bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychological Distress Among Bhutanese Refugees Living in the Northeast Region of the United States
Authors: Gautam Ramraj , Rydberg Jason , Ho Ivy , Siwakoti Bhola , Chadbourne William , Mawn Barbara E
Published: February 2021

The purpose of this study was to examine predictors of psychological distress among adult Bhutanese refugees living in the United States. We recruited 376 adult Bhutanese refugees living in the northeast US region, the majority of whom were employed, married men in their 40 s who were US citizens. Using Bayesian Negative Binomial Regression modelling, we examined the impact of sociodemographic measures, health status and refugee integration measures on psychological distress outcomes. The most common predictors of depression, stress and anxiety were social connection deficits and self-reported health conditions. Other associated factors included: health access deficits, number of years living in the US, paid employment, citizenship and living in more than one US city. The findings of our study revealed that mental health outcomes in this subset of the population of Bhutanese refugees are impacted by a variety of social and health related factors. Public policy makers and practitioners need to recognize the complex issues affecting mental health of Bhutanese refugees. Advocacy for expanded culturally congruent policies and evidence based mental health services are recommended. Future research needs to examine culturally relevant concepts and measures related to mental health and integration in this population.
A case of acute abdomen caused by spontaneous rupture of a splenic abscess secondary to cancer of the splenic flexure
Authors: Pavlidis Efstathios T , Martzivanou Eirini K , Symeonidis Nikolaos G , Psarras Kyriakos K , Marneri Alexandra G , Stavrati Kalliopi E , Pavlidis Theodoros E
Published: February 2021

Splenic abscesses are rare, difficult to diagnose, difficult to treat and usually appear in immunosuppressed patients. We present the case of a 64-year-old patient with left pleuritic chest pain, anorexia and fever with rigors diagnosed with splenic abscess due to splenic flexure colon cancer. The abscess spontaneously ruptured and the patient was operated on for acute abdomen. Splenectomy and Hartmann’s hemicolectomy were performed. The patient was discharged from the hospital and referred to the oncologic department. Continuous spread of infection and especially initiating from a cancer lesion is a usual mechanism of splenic abscess formation. Although computed tomography-guided percutaneous drainage is the treatment of choice, an exploratory laparotomy was necessary in this case because of the rupture of the abscess. It is important for the clinicians to include splenic abscesses and their complications in the differential diagnosis of acute abdomen.
What Is a Cartel and What Does it Do?
Authors: Veljanovski Cento
Published: February 2021

This chapter discusses cartels in detail. A cartel is a secret agreement or arrangement between firms or individuals who would otherwise compete to increase their profits by manipulating the market. There are three general types of illegal cartels: sellers’, buyers’, and bid-rigging cartels. A suppliers’ or sellers’ cartel is where a group of firms who would have otherwise competed agree to increase the selling price of the inputs, intermediate and/or final goods, and services they sell. Meanwhile, a buyers’ cartel is where a group of buyers who would otherwise have competed agree to reduce the prices they pay for the goods and services they purchase. A bid-rigging cartel is when sellers who would otherwise compete secretly agree to raise prices and other terms to those who acquire their products or services through a tendering or bidding process. However, there are also legal cartels such as export cartels. Ultimately, the main abuse in cartels is charging a price different from that which would have been charged in the absence of the collusive arrangements.
Interest
Authors: Veljanovski Cento
Published: February 2021

This chapter addresses interest, which is awarded ‘to compensate a claimant from being kept out of his money’. Pre-judgment interest rates set by statute or the courts vary across the EU. In English law, where the claimant can prove loss of interest, it will be compensated as a damage claim. In some cases, the claimant has sought interest calculated using the Weighted Average Cost of Capital (WACC). Otherwise, the court has discretion to apply a judicial simple interest rate for the whole or part of the damage award, usually at the Bank of England Base rate plus 1% to 4%. The award of interest can be significant in a competition claim were the cartel has operated for many years and during periods of high interest rates. At common law, however, interest was not payable on damages; there were exceptions in equity.
Simulation Models
Authors: Veljanovski Cento
Published: February 2021

This chapter focuses on the simulation approaches. A simulation is a structural economic model which seeks to replicate the pricing and competitive relationships in the industry to calculate the non-infringement prices and quantities. The simplest simulation is the use of elasticities to the volume effect as has been proposed in the Pass-on Guidelines. More technical approaches use the economist’s oligopoly models based on a series of equations, parameters, and derivations to calculate the overcharges and related pass-on and volume effects. The major drawbacks of simulations are that they are often fairly technical, based on models and ‘unrealistic assumptions’, and inevitably do not draw on and are easily aligned with the documentary and factual evidence adduced at trial. As a result, they are most likely not to be given much weight by the court.
Expert Evidence
Authors: Veljanovski Cento
Published: February 2021

This chapter explores expert evidence in English courts. Economists are used as experts, together with accountants, in competition damage cases to give opinion evidence on competition issues and quantification of damages. Experts have a duty to the court which overrides that to their clients to give independent and objective evidence. In England and Wales, there are strict rules regarding expert evidence in court. They are governed by expert rules and the rules of evidence. The chapter then details the process and the role played by experts in competition litigation. Litigation is an uncertain affair with no guaranteed outcome. Experts have a responsibility and legal duty to prepare a professional report and give evidence under oath at trial. Where an expert has been negligent and not fulfilled their duty to the court, they may be responsible for the costs incurred by the other side in dealing with their defective evidence.
The Nature and Significance of International Investment
Authors: Salacuse Jeswald W
Published: February 2021

This chapter explains the nature and significance of international investments and investors. All international investment treaties focus on two subjects: (1) investments, particularly international or ‘foreign investments’; and (2) investors, especially international or ‘foreign investors’. An understanding of these two phenomena is fundamental to understanding the growing role and significance of investment treaties in international economic life. The meaning of the term ‘investment’ at its most basic level is the commitment of resources by a physical or legal person to a specific purpose in order to earn a profit or to gain a return. Meanwhile, there are four basic categories of investors: private investors; state investors; international organizations; and mixed enterprises. The chapter then looks at the different forms of international investment.
The Process of Termination
Authors: Stannard John E , Capper David
Published: February 2021

This chapter assesses what termination is, how it should be described, and what it involves. The concept of termination is not easy to define, not least because of the inconsistent terminology used by the courts and by commentators, and also because of the overlap existing between termination itself and other concepts that are akin to it. Termination is one way in which a party to a contract is relieved of his undertaking to do that which he has agreed to do but has not yet done. There are three key factors distinguishing termination from other types of discharge, the first being that it requires proof of a serious breach by the party in default, the second being that it normally occurs only at the option of the innocent party, and the third that it leaves the party in default liable in damages. Though termination is traditionally described as involving the termination of the contract as a whole, it is perfectly possible for a contract to be terminated in part. The chapter then looks at the requirement of election in termination for breach. It also considers how the right to terminate may be limited.
Repudiation and Anticipatory Breach
Authors: Stannard John E , Capper David
Published: February 2021

This chapter studies repudiation and anticipatory breach. The essence of repudiation is the absence of readiness and willingness by the defaulting party to perform their obligations under the contract. Though the word ‘repudiation’ suggests an unwillingness or refusal to perform, it can also include the situation in which the defaulting party, though perfectly willing to perform when the time comes, is incapable of doing so. The chapter then looks at modes of repudiation. The two key questions in deciding whether repudiation has taken place are: (1) the ratio quantitatively which the breach bears to the contract as a whole, and (2) the degree of probability or improbability that such a breach will be repeated. The chapter also considers the law regarding the issue of notices making time of the essence.
Restitutionary Relief
Authors: Stannard John E , Capper David
Published: February 2021

This chapter assesses several inter-connected instances where the non-breaching party in a contract terminated for the other's breach might seek restitutionary relief under the law of unjust enrichment as opposed to damages for breach of contract. For claims where the claimant seeks to recover benefits transferred under a contract now terminated, it is still conventional to distinguish between claims for restitution of money benefits and claims for non-money benefits. The chapter also differentiates restitution for breach of contract from restitution following breach of contract. It then turns to situations where the party that committed the breach is seeking restitution of money and non-money benefits transferred under the contract. The first question to be addressed is why that breach does not of itself bar any restitutionary claim.
The International Tribunal for the Law of the Sea
Authors: Kittichaisaree Kriangsak
Published: February 2021

The International Tribunal for the Law of the Sea (ITLOS) plays a central role as a dispute settlement mechanism for the international law of the sea. This book provides a unique insight into its inner workings exploring both its limitations and its unutilized potentials. New fields such as sea-level rise and the conservation and sustainable use of marine biological diversity beyond areas of national jurisdiction play important roles in the ever-expanding scope of the law of the sea. The book charts the evolution of ITLOS and the role it continues to play in international law. It introduces the reader to the historical and legal context for the discussion of ITLOS’s place within this dispute settlement regime, as well as its relationship and interaction with the other choices of dispute settlement mechanisms. It is an invaluable resource for law students, practising lawyers, judges, government and international officials, academics, and those interested in law of the sea.
Twitter as social media arena for polarised social representations about the (im)migration: The controversial discourse in the Italian and international political frame
Authors: de Rosa Annamaria Silvana , Bocci Elena , Bonito Mattia , Salvati Marco
Published: February 2021

Grounded in social representation theory and its empirical investigation into the ‘social arena’, inspired by the ‘modelling paradigmatic approach’, the research presented in this article is part of a larger project aimed at reconstructing the ‘multi-voice’, and ‘multi-agent’ discourse about (im)migration. Specifically, this contribution’s focus is on the exploration of shaping and sharing social representations about (im)migrants through communication via the social medium ‘Twitter’. A total of 1,958 tweets (967 Italian and 991 English tweets) were analysed through Systeme Portable Pour L’Analyse Des Donnees Textuelles [Portable System for Textual Data Analysis]SPAD in two lexical correspondence analyses. The results show a dichotomous discourse organising a semantic space structured around five different factors for the two distinct Twitter corpora: both clearly show polarised social representations of ‘immigrants–migrants’, leading to exclusion–inclusion policies depending on the discursive agent’s ideological affiliation in the Italian and the international political frame. Used as a propaganda tool, Twitter echoes the related pro- and anti-immigration polemical representations of opposite political leaders in posts that are positioned differently in relation to the progressive/conservative ideology.
A stripped-companion origin for Be stars: clues from the putative black holes HR 6819 and LB-1
Authors: El-Badry Kareem , Quataert Eliot
Published: February 2021

HR 6819 is a bright (V = 5.36), blue star recently proposed to be a triple containing a detached black hole (BH). We show that the system is a binary and does not contain a BH. Using spectral decomposition, we disentangle the observed composite spectra into two components: a rapidly rotating Be star and a slowly rotating B star with low surface gravity (log g ≈ 2.75). Both stars show periodic radial velocity (RV) variability, but the RV semi-amplitude of the B star’s orbit is $K_{\rm B}= (62.7 \pm 1)\, \rm km\, s^{-1}$, while that of the Be star is only $K_{\rm Be} = (4.5\pm 2)\, \rm km\, s^{-1}$. This implies that the B star is less massive by at least a factor of 10. The surface abundances of the B star bear imprints of CNO burning. We argue that the B star is a bloated, recently stripped helium star with mass ${\approx}0.5\, \mathrm{ M}_{\odot }$ that is currently contracting to become a hot subdwarf. The orbital motion of the Be star obviates the need for a BH to explain the B star’s motion. A stripped-star model reproduces the observed luminosity of the system, while a normal star with the B star’s temperature and gravity would be more than 10 times too luminous. HR 6819 and the binary LB-1 probably formed through similar channels. We use MESA (Modules for Experiments in Stellar Astrophysics) models to investigate their evolutionary history, finding that they likely formed from intermediate-mass ($3\!-\!7\, \mathrm{ M}_{\odot }$) primaries stripped by slightly lower-mass secondaries and are progenitors to Be + sdOB binaries such as ϕ Persei. The lifetime of their current evolutionary phase is on average 2 × 105 yr, of the order of half a per cent of the total lifetime of the Be phase. This implies that many Be stars have hot subdwarf and white dwarf companions, and that a substantial fraction ($20\!-\!100{{\ \rm per\ cent}}$) of field Be stars form through accretion of material from a binary companion.
Characterizing the target selection pipeline for the Dark Energy Spectroscopic Instrument Bright Galaxy Survey
Authors: Ruiz-Macias Omar , Zarrouk Pauline , Cole Shaun , Baugh Carlton M , Norberg Peder , Lucey John , Dey Arjun , Eisenstein Daniel J , Doel Peter , Gaztañaga Enrique , Hahn ChangHoon , Kehoe Robert , Kitanidis Ellie , Landriau Martin , Lang Dustin , Moustakas John , Myers Adam D , Prada Francisco , Schubnell Michael , Weinberg David H , Wilson M J
Published: February 2021

We present the steps taken to produce a reliable and complete input galaxy catalogue for the Dark Energy Spectroscopic Instrument (DESI) Bright Galaxy Survey (BGS) using the photometric Legacy Survey DR8 DECam. We analyse some of the main issues faced in the selection of targets for the DESI BGS, such as star–galaxy separation, contamination by fragmented stars and bright galaxies. Our pipeline utilizes a new way to select BGS galaxies using Gaia photometry and we implement geometrical and photometric masks that reduce the number of spurious objects. The resulting catalogue is cross-matched with the Galaxy And Mass Assembly (GAMA) survey to assess the completeness of the galaxy catalogue and the performance of the target selection. We also validate the clustering of the sources in our BGS catalogue by comparing with mock catalogues and the Sloan Digital Sky Survey (SDSS) data. Finally, the robustness of the BGS selection criteria is assessed by quantifying the dependence of the target galaxy density on imaging and other properties. The largest systematic correlation we find is a 7 per cent suppression of the target density in regions of high stellar density.
Cosmic-ray current-driven instabilities – revisiting environmental conditions
Authors: Reville Brian , Giacinti Gwenael , Scott Robyn
Published: February 2021

The growth of magnetohydrodynamic fluctuations relevant to cosmic-ray (CR) confinement in and near their sources, and the effects of local plasma conditions is revisited. We consider cases where CRs penetrate a medium which may contain a fraction of neutral particles, and explore the possible effects of high-order CR anisotropies. An algorithm for calculating the dispersion relation for arbitrary distributions, and anisotropies is presented, and a general solution for power-law cosmic-ray distributions is provided. Implications for the resulting instabilities near to strong Galactic CR sources are discussed. We argue that CR streaming in weakly ionized plasmas eliminates the need for the existence of an evanescent band in the dispersion relation, a conclusion which may be confirmed by gamma-ray observations. The necessity for additional multiscale numerical simulations is highlighted, as understanding the non-linear behaviour is crucial.
Gravitational waves from mountains in newly born millisecond magnetars
Authors: Sur Ankan , Haskell Brynmor
Published: February 2021

In this paper, we study the spin-evolution and gravitational-wave luminosity of a newly born millisecond magnetar, formed either after the collapse of a massive star or after the merger of two neutron stars. In both cases, we consider the effect of fallback accretion; and consider the evolution of the system due to the different torques acting on the star, namely the spin-up torque due to accretion and spin-down torques due to magnetic dipole radiation, neutrino emission, and gravitational-wave emission linked to the formation of a ‘mountain’ on the accretion poles. Initially, the spin period is mostly affected by the dipole radiation, but at later times, accretion spin the star up rapidly. We find that a magnetar formed after the collapse of a massive star can accrete up to 1 M⊙, and survive on the order of 50 s before collapsing to a black hole. The gravitational-wave strain, for an object located at 1 Mpc, is hc ∼ 10−23 at kHz frequencies, making this a potential target for next-generation ground-based detectors. A magnetar formed after a binary neutron star merger, on the other hand, accretes at the most 0.2 M⊙ and emits gravitational waves with a lower maximum strain of the order of hc ∼ 10−24, but also survives for much longer times, and may possibly be associated with the X-ray plateau observed in the light curve of a number of short gamma-ray burst.
Magnetically modified spherical accretion in GRMHD: reconnection-driven convection and jet propagation
Authors: Ressler S M , Quataert E , White C J , Blaes O
Published: February 2021

We present 3D general relativistic magnetohydrodynamic simulations of zero angular momentum accretion around a rapidly rotating black hole, modified by the presence of initially uniform magnetic fields. We consider several angles between the magnetic field direction and the black hole spin. In the resulting flows, the mid-plane dynamics are governed by magnetic reconnection-driven turbulence in a magnetically arrested (or a nearly arrested) state. Electromagnetic jets with outflow efficiencies ∼10–200 per cent occupy the polar regions, reaching several hundred gravitational radii before they dissipate due to the kink instability. The jet directions fluctuate in time and can be tilted by as much as ∼30○ with respect to black hole spin, but this tilt does not depend strongly on the tilt of the initial magnetic field. A jet forms even when there is no initial net vertical magnetic flux since turbulent, horizon-scale fluctuations can generate a net vertical field locally. Peak jet power is obtained for an initial magnetic field tilted by 40○–80○ with respect to the black hole spin because this maximizes the amount of magnetic flux that can reach the black hole. These simulations may be a reasonable model for low luminosity black hole accretion flows such as Sgr A* or M87.
A Comprehensive Evolutionary Scenario of Cell Division and Associated Processes in the Firmicutes
Authors: Garcia Pierre S , Duchemin Wandrille , Flandrois Jean-Pierre , Gribaldo Simonetta , Grangeasse Christophe , Brochier-Armanet Céline
Published: February 2021

The cell cycle is a fundamental process that has been extensively studied in bacteria. However, many of its components and their interactions with machineries involved in other cellular processes are poorly understood. Furthermore, most knowledge relies on the study of a few models, but the real diversity of the cell division apparatus and its evolution are largely unknown. Here, we present a massive in-silico analysis of cell division and associated processes in around 1,000 genomes of the Firmicutes, a major bacterial phylum encompassing models (i.e. Bacillus subtilis, Streptococcus pneumoniae, and Staphylococcus aureus), as well as many important pathogens. We analyzed over 160 proteins by using an original approach combining phylogenetic reconciliation, phylogenetic profiles, and gene cluster survey. Our results reveal the presence of substantial differences among clades and pinpoints a number of evolutionary hotspots. In particular, the emergence of Bacilli coincides with an expansion of the gene repertoires involved in cell wall synthesis and remodeling. We also highlight major genomic rearrangements at the emergence of Streptococcaceae. We establish a functional network in Firmicutes that allows identifying new functional links inside one same process such as between FtsW (peptidoglycan polymerase) and a previously undescribed Penicilin-Binding Protein or between different processes, such as replication and cell wall synthesis. Finally, we identify new candidates involved in sporulation and cell wall synthesis. Our results provide a previously undescribed view on the diversity of the bacterial cell cycle, testable hypotheses for further experimental studies, and a methodological framework for the analysis of any other biological system.
Task-specific human capital and returns to specialization: evidence from association football
Authors: Kempa Karol
Published: February 2021

This paper analyses returns to task specialization using a unique panel data set of professional football players in the German Bundesliga. Based on accumulated task-specific human capital, I measure whether a player is rather a specialist in one task or a generalist able to perform several tasks. Using OLS, fixed effects, and quantile regression methods (with individual fixed effects), I analyse the impact of specialization on remuneration. Differentiating by player role in team production, I find that core team members, i.e. starting players, exhibit positive returns to specialization, which increase at higher salary quantiles. In contrast, substitutes, in particular those in the lower half of the conditional salary distribution, seem to benefit from being generalists, which renders them more attractive as substitute players for their teams. The paper discusses implications of the findings for other labour market contexts.
Variation in financial protection and its association with health expenditure indicators: an analysis of low- and middle-income countries
Authors: Anjorin Seun S , Ayorinde Abimbola A , Abba Mustapha S , Oyebode Oyinlola O , Uthman Olalekan A
Published: February 2021

Background

An insight into variation in financial protection among countries and the underpinning factors associated with the variations observed will help to inform public health policy and practice.

Method

Secondary datasets from Global Health Expenditure Database and World Bank Development Indicators collected between 2000 and 2016 were used. Financial protection was measured in 75 low- and middle-income countries (LMICs) using the sustainable development goals framework. Funnel plot charts were used to explore the variation, and regression models were used to measure associations.

Result

Fifty-three (67%) countries were within the 99% control limits indicating common-cause variation; 11 countries were above the upper control limit and 15 countries were below the lower control limit. In the fully adjusted model, country, spending on health relative to their economy had the strongest association with the variation in catastrophic spending. Every 1% increase in health spending relative to gross domestic product (GDP) was found to be associated with a reduction of 0.13% in the number of people that incurred catastrophic health spending.

Conclusion

There is substantial variation in financial protection, as measured by the number of people that incurred catastrophic health spending, in LMICs; a proportion of this could be explained by the difference in GDP and external health expenditure.
A platform for post-translational spatiotemporal control of cellular proteins
Authors: Jayanthi Brianna , Bachhav Bhagyashree , Wan Zengyi , Martinez Legaspi Santiago , Segatori Laura
Published: February 2021

Mammalian cells process information through coordinated spatiotemporal regulation of proteins. Engineering cellular networks thus relies on efficient tools for regulating protein levels in specific subcellular compartments. To address the need to manipulate the extent and dynamics of protein localization, we developed a platform technology for the target-specific control of protein destination. This platform is based on bifunctional molecules comprising a target-specific nanobody and universal sequences determining target subcellular localization or degradation rate. We demonstrate that nanobody-mediated localization depends on the expression level of the target and the nanobody, and the extent of target subcellular localization can be regulated by combining multiple target-specific nanobodies with distinct localization or degradation sequences. We also show that this platform for nanobody-mediated target localization and degradation can be regulated transcriptionally and integrated within orthogonal genetic circuits to achieve the desired temporal control over spatial regulation of target proteins. The platform reported in this study provides an innovative tool to control protein subcellular localization, which will be useful to investigate protein function and regulate large synthetic gene circuits.
Joint universal modular plasmids (JUMP): a flexible vector platform for synthetic biology
Authors: Valenzuela-Ortega Marcos , French Christopher
Published: February 2021

Generation of new DNA constructs is an essential process in modern life science and biotechnology. Modular cloning systems based on Golden Gate cloning, using Type IIS restriction endonucleases, allow assembly of complex multipart constructs from reusable basic DNA parts in a rapid, reliable and automation-friendly way. Many such toolkits are available, with varying degrees of compatibility, most of which are aimed at specific host organisms. Here, we present a vector design which allows simple vector modification by using modular cloning to assemble and add new functions in secondary sites flanking the main insertion site (used for conventional modular cloning). Assembly in all sites is compatible with the PhytoBricks standard, and vectors are compatible with the Standard European Vector Architecture (SEVA) as well as BioBricks. We demonstrate that this facilitates the construction of vectors with tailored functions and simplifies the workflow for generating libraries of constructs with common elements. We have made available a collection of vectors with 10 different microbial replication origins, varying in copy number and host range, and allowing chromosomal integration, as well as a selection of commonly used basic parts. This design expands the range of hosts which can be easily modified by modular cloning and acts as a toolkit which can be used to facilitate the generation of new toolkits with specific functions required for targeting further hosts.
Torsadogenic Action of Cisapride, dl-Sotalol, Bepridil, and Verapamil Analyzed by the Chronic Atrioventricular Block Cynomolgus Monkeys: Comparison With That Reported in the CiPA In Silico Mechanistic Model
Authors: Goto Ai , Sakamoto Kengo , Kambayashi Ryuichi , Nunoi Yoshio , Izumi-Nakaseko Hiroko , Kawai Shinichi , Takei Yoshinori , Matsumoto Akio , Kanda Yasunari , Sugiyama Atsushi
Published: February 2021

In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n = 5 for each dose), dl-sotalol (0, 1, 3, and 10 mg/kg, n = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl-sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl-sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol >bepridil ≥cisapride >verapamil in our study. Since the order was bepridil ≥dl-sotalol >cisapride >verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.
Elevated temperature increases genome-wide selection on de novo mutations
Authors: Berger David , Stångberg Josefine , Baur Julian , Walters Richard J.
Published: February 2021

Adaptation in new environments depends on the amount of genetic variation available for evolution, and the efficacy by which natural selection discriminates among this variation. However, whether some ecological factors reveal more genetic variation, or impose stronger selection pressures than others, is typically not known. Here, we apply the enzyme kinetic theory to show that rising global temperatures are predicted to intensify natural selection throughout the genome by increasing the effects of DNA sequence variation on protein stability. We test this prediction by (i) estimating temperature-dependent fitness effects of induced mutations in seed beetles adapted to ancestral or elevated temperature, and (ii) calculate 100 paired selection estimates on mutations in benign versus stressful environments from unicellular and multicellular organisms. Environmental stressper sedid not increase mean selection on de novo mutation, suggesting that the cost of adaptation does not generally increase in new ecological settings to which the organism is maladapted. However, elevated temperature increased the mean strength of selection on genome-wide polymorphism, signified by increases in both mutation load and mutational variance in fitness. These results have important implications for genetic diversity gradients and the rate and repeatability of evolution under climate change.
Limosilactobacillus balticus sp. nov., Limosilactobacillus agrestis sp. nov., Limosilactobacillus albertensis sp. nov., Limosilactobacillus rudii sp. nov. and Limosilactobacillus fastidiosus sp. nov., five novel Limosilactobacillus species isolated from the vertebrate gastrointestinal tract, and proposal of six subspecies of Limosilactobacillus reuteri adapted to the gastrointestinal tract of specific vertebrate hosts
Authors: Li Fuyong , Cheng Christopher C. , Zheng Jinshui , Liu Junhong , Quevedo Rodrigo Margain , Li Junjie , Roos Stefan , Gänzle Michael G. , Walter Jens
Published: February 2021

Ten strains, BG-AF3-AT, pH52_RY, WF-MT5-AT, BG-MG3-A, Lr3000T, RRLNB_1_1, STM3_1T, STM2_1, WF-MO7-1T and WF-MA3-C, were isolated from intestinal or faecal samples of rodents, pheasant and primate. 16S rRNA gene analysis identified them as

Limosilactobacillus reuteri

. However, average nucleotide identity and digital DNA–DNA hybridization values based on whole genomes were below 95 and 70 %, respectively, and thus below the threshold levels for bacterial species delineation. Based on genomic, chemotaxonomic and morphological analyses, we propose five novel species with the names Limosilactobacillus balticus sp. nov. (type strain BG-AF3-AT=DSM 110574T=LMG 31633T), Limosilactobacillus agrestis sp. nov. (type strain WF-MT5-AT=DSM 110569T=LMG 31629T), Limosilactobacillus albertensis sp. nov. (type strain Lr3000T=DSM 110573T=LMG 31632T), Limosilactobacillus rudii sp. nov. (type strain STM3_1T=DSM 110572T=LMG 31631T) and Limosilactobacillus fastidiosus sp. nov. (type strain WF-MO7-1T=DSM 110576T=LMG 31630T). Core genome phylogeny and experimental evidence of host adaptation of strains of

L. reuteri

further provide a strong rationale to consider a number of distinct lineages within this species as subspecies. Here we propose six subspecies of

L. reuteri

:

L. reuteri

subsp. kinnaridis subsp. nov. (type strain AP3T=DSM 110703T=LMG 31724T),

L. reuteri

subsp. porcinus subsp. nov. (type strain 3c6T=DSM 110571T=LMG 31635T),

L. reuteri

subsp. murium subsp. nov. (type strain lpuph1T=DSM 110570T=LMG 31634T),

L. reuteri

subsp.

reuteri

subsp. nov. (type strain F 275T=DSM 20016T=ATCC 23272T),

L. reuteri

subsp. suis subsp. nov. (type strain 1063T=ATCC 53608T=LMG 31752T) and

L. reuteri

subsp. rodentium subsp. nov. (type strain 100-23T=DSM 17509T=CIP 109821T).
DPP9 deficiency: an Inflammasomopathy which can be rescued by lowering NLRP1/IL-1 signaling
Authors: Harapas Cassandra R. , Robinson Kim S. , Lay Kenneth , Wong Jasmine , Moreno Traspas Ricardo , Nabavizadeh Nasrin , Raas-Rothschild Annick , Boisson Bertrand , Drutman Scott B. , Laohamonthonkul Pawat , Bonner Devon , Gorrell Mark , Davidson Sophia , Yu Chien-Hsiung , Kayserili Hulya , Hatipoglu Nevin , Casanova Jean-Laurent , Bernstein Jonathan A. , Zhong Franklin L. , Masters Seth L. , Reversade Bruno
Published: February 2021

Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo is not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate with biallelicDPP9rare variants. Using patient-derived primary cells and biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles that fail to repress NLRP1. Remarkably, the removal in mice, of a single copy of eitherNlrp1a/b/c, Asc, Gsdmd, Il-1r, but notIl-18, was sufficient to rescue the lethality ofDpp9mutant neonates. These experiments suggest that the deleterious consequences of DPP9 deficiency are mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in a mouse model of the disease.
Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial
Authors: Lescure Francois-Xavier , Honda Hitoshi , Fowler Robert A. , Lazar Jennifer Sloane , Shi Genming , Wung Peter , Patel Naimish , Hagino Owen
Published: February 2021

Background

Elevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.

Methods

This was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to ≥2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered withClinicalTrials.gov(NCT04327388).

Findings

Between March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to ≥2-point improvement between placebo (12·0 [9·0–15·0] days) and sarilumab groups (200 mg: 10·0 [9·0–12·0] days, p=0.96, log-rank test; 400 mg: 10·0 [9·0–13·0] days, p=0.34) or in proportions of patients alive (placebo, 91·7%; sarilumab 200 mg, 89·9%, p=0·63; sarilumab 400 mg, 91·9%, p=0·85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI −7·7 to 25·5, p=0·25) for critical patients. There were no unexpected safety signals.

Interpretation

This trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.

Funding

Sanofi and Regeneron Pharmaceuticals, Inc.
Diffusion kurtosis imaging of white matter in bipolar disorder
Authors: Goghari Vina M , Kusi Mavis , Shakeel Mohammed K , Beasley Clare , David Szabolcs , Leemans Alexander , De Luca Alberto , Emsell Louise
Published: February 2021

Objectives

White matter pathology is thought to contribute to the pathogenesis of bipolar disorder (BD). However, most studies of white matter in BD have used the simple diffusion tensor imaging (DTI) model, which has several limitations. DTI studies have reported heterogenous results, leading to a lack of consensus about the extent and location of white matter alterations. Here, we applied two advanced diffusion magnetic resonance imaging (MRI) techniques to investigate white matter microstructure in BD.

Methods

Twenty-five patients with BD and 24 controls comparable for age and sex were included in the study. Whole-brain voxel-based analysis (VBA) and a network-based connectivity approach using constrained spherical deconvolution (CSD)-tractography were used to assess group differences in diffusion kurtosis imaging (DKI) and DTI metrics.

Results

VBA showed lower mean kurtosis in the corona radiata and posterior association fibers in BD following threshold-free cluster enhancement. Regional differences in connectivity were indicated by lower mean kurtosis and kurtosis anisotropy in streamlines traversing the temporal and occipital lobes, and lower mean axial kurtosis in the right cerebellar, thalamo-subcortical pathways in BD. Significant differences were not seen in the DTI metrics following FDR- correction.

Conclusions

Differences between BD and controls were observed in DKI metrics in multiple brain regions, indicating altered connectivity across cortical, subcortical and cerebellar areas. DKI was more sensitive than DTI at detecting these differences, suggesting that DKI is useful for investigating white matter in BD.
A Remote Household-Based Approach to Influenza Self-Testing and Antiviral Treatment
Authors: Heimonen Jessica , McCulloch Denise J. , O’Hanlon Jessica , Kim Ashley E. , Emanuels Anne , Wilcox Naomi , Brandstetter Elisabeth , Stewart Mark , McCune David , Fry Scott , Parsons Sean , Hughes James P. , Jackson Michael L. , Uyeki Timothy M. , Boeckh Michael , Starita Lea M. , Bedford Trevor , Englund Janet A. , Chu Helen Y.
Published: February 2021

Background

Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery.

Methods

We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter.

Results

124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which 8 were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test was 72.7% and 96.2%, respectively. There were 8 home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription, and all within 48 hours of symptom onset.

Conclusions

We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.

In this pilot study, 481 individuals self-monitored for respiratory symptoms. Of 58 home tests, 12 were influenza-positive. There were 8 baloxavir home deliveries within 48 hours of illness onset. A home-based approach to influenza diagnosis and treatment could be feasible.
The color pattern inducing genewinglessis expressed in specific cell types of campaniform sensilla of a polka-dotted fruit fly,Drosophila guttifera
Authors: Koseki Masato , Tanaka Nobuaki K. , Koshikawa Shigeyuki
Published: February 2021

A polka-dotted fruit fly,Drosophila guttifera,has a unique pigmentation pattern on its wings and is used as a model for evo-devo studies exploring the mechanism of evolutionary gain of novel traits. In this species, a morphogen-encoding gene,wingless, is expressed in species-specific positions and induces a unique pigmentation pattern. To produce some of the pigmentation spots on wing veins,winglessis thought to be expressed in developing campaniform sensilla cells, but it was unknown which of the four cell types there express(es)wingless. Here we show that two of the cell types, dome cells and socket cells, expresswingless, as indicated byin situhybridization together with immunohistochemistry. This is a unique case in which non-neuronal SOP (sensory organ precursor) progeny cells produce Wingless as an inducer of pigmentation pattern formation. Our finding opens a path to clarifying the mechanism of evolutionary gain of a uniquewinglessexpression pattern by analyzing gene regulation in dome cells and socket cells.
Short report: Ethnicity and COVID-19 death in the early part of the COVID-19 second wave in England: an analysis of OpenSAFELY data from 1st September to 9th November 2020
Authors: Bhaskaran Krishnan , Mathur Rohini , Rentsch Christopher T , Morton Caroline E , Hulme William J , Schultze Anna , MacKenna Brian , Eggo Rosalind M , Wong Angel YS , Williamson Elizabeth J , Forbes Harriet , Wing Kevin , McDonald Helen I , Bates Chris , Bacon Seb , Walker Alex J , Evans David , Inglesby Peter , Mehrkar Amir , Curtis Helen J , DeVito Nicholas J , Croker Richard , Drysdale Henry , Cockburn Jonathan , Parry John , Hester Frank , Harper Sam , Douglas Ian J , Tomlinson Laurie , Evans Stephen JW , Grieve Richard , Smeeth Liam , Goldacre Ben
Published: February 2021

Black and minority ethnic groups were at raised risk of dying from COVID-19 during the first few months of the COVID-19 epidemic in England. We aimed to investigate whether ethnic inequalities in COVID-19 deaths were similar in the more recent “second wave” of the epidemic. Working on behalf of NHS England, we used primary care and linked ONS mortality data within the OpenSAFELY platform. All adults in the database at 1st September 2020 and with at least 1 year of prior follow-up and a record of ethnicity were included. The outcome was COVID-19-related death (death with COVID-19 listed as a cause of death on the death certificate). Follow-up was to 9th November 2020. Hazard ratios for ethnicity were calculated using Cox regression models adjusted for age and sex, and then further adjusted for deprivation. 13,223,154 people were included. During the study period, people of South Asian ethnicity were at higher risk of death due to COVID-19 than white people after adjusting for age and sex (HR = 3.47, 95% CI 2.99-4.03); the association attenuated somewhat on further adjustment for index of multiple deprivation (HR = 2.86, 2.46-3.33, Table 2). In contrast with the first wave of the epidemic, we found little evidence of a raised risk in black or other ethnic groups compared to white (HR for black vs white = 1.28, 0.87-1.88 adjusted for age and sex; and 1.01, 0.69-1.49 further adjusted for deprivation). Our findings suggest that ethnic inequalities in the risk of dying COVID-19-related death have changed between the first and early second wave of the epidemic in England.