bluuebunny/crossref_metadata_2025 huggingface dataset:
Protecting Healthcare Workers During the Coronavirus Disease 2019 (COVID-19) Outbreak: Lessons From Taiwan’s Severe Acute Respiratory Syndrome Response
Authors: Schwartz Jonathan , King Chwan-Chuen , Yen Muh-Yong
Published: March 2020

During major epidemic outbreaks, demand for healthcare workers (HCWs) grows even as the extreme pressures they face cause declining availability. We draw on Taiwan’s severe acute respiratory syndrome (SARS) experience to argue that a modified form of traffic control bundling (TCB) protects HCW safety and by extension strengthens overall coronavirus disease 2019 (COVID-19) epidemic control.
2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease
Authors: Mortensen Martin Bødtker , Nordestgaard Børge Grønne
Published: March 2020

Aims

The 2019 vs. 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines contains new recommendations for primary prevention with statins; however, the potential impact of these changes is unclear. We compared the 2019 and 2016 guidelines regarding statin eligibility and potential impact on prevention of atherosclerotic cardiovascular disease (ASCVD) in the general population.

Methods and results

We examined 45 750 individuals aged 40–75 from the Copenhagen General Population Study, all free of ASCVD and statin use at baseline. During the 9.2-year follow-up, 3337 experienced ASCVD (myocardial infarction, stroke, and cardiovascular death). For Class I/A recommendations, 32.3% (95% confidence interval: 31.8–32.7) and 15.4% (15.1–15.7) of individuals were statin eligible according to the 2019 and 2016 guidelines. The increased statin eligibility by the 2019 guidelines was explained by lower low-density lipoprotein cholesterol (LDL-C) thresholds alone (explaining 33.2%), older age range alone (49.4%), older age range in combination with lower LDL-C thresholds (14.7%), and updated SCORE risk algorithm (2.8%). If fully implemented, the estimated percentage of ASCVD events that can be prevented by using high-intensity statins for 10 years were 25% and 11% with the 2019 and 2016 guidelines. Mainly because of older age range in the 2019 guidelines, the corresponding estimated numbers needed to treat (NNT) to prevent one ASCVD event were 19 and 20.

Conclusion

Due to lower LDL-C threshold and older age range, the 2019 vs. 2016 ESC/EAS guidelines doubles the number of individuals eligible for primary prevention with statins. This considerably improves the potential for ASCVD prevention in the general population, with similar NNT to prevent one event.
Crustal domains in the Western Barents Sea
Authors: Shulgin Alexey , Faleide Jan Inge , Mjelde Rolf , Breivik Asbjørn , Huismans Ritske
Published: March 2020

The crustal architecture of the Barents Sea is still enigmatic due to complex evolution during the Timanian and Caledonian orogeny events, further complicated by several rifting episodes. In this study we present the new results on the crustal structure of the Caledonian–Timanian transition zone in the western Barents. We extend the work of Aarseth et al. (2017), by utilizing the seismic tomography approach to model Vp, Vs and Vp/Vs ratio, combined with the reprocessed seismic reflection line, and further complemented with gravity modelling. Based on our models we document in 3-D the position of the Caledonian nappes in the western Barents Sea. We find that the Caledonian domain is characterized by high crustal reflectivity, caused by strong deformation and/or emplacement of mafic intrusions within the crystalline crust. The Timanian domain shows semi-transparent crust with little internal reflectivity, suggesting less deformation. We find, that the eastern branch of the earlier proposed Caledonian suture, cannot be associated with the Caledonian event, but can rather be a relict from the Timanian terrane assemblance, marking one of the crustal microblocks. This crustal block may have an E–W striking southern boundary, along which the Caledonian nappes were offset. A high-velocity/density crustal body, adjacent to the Caledonian–Timanian contact zone, is interpreted as a zone of metamorphosed rocks based on the comparison with global compilations. The orientation of this body correlates with regional gravity maxima zone. Two scenarios for the origin of the body are proposed: mafic emplacement during the Timanian assembly, or massive mafic intrusions associated with the Devonian extension.
HNK-1 sulfotransferase modulates α-dystroglycan glycosylation by 3-O-sulfation of glucuronic acid on matriglycan
Authors: Sheikh M Osman , Venzke David , Anderson Mary E , Yoshida-Moriguchi Takako , Glushka John N , Nairn Alison V , Galizzi Melina , Moremen Kelley W , Campbell Kevin P , Wells Lance
Published: March 2020

Mutations in multiple genes required for proper O-mannosylation of α-dystroglycan are causal for congenital/limb-girdle muscular dystrophies and abnormal brain development in mammals. Previously, we and others further elucidated the functional O-mannose glycan structure that is terminated by matriglycan, [(-GlcA-β3-Xyl-α3-)n]. This repeating disaccharide serves as a receptor for proteins in the extracellular matrix. Here, we demonstrate in vitro that HNK-1 sulfotransferase (HNK-1ST/carbohydrate sulfotransferase) sulfates terminal glucuronyl residues of matriglycan at the 3-hydroxyl and prevents further matriglycan polymerization by the LARGE1 glycosyltransferase. While α-dystroglycan isolated from mouse heart and kidney is susceptible to exoglycosidase digestion of matriglycan, the functional, lower molecular weight α-dystroglycan detected in brain, where HNK-1ST expression is elevated, is resistant. Removal of the sulfate cap by a sulfatase facilitated dual-glycosidase digestion. Our data strongly support a tissue specific mechanism in which HNK-1ST regulates polymer length by competing with LARGE for the 3-position on the nonreducing GlcA of matriglycan.
DNA methylation QTL analysis identifies new regulators of human longevity
Authors: Szymczak Silke , Dose Janina , Torres Guillermo G , Heinsen Femke-Anouska , Venkatesh Geetha , Datlinger Paul , Nygaard Marianne , Mengel-From Jonas , Flachsbart Friederike , Klapper Wolfram , Christensen Kaare , Lieb Wolfgang , Schreiber Stefan , Häsler Robert , Bock Christoph , Franke Andre , Nebel Almut
Published: March 2020

Human longevity is a complex trait influenced by both genetic and environmental factors, whose interaction is mediated by epigenetic mechanisms like DNA methylation. Here, we generated genome-wide whole-blood methylome data from 267 individuals, of which 71 were long-lived (90–104 years), by applying reduced representation bisulfite sequencing. We followed a stringent two-stage analysis procedure using discovery and replication samples to detect differentially methylated sites (DMSs) between young and long-lived study participants. Additionally, we performed a DNA methylation quantitative trait loci analysis to identify DMSs that underlie the longevity phenotype. We combined the DMSs results with gene expression data as an indicator of functional relevance. This approach yielded 21 new candidate genes, the majority of which are involved in neurophysiological processes or cancer. Notably, two candidates (PVRL2, ERCC1) are located on chromosome 19q, in close proximity to the well-known longevity- and Alzheimer’s disease-associated loci APOE and TOMM40. We propose this region as a longevity hub, operating on both a genetic (APOE, TOMM40) and an epigenetic (PVRL2, ERCC1) level. We hypothesize that the heritable methylation and associated gene expression changes reported here are overall advantageous for the LLI and may prevent/postpone age-related diseases and facilitate survival into very old age.
Reflection on modern methods: generalized linear models for prognosis and intervention—theory, practice and implications for machine learning
Authors: Arnold Kellyn F , Davies Vinny , de Kamps Marc , Tennant Peter W G , Mbotwa John , Gilthorpe Mark S
Published: March 2020

Prediction and causal explanation are fundamentally distinct tasks of data analysis. In health applications, this difference can be understood in terms of the difference between prognosis (prediction) and prevention/treatment (causal explanation). Nevertheless, these two concepts are often conflated in practice. We use the framework of generalized linear models (GLMs) to illustrate that predictive and causal queries require distinct processes for their application and subsequent interpretation of results. In particular, we identify five primary ways in which GLMs for prediction differ from GLMs for causal inference: (i) the covariates that should be considered for inclusion in (and possibly exclusion from) the model; (ii) how a suitable set of covariates to include in the model is determined; (iii) which covariates are ultimately selected and what functional form (i.e. parameterization) they take; (iv) how the model is evaluated; and (v) how the model is interpreted. We outline some of the potential consequences of failing to acknowledge and respect these differences, and additionally consider the implications for machine learning (ML) methods. We then conclude with three recommendations that we hope will help ensure that both prediction and causal modelling are used appropriately and to greatest effect in health research.
Activity of cefiderocol against high-risk clones of multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia
Authors: Delgado-Valverde Mercedes , Conejo M del Carmen , Serrano Lara , Fernández-Cuenca Felipe , Pascual Álvaro
Published: March 2020

Background

Cefiderocol is a novel siderophore cephalosporin, developed for activity against MDR Gram-negative bacilli (MDR-GNB).

Objectives

To assess the in vitro antibacterial activity of cefiderocol against a collection of MDR-GNB clinical isolates from hospitals in southern Spain.

Methods

Two hundred and thirty-one isolates of successful clones were tested: 125 Enterobacterales (121 ESBL- and/or carbapenemase-producing Klebsiella pneumoniae and 4 carbapenemase-producing Enterobacter cloacae), 80 Acinetobacter baumannii, 6 Pseudomonas aeruginosa and 20 Stenotrophomonas maltophilia. Ceftolozane/tazobactam, ceftazidime, ceftazidime/avibactam, cefepime, aztreonam, meropenem, amikacin, ciprofloxacin, colistin and tigecycline were used as comparators against Enterobacterales, P. aeruginosa and A. baumannii. Minocycline, levofloxacin and trimethoprim/sulfamethoxazole were studied against S. maltophilia instead of aztreonam, ciprofloxacin and cefepime. MICs were determined by broth microdilution according to CLSI guidelines. MIC determination was performed in CAMHB for all antimicrobials except cefiderocol, where iron-depleted CAMHB was used.

Results

Cefiderocol showed potent in vitro activity against the isolates analysed. MIC50 and MIC90 values were in the ranges 0.125–8 mg/L and 0.5–8 mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed cefiderocol MICs of >4 mg/L: three ST2/OXA-24/40-producing A. baumannii, one ST114/VIM-1-producing E. cloacae and one ST114/VIM-1 + OXA-48-producing E. cloacae. All KPC-3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to ceftazidime/avibactam. P. aeruginosa isolates showed cefiderocol MICs of <4 mg/L, including those resistant to ceftolozane/tazobactam. S. maltophilia isolates displayed cefiderocol MICs of <4 mg/L, including those resistant to levofloxacin and/or trimethoprim/sulfamethoxazole.

Conclusions

Cefiderocol showed excellent activity against MDR-GNB, including carbapenem-resistant isolates, and was the most active antimicrobial tested against this collection.
Tailoring plant-associated microbial inoculants in agriculture: a roadmap for successful application
Authors: Saad Maged M , Eida Abdul Aziz , Hirt Heribert
Published: March 2020

Plants are now recognized as metaorganisms which are composed of a host plant associated with a multitude of microbes that provide the host plant with a variety of essential functions to adapt to the local environment. Recent research showed the remarkable importance and range of microbial partners for enhancing the growth and health of plants. However, plant–microbe holobionts are influenced by many different factors, generating complex interactive systems. In this review, we summarize insights from this emerging field, highlighting the factors that contribute to the recruitment, selection, enrichment, and dynamic interactions of plant-associated microbiota. We then propose a roadmap for synthetic community application with the aim of establishing sustainable agricultural systems that use microbial communities to enhance the productivity and health of plants independently of chemical fertilizers and pesticides. Considering global warming and climate change, we suggest that desert plants can serve as a suitable pool of potentially beneficial microbes to maintain plant growth under abiotic stress conditions. Finally, we propose a framework for advancing the application of microbial inoculants in agriculture.
Beneficial soil-borne bacteria and fungi: a promising way to improve plant nitrogen acquisition
Authors: Dellagi Alia , Quillere Isabelle , Hirel Bertrand
Published: March 2020

Nitrogen (N) is an essential element for plant productivity, thus, it is abundantly applied to the soil in the form of organic or chemical fertilizers that have negative impacts on the environment. Exploiting the potential of beneficial microbes and identifying crop genotypes that can capitalize on symbiotic associations may be possible ways to significantly reduce the use of N fertilizers. The best-known example of symbiotic association that can reduce the use of N fertilizers is the N2-fixing rhizobial bacteria and legumes. Bacterial taxa other than rhizobial species can develop associative symbiotic interactions with plants and also fix N. These include bacteria of the genera Azospirillum, Azotobacter, and Bacillus, some of which are commercialized as bio-inoculants. Arbuscular mycorrhizal fungi are other microorganisms that can develop symbiotic associations with most terrestrial plants, favoring access to nutrients in a larger soil volume through their extraradical mycelium. Using combinations of different beneficial microbial species is a promising strategy to boost plant N acquisition and foster a synergistic beneficial effect between symbiotic microorganisms. Complex biological mechanisms including molecular, metabolic, and physiological processes dictate the establishment and efficiency of such multipartite symbiotic associations. In this review, we present an overview of the current knowledge and future prospects regarding plant N nutrition improvement through the use of beneficial bacteria and fungi associated with plants, individually or in combination.
Inclusion Versus Exclusion in Intra-Orthodox Politics: Between Agudat Israel and Hungarian Orthodoxy*
Authors: Keren-Kratz Menachem
Published: March 2020

Ever since the concept of Jewish Orthodoxy emerged in the early-19th century, and especially after Jews were awarded equal civic rights in the 1860s, several religious leaders sought to establish Orthodox organizations. They, however, faced two main obstacles: first, the concept of an Orthodox organization was new to Jewish history and conservative rabbis automatically opposed anything new and condemned it as “modern.” Second, an Orthodox organization meant a religious jurisdiction superior to that of the local rabbis who were reluctant to give up the full authority they enjoyed. Following a long period of deterioration in the power and influence of the rabbis, local Orthodox organizations were established in Hungary, Galicia and Germany. In 1912, after the establishment of international movements by Reform rabbis, Maskilim, Jewish socialists, and finally the Zionists, leading Orthodox figures decided to establish the international Orthodox organization titled Agudat Israel. Recognizing its critical role in preserving traditional Judaism, individual rabbis and local Orthodox organizations from many countries joined Agudat Israel. The only country whose rabbis refused to join was Hungary. There, Jewish Orthodoxy enjoyed a special civil status and had its own separate communities. Seeking to maintain their distinct status, Hungarian leaders demanded that Agudat Israel declare itself an Orthodox organization and refrain from accepting Jews who belonged to non-Orthodox communities, who were lax in their religious conduct, or who supported Zionism. After deliberating the pros and cons, Agudat Israel decided to decline the “Hungarian demand” and, instead, to accept every Jew who wanted to join. Consequently, most Hungarian rabbis banned the organization. Nevertheless, the political and social circumstances following World War I drove some Hungarian rabbis and their communities to join Agudat Israel.
Spectral variability of a sample of extreme variability quasars and implications for the Mg iibroad-line region
Authors: Yang Qian , Shen Yue , Chen Yu-Ching , Liu Xin , Annis James , Avila Santiago , Bertin Emmanuel , Brooks David , Buckley-Geer Elizabeth , Carnero Rosell Aurelio , Carrasco Kind Matias , Carretero Jorge , da Costa Luiz , Desai Shantanu , Thomas Diehl H , Doel Peter , Frieman Josh , Garcia-Bellido Juan , Gaztanaga Enrique , Gerdes David , Gruen Daniel , Gruendl Robert , Gschwend Julia , Gutierrez Gaston , Hollowood Devon L , Honscheid Klaus , Hoyle Ben , James David , Krause Elisabeth , Kuehn Kyler , Lidman Christopher , Lima Marcos , Maia Marcio , Marshall Jennifer , Martini Paul , Menanteau Felipe , Miquel Ramon , Plazas Malagón Andrés , Sanchez Eusebio , Scarpine Vic , Schindler Rafe , Schubnell Michael , Serrano Santiago , Sevilla Ignacio , Smith Mathew , Soares-Santos Marcelle , Sobreira Flavia , Suchyta Eric , Swanson Molly , Tarle Gregory , Vikram Vinu , Walker Alistair
Published: March 2020

We present new Gemini/GMOS optical spectroscopy of 16 extreme variability quasars (EVQs) that dimmed by more than 1.5 mag in the g band between the Sloan Digital Sky Survey (SDSS) and the Dark Energy Survey epochs (separated by a few years in the quasar rest frame). These EVQs are selected from quasars in the SDSS Stripe 82 region, covering a redshift range of 0.5 < z < 2.1. Nearly half of these EVQs brightened significantly (by more than 0.5 mag in the g band) in a few years after reaching their previous faintest state, and some EVQs showed rapid (non-blazar) variations of greater than 1–2 mag on time-scales of only months. To increase sample statistics, we use a supplemental sample of 33 EVQs with multi-epoch spectra from SDSS that cover the broad Mg ii λ2798 line. Leveraging on the large dynamic range in continuum variability between the multi-epoch spectra, we explore the associated variations in the broad Mg ii line, whose variability properties have not been well studied before. The broad Mg ii flux varies in the same direction as the continuum flux, albeit with a smaller amplitude, which indicates at least some portion of Mg ii is reverberating to continuum changes. However, the full width at half-maximum (FWHM) of Mg ii does not vary accordingly as continuum changes for most objects in the sample, in contrast to the case of the broad Balmer lines. Using the width of broad Mg ii to estimate the black hole mass with single epoch spectra therefore introduces a luminosity-dependent bias.
Wave propagation in semiconvective regions of giant planets
Authors: Pontin C M , Barker A J , Hollerbach R , André Q , Mathis S
Published: March 2020

Recent observations of Jupiter and Saturn suggest that heavy elements may be diluted in the gaseous envelope, providing a compositional gradient that could stabilize ordinary convection and produce a stably stratified layer near the core of these planets. This region could consist of semiconvective layers with a staircase-like density profile, which have multiple convective zones separated by thin stably stratified interfaces, as a result of double-diffusive convection. These layers could have important effects on wave propagation and tidal dissipation that have not been fully explored. We analyse the effects of these layers on the propagation and transmission of internal waves within giant planets, extending prior work in a local Cartesian model. We adopt a simplified global Boussinesq planetary model in which we explore the internal waves in a non-rotating spherical body. We begin by studying the free modes of a region containing semiconvective layers. We then analyse the transmission of internal waves through such a region. The free modes depend strongly on the staircase properties, and consist of modes with both internal and interfacial gravity wave-like behaviour. We determine the frequency shifts of these waves as a function of the number of steps to explore their potential to probe planetary internal structures. We also find that wave transmission is strongly affected by the presence of a staircase. Very large wavelength waves are transmitted efficiently, but small-scale waves are only transmitted if they are resonant with one of the free modes. The effective size of the core is therefore larger for non-resonant modes.
Different modes of star formation – II. Gas accretion phase of initially subcritical star-forming clouds
Authors: Machida Masahiro N , Basu Shantanu
Published: March 2020

The accretion phase of star formation is investigated in magnetically dominated clouds that have an initial subcritical mass-to-flux ratio. We employ non-ideal magnetohydrodynamic simulations that include ambipolar diffusion and ohmic dissipation. During the early prestellar phase, the mass-to-flux ratio rises towards the critical value for collapse, and during this time the angular momentum of the cloud core is reduced significantly by magnetic braking. Once a protostar is formed in the core, the accretion phase is characterized by the presence of a small amount of angular momentum but a large amount of magnetic flux in the near-protostellar environment. The low angular momentum leads to a very small (or even non-existent) disc and weak outflow, while the large magnetic flux can lead to an interchange instability that rapidly removes flux from the central region. The effective magnetic braking in the early collapse phase can even lead to a counterrotating disc and outflow, in which the rotation direction of the disc and outflow is opposite to that of the infalling envelope. The solutions with a counterrotating disc, tiny disc, or non-existent disc (direct collapse) are unique outcomes that are realized in collapse from magnetically dominated clouds with an initial subcritical mass-to-flux ratio.
Blazhko effect in the Galactic bulge fundamental mode RR Lyrae stars – II. Modulation shapes, amplitudes, and periods
Authors: Skarka M , Prudil Z , Jurcsik J
Published: March 2020

The number of stars observed by the Optical Gravitational Lensing Experiment (OGLE) project in the Galactic bulge offers an invaluable chance to study RR Lyrae stars in a statistical manner. We used data of 3141 fundamental-mode RR Lyrae stars showing the Blazhko effect observed in OGLE-IV to investigate a possible connection between modulation amplitudes and periods, light curve, and pulsation characteristics. We found that there is no simple monotonic correlation between any combination of two parameters concerning the Blazhko and pulsation amplitudes, periods, and the shape of the light curves. There are only systematic limits. There is a bottom limit of the modulation period with respect to the pulsation period. We also found that the possible range of modulation amplitudes decreases with increasing pulsation period, which could point towards that the Blazhko effect is suppressed in cooler, larger, more luminous, and less metal abundant bulge RR Lyrae stars. Our investigation revealed that the distribution of the modulation periods can be described with two populations of stars with the mean modulation periods of 48 and 186  d. There is a certain region with a low density of the modulated stars, which we call the Blazhko valley, in the pulsation period–modulation period plane. Based on the similarity of the modulation envelopes, basically every star can be assigned to one of six morphological classes. The double modulation was found in 25 per cent of the studied stars. Only 6.3 per cent of modulated stars belong to the Oosterhoff group II.
X-ray properties of the X-CLASS-redMaPPer galaxy cluster sample: the luminosity–temperature relation
Authors: Molham Mona , Clerc Nicolas , Takey Ali , Sadibekova Tatyana , Morcos A B , Yousef Shahinaz , Hayman Z M , Lieu Maggie , Raychaudhury Somak , Gaynullina Evelina R
Published: March 2020

This article presents the results of a spectroscopic analysis of the X-CLASS-redMaPPer (XC1-RM) galaxy cluster sample. X-CLASS is a serendipitous search for clusters in X-ray wavebands based on the XMM–Newton archive, whereas redMaPPer is an optical cluster catalogue derived from the Sloan Digital Sky Survey (SDSS). The present sample comprises 92 X-ray extended sources identified in optical images within 1 arcmin separation. The area covered by the cluster sample is ∼ 27 deg2. The clusters span a wide redshift range (0.05 < z < 0.6) and 88 clusters benefit from spectrosopically confirmed redshifts using data from SDSS Data Release 14. We present an automated pipeline to derive the X-ray properties of the clusters in three distinct apertures: R500 (at fixed mass overdensity), Rfit (at fixed signal-to-noise ratio) and ${R}_{300\, {\rm kpc}}$ (fixed physical radius). The sample extends over wide temperature and luminosity ranges: from 1–10 keV and from 6 × 1042 to 11 × 1044 erg s−1, respectively. We investigate the luminosity–temperature (L–T) relation of the XC1-RM sample and find a slope equal to 3.03 ± 0.26. It is steeper than predicted by self-similar assumptions, in agreement with independent studies. A simplified approach is developed to estimate the amount and impact of selection biases that might be affecting our recoveredL–Tparameters. The result of this simulation process suggests that the measuredL–Trelation is biased to a steeper slope and higher normalization.
The haloes and environments of nearby galaxies (HERON) – II. The outer structure of edge-on galaxies
Authors: Mosenkov Aleksandr , Rich R Michael , Koch Andreas , Brosch Noah , Thilker David , Román Javier , Müller Oliver , Smirnov Anton , Usachev Pavel
Published: March 2020

The haloes and environments of nearby galaxies (HERON) project is aimed at studying haloes and low surface brightness (LSB) details near galaxies. In this second HERON paper, we consider in detail deep imaging (down to surface brightness of ∼28 mag arcsec−2 in the r band) for 35 galaxies, viewed edge-on. We confirm a range of LSB features previously described in the literature but also report new ones. We classify the observed outer shapes of the galaxies into three main types (and their prototypes): disc/diamond-like (NGC 891), oval (NGC 4302), and boxy (NGC 3628). We show that the shape of the outer disc in galaxies does not often follow the general 3D model of an exponential disc: 17 galaxies in our sample exhibit oval or even boxy isophotes at the periphery. Also, we show that the less flattened the outer disc, the more oval or boxy its structure. Many galaxies in our sample have an asymmetric outer structure. We propose that the observed diversity of the galaxy outer shapes is defined by the merger history and its intensity: if no recent multiple minor or single major merging took place, the outer shape is diamond-like or discy. On the contrary, interacting galaxies show oval outer shapes, whereas recent merging appears to transform the outer shape to boxy.
Introduction to immunotherapy for brain tumor patients: challenges and future perspectives
Authors: Montoya Megan L , Kasahara Noriyuki , Okada Hideho
Published: March 2020

Malignant gliomas, including glioblastoma (GBM) as the most aggressive type of adult CNS tumors, are notoriously resistant to current standard of care treatments, including surgery, systemic chemotherapy, and radiation therapy (RT). This lack of effective treatment options highlights the urgent need for novel therapies, including immunotherapies. The overarching goal of immunotherapy is to stimulate and activate the patient’s immune system in a targeted manner to kill tumor cells. The success of immunotherapeutic interventions in other cancer types has led to interest in and evaluation of various experimental immunotherapies in patients with malignant gliomas. However, these primary malignant brain tumors present a challenge because they exist in a vital and sensitive organ with a unique immune environment. The challenges and current status of experimental immunotherapeutic approaches, including vaccines, immune-checkpoint blockade, chimeric antigen receptor T-cell therapy, and oncolytic viruses will be discussed, as well as the potential for combinatorial therapies.
A Pilot Randomized Clinical Trial of Brief Interventions to Encourage Quit Attempts in Smokers From Socioeconomic Disadvantage
Authors: Steinberg Marc L , Rosen Rachel L , Versella Mark V , Borges Allison , Leyro Teresa M
Published: March 2020

Introduction

Cigarette smoking disproportionately affects communities of low socioeconomic status where greater smoking prevalence and poorer cessation rates have been observed. Utilizing brief evidence-based interventions to increase cessation attempts may be an effective and easily disseminable means by which to mitigate undue burden in this population.

Aims and Methods

The current intervention randomized daily smokers (N = 57) recruited from a local community soup kitchen to receive either Brief (eg, 30 m) Motivational Interviewing, Nicotine Replacement Therapy (NRT) sampling, or a Referral-Only intervention. Approximately half of participants (50.9%) reported not completing high school and many reported either just (41.4%) or not (40.4%) meeting basic expenses. Follow-up was completed approximately 1-month postintervention.

Results

Nonsignificant group differences indicated that participants randomized to the NRT sampling condition were more likely to make a quit attempt (moderate effect size). Approximately 40% of the sample reported making a serious quit attempt at follow-up. Significant differences in cigarettes per day at follow-up, controlling for baseline, were observed, with participants in the Motivational Interviewing condition, only, reporting significant reductions. Participants randomized to the NRT condition were significantly more likely to report using NRT patch and lozenge at follow-up (large effect). There were no differences between groups with respect to seeking behavioral support. Finally, we found that subjective financial strain moderated the effect of condition on change in cigarette consumption where NRT sampling was more effective for participants reporting less financial strain.

Conclusions

Findings provide initial evidence for personalizing brief interventions to promote quit attempts in low-income smokers.

Implications

While most clinical research on tobacco use and dependence focuses on successful sustained abstinence, the current study is novel because it examined three brief interventions designed to increase the number of quit attempts made by a nontreatment-seeking group suffering from health disparities (ie, smokers from socioeconomic disadvantage). These data suggest that nontreatment-seeking smokers from socioeconomic disadvantage can be influenced by Brief MIs and these interventions should be used to motivate smokers from socioeconomic disadvantage to make a quit attempt. Future studies should examine combined MIs including pharmacological and behavioral interventions.
Relapsing Uveitis due to Human T-lymphotropic Virus Type 1 in a Patient Living With HIV Diagnosed by Metagenomic Deep Sequencing
Authors: Phadke Varun K , Shantha Jessica G , O’Keefe Ghazala
Published: March 2020

HIV infection can result in vision loss from different causes, including HIV retinopathy and uveitis secondary to other infections, such as toxoplasmosis and viral retinitis. It is imperative to identify any infectious causes of uveitis to successfully treat the condition and prevent further vision loss. Metagenomic deep sequencing (MDS) is an emerging technology that presents an unbiased approach to the evaluation of clinical syndromes, including uveitis, that have not been diagnosed by pathogen-specific testing. Herein we present a case of a woman living with HIV with 11 years of relapsing bilateral uveitis refractory to systemic corticosteroid therapy who was diagnosed with human T-lymphotropic virus type 1 (HTLV-1)–associated uveitis by this technology. We also briefly review the literature of MDS as a diagnostic tool and the epidemiology, pathogenesis, and diagnosis of HTLV-1-associated uveitis.
Mitochondrial Pentatricopeptide Repeat Protein, EMB2794, Plays a Pivotal Role in NADH Dehydrogenase Subunit nad2 mRNA Maturation in Arabidopsis thaliana
Authors: Marchetti Fernanda , Cainzos Maximiliano , Shevtsov Sofía , Córdoba Juan Pablo , Sultan Laure Dora , Brennicke Axel , Takenaka Mizuki , Pagnussat Gabriela , Ostersetzer-Biran Oren , Zabaleta Eduardo
Published: March 2020

The Arabidopsis genome encodes >450 proteins containing the pentatricopeptide repeat (PPR) motif. The PPR proteins are classified into two groups, termed as P and P Long-Short (PLS) classes. Typically, the PLS subclass proteins are mainly involved in the RNA editing of mitochondrial and chloroplast transcripts, whereas most of the analyzed P subclass proteins have been mainly implicated in RNA metabolism, such as 5′ or 3′ transcript stabilization and processing, splicing and translation. Mutations of PPR genes often result in embryogenesis and altered seedling developmental defect phenotypes, but only a limited number of ppr mutants have been characterized in detail. In this report, we show that null mutations in the EMB2794 gene result in embryo arrest, due to altered splicing of nad2 transcripts in the Arabidopsis mitochondria. In angiosperms, nad2 has five exons that are transcribed individually from two mitochondrial DNA regions. Biochemical and in vivo analyses further indicate that recombinant or transgenic EMB2794 proteins bind to the nad2 pre-mRNAs in vitro as well as in vivo, suggesting a role for this protein in trans-splicing of nad2 intron 2 and possibly in the stability of the second pre-mRNA of nad2. Homozygous emb2794 lines, showing embryo-defective phenotypes, can be partially rescued by the addition of sucrose to the growth medium. Mitochondria of rescued homozygous mutant plants contain only traces of respiratory complex I, which lack the NADH-dehydrogenase activity.
Feeding and growth efficiency in a pelagic chaetognath, Zonosagitta nagae reared in the laboratory
Authors: Otake Shiori , Shimode Shinji , Takahashi Kazutaka
Published: March 2020

Chaetognaths are ubiquitous in the marine environment and are among the most abundant carnivorous plankton. Nevertheless, characterization of physiological parameters remains limited largely due to the difficulty in obtaining the data from pelagic chaetognaths in laboratory studies. This study therefore aimed to determine the feeding and growth rates of Zonosagitta nagae under laboratory rearing condition. A total of 54 field-collected chaetognaths with maturity Stage I and II ranging from 5 to 12 mm in body length collected in June, August and October were individually incubated at 20–22°C with excess copepod prey and growth parameters were obtained from 26 individuals that survived ~10–46 days. For Z. nagae, ingestion and growth rates increased with body dry weight, and both parameters were significantly related, indicating that gross growth efficiency was ~47%. Specific ingestion rates ranged from 0.03 to 0.43 d−1 and tended to decrease with an increase of size of the chaetognaths. Individual specific growth rate varied widely in small-sized individuals (~6 mm), ranging from −0.103 to 0.135, but became relatively constant (~0.032) with increasing size. Overall the study results suggest that Z. nagae is characterized by high gross growth efficiency, which is in striking contrast with previously studied inshore species.
Can Patient Expectations of Returning to Work Documented Before, During, or at the End of Treatment Predict Actual Return to Work Post-treatment? An Evidence-Based Structured Systematic Review
Authors: Fishbain David A , Pulikal Aditya
Published: March 2020

Background

There is significant evidence that patient expectations can impact their treatment outcomes. The hypothesis of this systematic review was then the following. There will be significant consistent evidence as specified by the Agency for Health Care Policy and Research (AHCPR) guidelines that chronic pain patient (CPP) expectations for returning to work documented before, during, or at the end of treatment will predict actual return to work post-treatment.

Methods

Of 316 references, 12 studies fulfilled inclusion criteria. These studies analyzed expectations of returning to work documented before, during, or at the end of treatment and utilized these for predicting return to work post-treatment. Relevant aspects of these studies were abstracted into tabular form for numerical analysis. All studies were rated independently by two reviewers for quality. The percentage of the 12 studies supporting the hypothesis was determined. This was then utilized to determine an AHCPR guideline rating for consistency.

Results

No studies had a rejection quality score. All studies were type 4. The hypothesis was supported by 91.6% of the studies. According to the AHCPR guidelines, this translated into an A rating: consistent findings from multiple type 4 studies.

Conclusions

CPP expectations of returning to work as documented before, during, or at the end of treatment may predict actual return to work post-treatment.
A systematic review exploring the evidence reported to underpin exercise dose in clinical trials of rheumatoid arthritis
Authors: Boniface Graham , Gandhi Varsha , Norris Meriel , Williamson Esther , Kirtley Shona , O’Connell Neil E
Published: March 2020

We aimed to evaluate the evidence reported to underpin exercise dose in randomised controlled trials (RCTs) using strengthening exercise in RA. We searched six different databases between 1 January 2000 and 3 April 2019. We included RCTs, where a main component of the intervention and/or control used strengthening exercise. Evidence sources cited to underpin dose were judged for their quality, consistency and applicability. Thirty-two RCTs were reviewed. Four (12.5%) piloted the intervention without using dose-escalation designs to determine optimal dose-response. Twenty (62.5%) reported no evidence underpinning dose. Where reported, quality, consistency and applicability of the underpinning evidence was a cause for methodological concern. The majority of RCTs did not report the evidence underpinning dose. When reported, the evidence was often not applicable to the clinical population. Frequently, the dose used differed to the dose reported/recommended by the underpinning evidence. Our findings illustrate exercise dose may not be optimised for use with clinical populations prior to evaluation by RCT.
DOES LOSS OF 131I COUNTS NEED CORRECTION IN GAMMA-CAMERA IMAGING IN CHILDREN AND YOUNG ADULTS IN POST-THERAPEUTIC SCANS? COMPARISON OF PHANTOM VERSUS PATIENT STUDY
Authors: Kumar Praveen , Bal Chandrasekhar , Damle Nishikant A , Dwivedi S N , Agarwala Sandeep
Published: March 2020

This study aimed to verify whether there is whole-body (WB) count loss due to dead time of gamma camera when high amount of 131I is administered to patients. Planar views of a phantom containing 5751 MBq of 131I were acquired at 24-h intervals for 68 d. Eighty-two patients ≤21 y old were given diagnostic activity (74 MBq) followed by therapeutic activity (1110–5772 MBq). WB scans of patients were acquired at 2 h after diagnostic and therapeutic activity administration. Count loss in patients and phantom were compared. In phantom, there was no count loss up to 139 MBq. At maximum activity of 5751 MBq 131I, the loss was 46%. In patients, the average WB count loss was insignificant after the administration of therapeutic activity. Count loss due to dead time in phantom differed significantly from patient results that can probably be explained by the distribution of activity over a large area in vivo.
Modeling multipartite virus evolution: the genome formula facilitates rapid adaptation to heterogeneous environments†
Authors: Zwart Mark P , Elena Santiago F
Published: March 2020

Multipartite viruses have two or more genome segments, and package different segments into different particle types. Although multipartition is thought to have a cost for virus transmission, its benefits are not clear. Recent experimental work has shown that the equilibrium frequency of viral genome segments, the setpoint genome formula (SGF), can be unbalanced and host-species dependent. These observations have reinvigorated the hypothesis that changes in genome-segment frequencies can lead to changes in virus-gene expression that might be adaptive. Here we explore this hypothesis by developing models of bipartite virus infection, leading to a threefold contribution. First, we show that the SGF depends on the cellular multiplicity of infection (MOI), when the requirements for infection clash with optimizing the SGF for virus-particle yield per cell. Second, we find that convergence on the SGF is very rapid, often occurring within a few cellular rounds of infection. Low and intermediate MOIs lead to faster convergence on the SGF. For low MOIs, this effect occurs because of the requirements for infection, whereas for intermediate MOIs this effect is also due to the high levels of variation generated in the genome formula (GF). Third, we explored the conditions under which a bipartite virus could outcompete a monopartite one. As the heterogeneity between environments and specificity of gene-expression requirements for each environment increased, the bipartite virus was more likely to outcompete the monopartite virus. Under some conditions, changes in the GF helped to exclude the monopartite competitor, highlighting the versatility of the GF. Our results show the inextricable relationship between MOI and the SGF, and suggest that under some conditions, the cost of multipartition can be outweighed by its benefits for the rapid tuning of viral gene expression.
Niche divergence corresponds to genetic differentiation within the parrot-beaked tortoiseHomopus areolatus(Reptilia: Testudinidae), endemic to South Africa
Authors: Hofmeyr Margaretha D , Ihlow Flora , Fouche Pierre , Daniels Savel R
Published: March 2020

We assessed genetic differentiation and habitat suitability for Homopus areolatus during current and Last Glacial Maximum (LGM) conditions. The ND4 locus retrieved two monophyletic mtDNA clades with lower diversity in clade 1, in the west, than in clade 2, in the south-east. Clade 1 showed a north–south and clade 2 a west-to-east genetic divergence, and the clades co-occur in the syntaxis zone of the Cape Fold Mountains. The clades occupy distinct niches with limited overlap. Rainfall seasonality contributed most to habitat suitability, with clade 1 being restricted to winter rainfall and clade 2 to all-year rainfall regions. Precipitation variables contributed 90% and 60%, respectively, to habitat suitability of clades 1 and 2, with temperature, particularly mean temperature of the driest quarter, being of greater importance for clade 2 than clade 1. Suitable habitat shrank from the LGM to current conditions, probably due to reduced rainfall in the west and higher temperatures in most regions. We conclude that patterns of genetic divergence are strongly associated with ecological niche divergence of H. areolatus clades. More studies are needed to assess the taxonomic status of clade 1, particularly in view of its shrinking habitat due to climate change and anthropogenic factors.
Sex Bias and Genotype Influence on Opioid Safety Profile in Chronic Low Back Pain
Authors: Margarit César , Roca Reyes , Inda María-del-Mar , Muriel Javier , Ballester Pura , Flor Andrea , Morales Domingo , Peiró Ana M.
Published: March 2020

Objectives:

The use of opioids to relieve pain is a challenge because of the high variability in dose requirements and tolerance profiles. Among potential modulators are the individual’s genetic background and being female. Our aim was to evaluate sex bias and genotype-related influence on opioid titration safety, in chronic low back pain (CLBP), the most frequent chronic noncancer pain.

Methods:

A 3-year prospective study was developed in opioid-naive CLBP patients. Data were self-reported by patients (pain [Visual Analogy Scale], adverse events [AEs], and health care resource utilization) and physicians (analgesic prescription, morphine equivalent daily dose, and suspected adverse drug reactions [ADRs]). Outcomes were analyzed as patients with AEs (case) or without (control) together with patients’ sex and genotype. Gene variants inOPRM1(rs1799971),COMT(rs4680),ABCB1(rs1045642),UGT2B7(rs12233719 and rs7438135),KCNJ6(rs2070995 and rs6517442), andCYP3A5*3(rs776746) were assessed. The hospital ethics committee approved the study, and statistical analyses were performed with R, v.3.2.4.

Results:

A total of 179 patients were included (64% female, mean pain intensity 73±16 mm), and 90% of them presented at least 1 AE (median of 3 (1 to 6) AEs/patient) with a rate of 5 AEs: 1 ADR without differences due to sex. However, there is a significant delay in referral of female patients (a mean of 6 years) to the Pain Unit, being significantly 3 to 5 times more likely to present sleep or psychiatric disorders. Meanwhile male individuals showed more sexual and reproductive system disorders. Genotypes influenced skin (COMT, G472A-GG) and gastrointestinal (ABCB1, C3435T-CC) related problems.

Conclusions:

Sex bias affects female patients resulting in a CLBP diagnostic delay and a different analgesic safety profile. Moreover, the individual’s genetic background might be useful to predict certain AEs in opioid-naive patients under an opioid titration procedure. Addressing sex in necessary to resolve inequalities in health care access.