Turco Annalisa , Oggionni Tiberio , Corsico Angelo , Codullo Veronica , Morosini Monica , Gnecchi Massimiliano , Pellegrini Carlo , Meloni Federica
Published: May 2020

The clinical course of COVID-19 in patients undergoing chronic immunosuppressive therapy is yet poorly known. We performed a monocentric cross-sectional study describing the clinical course of COVID-19 in a cohort of patients from northern Italy treated with calcineurin-inhibitors for organ transplantation or rheumatic diseases. Data were collected by phone call and clinical chart review between March 27th- 31st2020. COVID-19 related symptoms, rynopharingeal swab, therapeutic changes and outcome were assessed in 384 consecutive patients (57% males; median age 61 years, IQR 48-69). 331 patients (86%) received solid organ transplantation (kidney n=140, 36%, heart n=100, 26%, lung n=91, 24%) and 53 (14%) had a rheumatic disease. Calcineurin inhibitors were the only immunosuppressant administered in 46 patients (12%). 14 patients developed a “confirmed COVID-19” (swab positivity) and 14 a “clinical COVID-19” (only typical symptoms). Fever (75%) and diarrhoea (50%) were the most common symptoms. Fourteen patients were hospitalized and 11 have already been dismissed. No patient required start/changes of the O2 therapy or developed superinfection. Only one patient, with metastatic lung cancer, died. In conclusion, COVID-19 showed a mild course in our cohort, with low mortality. Calcineurin inhibitor-based immunosuppressive regimens appear safe in this context and should not be discontinued.
Fitting SIR model to COVID-19 pandemic data and comparative forecasting with machine learning
Authors: Baldé Mouhamadou A.M.T.
Published: May 2020

In this work, we use a classical SIR model to study COVID-19 pandemic. We aim, to deal with the SIR model fitting to COVID-19 data by using different technics and tools. We particularly use two ways: the first one start by fitting the total number of the confirmed cases and the second use a parametric solver tool. Finally a comparative forecasting, machine learning tools, is given.
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

Background

The 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).

Methods

This 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.

Results

QTc 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.

Conclusion

The 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).

Disclaimer

This 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

Aims

The 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 results

We 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.

Conclusions

Our 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

Purpose

To estimate health and economic outcomes associated with NBS for infantile-onset Pompe disease in the United States.

Methods

A 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.

Results

Universal 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.

Conclusions

Newborn 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

Background & aims

Spinal 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).

Methods

Biochemical, histological, electron microscopy, proteomic, and high-resolution respirometry were used.

Results

TheSmn2B/-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.

Conclusion

TheSmn2B/-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

The 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

We 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

Low-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

Bovine 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

We 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

Ageing 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

Quantitative 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

Keratin 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

Mumps 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.
Characterization ofVibrio choleraeisolates from freshwater sources in northwest Ohio
Authors: Daboul Judy , Weghorst Logan , DeAngelis Cara , Plecha Sarah , Saul-McBeth Jessica , Matson Jyl S.
Published: May 2020

Vibrio choleraeis a natural inhabitant of aquatic ecosystems worldwide, typically residing in coastal or brackish water. While more than 200 serogroups have been identified, only serogroups O1 and O139 have been associated with epidemic cholera. However, infections other than cholera can be caused by nonepidemic, non-O1/non-O139V.choleraestrains, including gastroenteritis and extraintestinal infections. WhileV.choleraecan also survive in freshwater, that is typically only observed in regions of the world where cholera is endemic. We recently isolatedV.choleraefrom several locations in lakes and rivers in northwest Ohio. These isolates were all found to be non-O1/non-O139V.choleraestrains, that would not cause cholera. However, these isolates contained a variety of virulence genes, includingctxA, rtxA, rtxC, hlyA, andompU. Therefore, it is possible that some of these isolates have the potential to cause gastroenteritis or other infections in humans. We also investigated the relative motility of the isolates and their ability to form biofilms as this is important forV.choleraesurvival in the environment. We identified one isolate that forms very robust biofilms, up to 4x that of our laboratory control strains. Finally, we investigated the susceptibility of these isolates to a panel of antibiotics. We found that many of the isolates showed decreased susceptibility to some of the antibiotics tested, which could be of concern. While we do not know if these isolates are pathogenic to humans, increased surveillance to better understand the public health risk to the local community should be considered.

Importance

This study found thatVibrio choleraebelonging to non-O1/non-O139 serogroups is present in freshwater lakes and rivers in northwest Ohio. Although non-O1/non-O139V.choleraestrains generally do not produce cholera toxin, and thus do not cause epidemic cholera, they often contain other virulence factors that may contribute to pathogenicity. In fact, we found that these local isolates contained an assortment of potential virulence genes. We also found that some of the isolates showed antibiotic resistance. While we do not currently know if the localV.choleraestrains are capable of causing disease in humans, increased monitoring forV.choleraein the region is warranted in the interest of public health.