bluuebunny/crossref_metadata_2025 huggingface dataset:
Late-time approaches to the Hubble tension deforming H(z), worsen the growth tension
Authors: Alestas George , Perivolaropoulos Leandros
Published: April 2021

Many late-time approaches for the solution of the Hubble tension use late time smooth deformations of the Hubble expansion rate H(z) of the Planck18/ΛCDM best fit to match the locally measured value of H0 while effectively keeping the comoving distance to the last scattering surface and Ω0mh2 fixed to maintain consistency with Planck CMB measurements. A well-known problem of these approaches is that they worsen the fit to low z distance probes. Here, we show that another problem of these approaches is that they worsen the level of the Ω0m − σ8 growth tension. We use the generic class of CPL parametrizations corresponding to evolving dark energy equation of state parameter $w(z)=w_0+w_1\frac{z}{1+z}$ with local measurements H0 prior and identify the pairs (w0, w1) that satisfy this condition. This is a generic class of smooth deformations of H(z) that are designed to address the Hubble tension. We show that for these models the growth tension between dynamical probe data and CMB constraints is worse than the corresponding tension of the standard Planck18/ΛCDM model. We justify this feature using a full numerical solution of the growth equation and fit to the data, as well as by using an approximate analytic approach. The problem does not affect recent proposed solutions of the Hubble crisis involving a SnIa intrinsic luminosity transition at zt ≃ 0.01.
The Three Hundred project: dynamical state of galaxy clusters and morphology from multiwavelength synthetic maps
Authors: De Luca Federico , De Petris Marco , Yepes Gustavo , Cui Weiguang , Knebe Alexander , Rasia Elena
Published: April 2021

We study the connection between morphology and dynamical state of the simulated galaxy clusters in z ∈ [0, 1.031] from The Three Hundred project. We quantify cluster dynamical state using a combination of dynamical indicators from theoretical measures and compare this combined parameter, χ, with the results from morphological classifications. The dynamical state of the cluster sample shows a continuous distribution from dynamically relaxed, more abundant at lower redshift, to hybrid and disturbed. The dynamical state presents a clear dependence on the radius, with internal regions more relaxed than outskirts. The morphology from multiwavelength mock observation of clusters in X-ray, optical, and Sunyaev–Zel’dovich (SZ) effect images is quantified by M – a combination of six parameters for X-ray and SZ maps and the offsets between the optical position of the brightest cluster galaxy (BCG) and the X-ray/SZ centroids. All the morphological parameters are highly correlated with each other, while they show a moderately strong correlation with the dynamical χ parameter. The X-ray or SZ peaks are less affected by the dynamical state than centroids, which results in reliable tracers of the cluster density peak. The principal source of contamination in the relaxed cluster fraction, inferred from morphological parameters, is due to dynamically hybrid clusters. Compared to individual parameters, which consider only one aspect of cluster property (e.g. only clumping or asymmetry), the combined morphological and dynamical parameters (M and χ) collect more information and provide a single and more accurate estimation of the cluster dynamical state.
Stellar substructures in the periphery of the Magellanic Clouds with the VISTA hemisphere survey from the red clump and other tracers
Authors: El Youssoufi Dalal , Cioni Maria-Rosa L , Bell Cameron P M , de Grijs Richard , Groenewegen Martin A T , Ivanov Valentin D , Matijevĭc Gal , Niederhofer Florian , Oliveira Joana M , Ripepi Vincenzo , Schmidt Thomas , Subramanian Smitha , Sun Ning-Chen , van Loon Jacco Th
Published: April 2021

We study the morphology of the stellar periphery of the Magellanic Clouds in search of substructure using near-infrared imaging data from the Visible and Infrared Survey Telescope for Astronomy Hemisphere Survey. Based on the selection of different stellar populations using the (J − Ks, Ks) colour–magnitude diagram, we confirm the presence of substructures related to the interaction history of the Clouds and find new substructures on the eastern side of the LMC disc, which may be owing to the influence of the Milky Way, and on the northern side of the SMC, which is probably associated with the ellipsoidal structure of the galaxy. We also study the luminosity function of red clump stars in the SMC and confirm the presence of a bi-modal distance distribution, in the form of a foreground population. We find that this bi-modality is still detectable in the eastern regions of the galaxy out to a 10○ distance from its centre. Additionally, a background structure is detected in the North between 7○ and 10○ from the centre that might belong to the Counter Bridge, and a foreground structure is detected in the South between 6○ and 8○ from the centre that might be linked to the Old Bridge.
An HST/STIS view of protoplanetary discs in Upper Scorpius: observations of three young M stars
Authors: Walker Sam , Millar-Blanchaer Maxwell Andrew , Ren Bin , Kalas Paul , Carpenter John
Published: April 2021

We present observations of three protoplanetary discs in visible scattered light around M-type stars in the Upper Scorpius OB association using the Space Telescope Imaging Spectrograph (STIS) instrument on the Hubble Space Telescope (HST). The discs around stars 2MASS J16090075–1908526, 2MASS J16142029–1906481, and 2MASS J16123916–1859284 have all been previously detected with the Atacama Large Millimeter/submillimeter Array (ALMA), and 2MASS J16123916–1859284 has never previously been imaged at scattered light wavelengths. We process our images using reference star differential imaging, comparing and contrasting three reduction techniques – classical subtraction, Karhunen–Loève Image Projection, and non-negative matrix factorization, selecting the classical method as the most reliable of the three for our observations. Of the three discs, two are tentatively detected (2MASS J16142029–1906481 and 2MASS J16123916–1859284), with the third going undetected. Our two detections are shown to be consistent when varying the reference star or reduction method used, and both detections exhibit structure out to projected distances of ≳200 au. Structures at these distances from the host star have never been previously detected at any wavelength for either disc, illustrating the utility of visible-wavelength observations in probing the distribution of small dust grains at large angular separations.
Systematic identification of A-to-I RNA editing in zebrafish development and adult organs
Authors: Buchumenski Ilana , Holler Karoline , Appelbaum Lior , Eisenberg Eli , Junker Jan Philipp , Levanon Erez Y
Published: April 2021

A-to-I RNA editing is a common post transcriptional mechanism, mediated by the Adenosine deaminase that acts on RNA (ADAR) enzymes, that increases transcript and protein diversity. The study of RNA editing is limited by the absence of editing maps for most model organisms, hindering the understanding of its impact on various physiological conditions. Here, we mapped the vertebrate developmental landscape of A-to-I RNA editing, and generated the first comprehensive atlas of editing sites in zebrafish. Tens of thousands unique editing events and 149 coding sites were identified with high-accuracy. Some of these edited sites are conserved between zebrafish and humans. Sequence analysis of RNA over seven developmental stages revealed high levels of editing activity in early stages of embryogenesis, when embryos rely on maternal mRNAs and proteins. In contrast to the other organisms studied so far, the highest levels of editing were detected in the zebrafish ovary and testes. This resource can serve as the basis for understanding of the role of editing during zebrafish development and maturity.
miRMaster 2.0: multi-species non-coding RNA sequencing analyses at scale
Authors: Fehlmann Tobias , Kern Fabian , Laham Omar , Backes Christina , Solomon Jeffrey , Hirsch Pascal , Volz Carsten , Müller Rolf , Keller Andreas
Published: April 2021

Analyzing all features of small non-coding RNA sequencing data can be demanding and challenging. To facilitate this process, we developed miRMaster. After the analysis of over 125 000 human samples and 1.5 trillion human small RNA reads over 4 years, we present miRMaster 2 with a wide range of updates and new features. We extended our reference data sets so that miRMaster 2 now supports the analysis of eight species (e.g. human, mouse, chicken, dog, cow) and 10 non-coding RNA classes (e.g. microRNAs, piRNAs, tRNAs, rRNAs, circRNAs). We also incorporated new downstream analysis modules such as batch effect analysis or sample embeddings using UMAP, and updated annotation data bases included by default (miRBase, Ensembl, GtRNAdb). To accommodate the increasing popularity of single cell small-RNA sequencing data, we incorporated a module for unique molecular identifier (UMI) processing. Further, the output tables and graphics have been improved based on user feedback and new output formats that emerged in the community are now supported (e.g. miRGFF3). Finally, we integrated differential expression analysis with the miRNA enrichment analysis tool miEAA. miRMaster is freely available at https://www.ccb.uni-saarland.de/mirmaster2.
mmCSM-PPI: predicting the effects of multiple point mutations on protein–protein interactions
Authors: Rodrigues Carlos H M , Pires Douglas E V , Ascher David B
Published: April 2021

Protein–protein interactions play a crucial role in all cellular functions and biological processes and mutations leading to their disruption are enriched in many diseases. While a number of computational methods to assess the effects of variants on protein–protein binding affinity have been proposed, they are in general limited to the analysis of single point mutations and have been shown to perform poorly on independent test sets. Here, we present mmCSM-PPI, a scalable and effective machine learning model for accurately assessing changes in protein–protein binding affinity caused by single and multiple missense mutations. We expanded our well-established graph-based signatures in order to capture physicochemical and geometrical properties of multiple wild-type residue environments and integrated them with substitution scores and dynamics terms from normal mode analysis. mmCSM-PPI was able to achieve a Pearson's correlation of up to 0.75 (RMSE = 1.64 kcal/mol) under 10-fold cross-validation and 0.70 (RMSE = 2.06 kcal/mol) on a non-redundant blind test, outperforming existing methods. Our method is freely available as a user-friendly and easy-to-use web server and API at http://biosig.unimelb.edu.au/mmcsm_ppi.
Folding and persistence times of intramolecular G-quadruplexes transiently embedded in a DNA duplex
Authors: Tran Phong Lan Thao , Rieu Martin , Hodeib Samar , Joubert Alexandra , Ouellet Jimmy , Alberti Patrizia , Bugaut Anthony , Allemand Jean-François , Boulé Jean-Baptiste , Croquette Vincent
Published: April 2021

G-quadruplex (G4) DNA structures have emerged as important regulatory elements during DNA metabolic transactions. While many in vitro studies have focused on the kinetics of G4 formation within DNA single-strands, G4 are found in vivo in double-stranded DNA regions, where their formation is challenged by the complementary strand. Since the energy of hybridization of Watson-Crick structures dominates the energy of G4 folding, this competition should play a critical role on G4 persistence. To address this, we designed a single-molecule assay allowing to measure G4 folding and persistence times in the presence of the complementary strand. We quantified both folding and unfolding rates of biologically relevant G4 sequences, such as the cMYC and cKIT oncogene promoters, human telomeres and an avian replication origin. We confirmed that G4s are found much more stable in tested replication origin and promoters than in human telomere repeats. In addition, we characterized how G4 dynamics was affected by G4 ligands and showed that both folding rate and persistence time increased. Our assay opens new perspectives for the measurement of G4 dynamics in double-stranded DNA mimicking a replication fork, which is important to understand their role in DNA replication and gene regulation at a mechanistic level.
Minimized combinatorial CRISPR screens identify genetic interactions in autophagy
Authors: Diehl Valentina , Wegner Martin , Grumati Paolo , Husnjak Koraljka , Schaubeck Simone , Gubas Andrea , Shah Varun Jayeshkumar , Polat Ibrahim H , Langschied Felix , Prieto-Garcia Cristian , Müller Konstantin , Kalousi Alkmini , Ebersberger Ingo , Brandts Christian H , Dikic Ivan , Kaulich Manuel
Published: April 2021

Combinatorial CRISPR-Cas screens have advanced the mapping of genetic interactions, but their experimental scale limits the number of targetable gene combinations. Here, we describe 3Cs multiplexing, a rapid and scalable method to generate highly diverse and uniformly distributed combinatorial CRISPR libraries. We demonstrate that the library distribution skew is the critical determinant of its required screening coverage. By circumventing iterative cloning of PCR-amplified oligonucleotides, 3Cs multiplexing facilitates the generation of combinatorial CRISPR libraries with low distribution skews. We show that combinatorial 3Cs libraries can be screened with minimal coverages, reducing associated efforts and costs at least 10-fold. We apply a 3Cs multiplexing library targeting 12,736 autophagy gene combinations with 247,032 paired gRNAs in viability and reporter-based enrichment screens. In the viability screen, we identify, among others, the synthetic lethal WDR45B-PIK3R4 and the proliferation-enhancing ATG7-KEAP1 genetic interactions. In the reporter-based screen, we identify over 1,570 essential genetic interactions for autophagy flux, including interactions among paralogous genes, namely ATG2A-ATG2B, GABARAP-MAP1LC3B and GABARAP-GABARAPL2. However, we only observe few genetic interactions within paralogous gene families of more than two members, indicating functional compensation between them. This work establishes 3Cs multiplexing as a platform for genetic interaction screens at scale.
Recurrent Chordoma Resection in the Advanced Multimodality Image Guided Operating Suite: 2-Dimensional Operative Video
Authors: Ibn Essayed Walid , Almefty Kaith K , Al-Mefty Ossama
Published: April 2021

Recurrent skull base chordomas are challenging lesions. They already had maximum radiation, and in the absence of any effective medical treatment, surgical resection is the only treatment.
1,2
Surgery on recurrent previously radiated chordomas, however, carries much higher risk and the likelihood of subtotal resection. Maximizing tumor resection allows longer tumor control.
3-5
The Advanced Multimodality Image Guided Operating Suite developed at the Brigham and Women's Hospital, Harvard Medical School, with the support of the National Institutes of Health, provides an optimal environment to manage these tumors. It offers the capability to obtain and integrate multiple modalities during surgery, including magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), endoscopy, ultrasound, fluoroscopy, and the ability to perform emergent endovascular procedures.
5-7

The patient is a 39-yr-old male, presenting after 19 yr follow-up of a surgical resection and proton beam treatment for a skull base chordoma. He developed progressive ophthalmoplegia due to recurrence of his chordoma at the right petrous apex and cavernous sinus. Preoperative angiography demonstrated narrowing of the petrous segment of the right carotid artery suspect of radiation-induced angiopathy. The presence of radiation-induced angiopathy increases the risk of intraoperative carotid rupture, and the availability of endovascular intervention in the operative suite added favorable preparedness to deal with such complications if they happen. Given the clinical and radiological progression, surgical intervention was carried out through the prior zygomatic approach with the goal of performing maximum resection.
8
The patient had an uneventful postoperative course and remained stable until he had a second recurrence 4 yr later. The patient consented to the procedure.
On the Theory of Instrumentation (1985)
Authors: Dahlhaus Carl
Published: April 2021

In this essay, originally published in 1985, Carl Dahlhaus addresses the problem of how to integrate timbre into our understanding of music while honoring its resistance to description and quantification. In particular, he explores the history of orchestration in terms of an opposition between “coloristic” and “structural instrumentation,” the latter defined as that which “actively intervenes in the compositional logic [Tonsatz] of the music, rather than being merely dependent on it.” Dahlhaus’ essay is grounded squarely in the common-practice era: his compositional points of reference span from Haydn to Richard Strauss, and he is particularly concerned with how instrumentation can reveal structural patterns that stand athwart the formal trajectories suggested by tonal analyses.
Research with Human Participants in the European Union
Authors: Shaw David , Townend David
Published: April 2021

This chapter examines research with human participants in the European Union. In the EU, the driving force for legislation is the creation of the single market. Research with human participants is both a response to the urgent demand to advance the health of EU citizens through the efficiencies of the single market, and to the commitment of the EU to act in accordance with the shared social and cultural values of the Member States. One might expect, therefore, that EU legislation on research with human participants would be clear, creating a harmonized framework within the single market both for internal consistency and to enhance external competitiveness. However, each of the 27 Member States of the EU operates with a large amount of independence in relation to the governance of research with human participants. The chapter then describes the EU legislation on clinical trials and considers the protection of privacy through the General Data Protection Regulation.
Meaning and Value Across the Generations
Authors: Scheffler Samuel
Published: April 2021

This chapter argues that our relations to our successors are richer, more varied, and more complex than is sometimes recognized. Although we cannot in any straightforward sense interact or form personal relationships with people who will live long after we have died, future generations nevertheless matter greatly to us and in a variety of ways. These facts, which reflect our underappreciated historicist sensibility, must be taken into account in developing an adequate theory of intergenerational ethics. They are also facts of great motivational significance. To ensure the survival of humanity, sufficient numbers of people must be strongly and stably motivated to solve the problems that threaten future generations, and people’s sense of moral obligation may not, by itself, be sufficiently robust or reliable to provide all the necessary motivational support. So one challenge we face, in seeking to address problems like climate change and nuclear proliferation, is to overcome this potentially disabling motivational deficit. Yet once one appreciates the complexity of our attitudes toward future generations, one can see that we have a variety of reasons for caring about the fate of our successors. These reasons provide additional motivational resources that may complement and cooperate with our distinctively moral motivations for addressing threats to future generations.
Rethinking Representations of Trade Unionism in South Africa
Authors: Naicker Camalita
Published: April 2021

This essay reviews the literature on trade unions in South Africa in the last century. It points to some of its limitations seeking to challenge narrow conceptions and worn binaries of worker resistance and trade unionism, spontaneity and organization, that still plague some histories of labor and labor unions. It therefore attempts to review the literature in a way that opens up new readings and theoretical perspectives on labor and trade unions. It seeks to show how migrant and women’s organizing continue to be two areas that the literature has not adequately grasped. That women have often organized themselves outside of unions and dominant political structures implies that there is broad scope for theoretical perspectives that challenge masculine notions of organizing and institutional culture. In addition, there needs to be more attention paid to the issue that migrant members of unions themselves are finding more expression for their grievances outside of trade union bureaucratic structures. Moreover, in a country such as South Africa, with extremely high unemployment in a global economy of fewer and fewer jobs, it is necessary to ask whether the notion of industrial unionism, which has for so long excluded those on the margins of the so-called formal economy, is still viable, or whether new forms of organizing that are more cognizant of the local and global interconnectedness of all spheres of the economy, beyond the public/private divide, must be sought. In order for these perspectives to emerge, however, it is necessary to rethink the categories that people impose on history and how it limits future possibilities.
Digital Youth Politics
Authors: Earl Jennifer , Scovill Sam , Ramo Elliot
Published: April 2021

The authors examine the debate over youth engagement as it has developed since 1990, especially the role of digital and social media. Despite panics over youth disengagement and the pervasiveness of the youth deficit model, contemporary research largely finds that young people are politically engaged, that new media facilitate youth engagement, and that new media usage tends to reduce inequalities between youth in political engagement. Beyond these general findings, the authors also examine how youth use digital and social media in the development of political knowledge and interest and when participating in campaigns and elections, social movements and protest, political consumption (e.g., boycotts and buycotts), and participatory politics (i.e., traditional and new forms of engagement such as making cultural interventions and circulating information and opinions). For each form of engagement, the authors also assess the role of digital and social media usage in making engagement more inclusive and equitable. The authors close by introducing evidence-based resources that young people have access to online to aid their engagement and thoughts about future research.
Normative and Legal Pluralism: A Global Perspective
Authors: Twining William
Published: April 2021

This chapter sets out to demystify the topic of legal pluralism by examining the relationship between legal pluralism, normative pluralism, and general normative theory from a global perspective. The central theme is that treating legal pluralism as a species of normative pluralism decenters the state, links legal pluralism to a rich body of literature, and helps to show that some of the central puzzlements surrounding the topic can usefully be viewed as much broader issues in the general theory of norms and legal theory. A second theme is that so-called “global legal pluralism” is in several respects qualitatively different from the older anthropological and sociolegal accounts of legal pluralism and is largely based on a different set of concerns. Following the introduction in section I, section II considers normative pluralism. It explores the ambiguity of “pluralism” and some themes in general normative theory. Section III introduces the heritage of literature on legal pluralism. It presents an ideal type of social fact legal pluralism to which much, but by no means all, of the mainstream literature approximates. Some brief case studies illustrate some distinctions that are increasingly under attack. Section III suggests that social fact pluralism has achieved much in raising awareness of nonstate normative orders, but provides little guidance on issues of state policy and institutional design. Section IV considers the implications of adopting a global perspective in this context. It questions how far social fact legal pluralism is helpful in addressing a wide range of concerns raised by “globalization” and argues that the radically ambiguous idea of “global legal pluralism” is being applied to such a variety of phenomena and concerns as to be virtually meaningless.
Reclaiming Sovereignty: Resistance to Transnational Authority and the Investor-State Regime
Authors: Cutler A. Claire
Published: April 2021

This chapter focuses upon the contesting social forces seeking to reclaim national control over processes of investor-protection. The investor-state regime constitutes a form of transnational authority that is reconfiguring state sovereignty in the world and creating a new constitutionalism by delocalizing and denationalizing the regulation of foreign direct investment. Indeed, this regime plays an integral role in the operation of contemporary capitalism by disrupting conventional understandings and practices of sovereignty, but this is obscured by the theories underpinning these conventions. Adopting a critical political economy approach, the analysis places politics at the center of analysis by questioning “who gets what” from transnational law. It challenges conventional approaches to transnational law for obscuring the powerful corporate forces that are driving the regime and eroding democracy by facilitating the loss of national sovereignty. However, growing resistance to the regime suggests the emergence of a new form of sovereignty: transnational sovereignty.
Cybercultures
Authors: Johansson Sverker , Lindberg Ylva
Published: April 2021

This chapter aims to describe how cultures have emerged in interactions among users of the multitude of online platforms that have become available over the past few decades. It discusses innovations regarding uses of representations to communicate identity, time, and space in social practices with technology, and how cybercultures are played out in theory and in practice. Cybercultures resemble cultures in the non-virtual world—but display significant differences regarding social rules, identity, and spatiotemporal issues. Case studies of three types of cybercultures in social media: information and knowledge building on Wikipedia, culture, and virtual world building on Second Life, and dating practices on online dating services, such as Tinder, will shed light on how cyberspace allows for developing both symbolic representations and social practices through computer-mediated communication (CMC), and how users are situated in the continuum virtual-real.
How to Tell a Slave
Authors: duBois Page
Published: April 2021

After pointing out the significant differences between ancient slavery and modern racialized slavery, this chapter considers the manifold difficulties entailed in distinguishing between enslaved and free persons in the ancient Greek and Roman worlds. It stresses the social, economic, and legal importance of maintaining these distinctions even as it acknowledges their elusive nature. It goes on to describe the ways in which behaviours, bodies—often scarred or tattooed, sometimes tortured—dress, disguise, names, and language, revealed or disguised the status of enslaved persons. It ends with a brief discussion of a dramatic text that stages the complexities of policing the boundaries between enslaved and free persons.
The Precautionary Principle in Zoonotic Disease Control
Authors: van Herten J , Bovenkerk B
Published: April 2021

The COVID-19 pandemic has shown that zoonotic diseases are a great threat for humanity. During the course of such a pandemic, public health authorities often apply the precautionary principle to justify disease control measures. However, evoking this principle is not without ethical implications. Especially within a One Health strategy, that requires us to balance public health benefits against the health interests of animals and the environment, unrestricted use of the precautionary principle can lead to moral dilemmas. In this article, we analyze the ethical dimensions of the use of the precautionary principle in zoonotic disease control and formulate criteria to protect animals and the environment against one-sided interpretations. Furthermore, we distinguish two possible conceptions of the precautionary principle. First, we notice that because of the unpredictable nature of zoonotic diseases, public health authorities in general focus on the idea of precaution as preparedness. This reactive response often leads to difficult trade-offs between human and animal health. We therefore argue that this policy should always be accompanied by a second policy, that we refer to as precaution as prevention. Although zoonotic diseases are part of our natural world, we have to acknowledge that their origin and global impact are often a consequence of our disturbed relation with animals and the environment.
Association of adalimumab trough concentrations and treatment response in patients with juvenile idiopathic arthritis
Authors: Doeleman Martijn J H , de Roock Sytze , El Amrani Mohsin , van Maarseveen Erik M , Wulffraat Nico M , Swart Joost F
Published: April 2021

Objective

The objective of this study was to assess the relationship between adalimumab trough concentrations and treatment response in paediatric patients with JIA.

Methods

This was a monocentric cohort study of JIA patients treated with adalimumab. Clinical data and samples were collected during routine follow-up. Adalimumab trough concentrations were quantified by a novel liquid chromatography–tandem mass spectrometry assay. Anti-adalimumab antibodies were measured in samples with trough concentrations of ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis DAS with 71-joint count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines.

Results

A total of 35 adalimumab trough samples were available from 34 paediatric patients with JIA. Although there was no significant difference in adalimumab dose, trough concentrations were significantly lower in patients with secondary failure [median 1.0 mg/l; interquartile range (IQR) 1.0–5.3] compared with patients with primary failure (median 13.97 mg/l; IQR 11.81–16.67) or an adequate response (median 14.94 mg/l; IQR 10.31–16.19) to adalimumab.

Conclusion

Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Our results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.
Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors
Authors: Fleischmann Roy , Genovese Mark C , Maslova Karina , Leher Henry , Praestgaard Amy , Burmester Gerd R
Published: April 2021

Objective

The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis).

Methods

Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators’ judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive.

Results

Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years’ exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years’ follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg.

Conclusion

In patients with RA refractory to TNFi, sarilumab’s long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years.

Trial registration

TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.
Polymorphism of genetic ambigrams
Authors: Dudas Gytis , Huber Greg , Wilkinson Michael , Yllanes David
Published: April 2021

Double synonyms in the genetic code can be used as a tool to test competing hypotheses regarding ambigrammatic narnavirus genomes. Applying the analysis to recent observations of Culex narnavirus 1 and Zhejiang mosquito virus 3 ambigrammatic viruses indicates that the open reading frame on the complementary strand of the segment coding for RNA-dependent RNA polymerase does not code for a functional protein. Culex narnavirus 1 has been shown to possess a second segment, also ambigrammatic, termed ‘Robin’. We find a comparable segment for Zhejiang mosquito virus 3, a moderately diverged relative of Culex narnavirus 1. Our analysis of Robin polymorphisms suggests that its reverse open reading frame also does not code for a functional protein. We make a hypothesis about its role.
Oil Price Shocks and Civil Conflict: Evidence from Nigeria
Authors: Nwokolo Arinze
Published: April 2021

When and for what reason do governments choose to monopolize violence and consolidate power? Theory suggests three channels: when the government has coercive power against the opposition, if it shifts the distribution of power in its favor, and when contingent spoils are large. Using international oil price shocks and a novel dataset on oil-producing local government areas, this article examines how commodity prices affect civil conflict in Nigeria. Results show that a rise in oil price leads to a more than proportionate increase in government attacks on rebel groups in the oil region. The findings are consistent with the theoretical predictions: positive oil price shocks increase the monopoly of violence by the government through an increase in coercion, a rise in regaining territories from rebel groups, and an increase of violence in areas with large oil fields.
Diabetic Foot Amputation Prevention During COVID-19
Authors: Shankhdhar Kshitij
Published: April 2021

In this case report, the treatment of a patient with a diabetic foot ulcer on his left foot was interrupted by the novel coronavirus 2019 pandemic lockdown in India. The author guided the patient via telephone and online services. Based on the history given by the patient, the lesion started as blistering from improperly fitted footwear that then evolved into multiple infected ulcerations on the dorsal surface of the great toe (osteomyelitis with septic arthritis of the joint). Based on a radiograph and other photographs of the foot lesions, the author prescribed amoxicillin/clavulanic acid in combination with linezolid for 2 weeks. Further, the author guided the patient to dress the wound at home using a medical-grade honey-based product. With no option for an outpatient visit, the author guided the patient to use a plastic ruler and place it below the toe during each dressing. Healing (complete epithelialization) was achieved within 4 weeks.
Virtual reality for pediatric periprocedural care
Authors: Wang Ellen , Thomas James J. , Rodriguez Samuel T. , Kennedy Kristin M. , Caruso Thomas J.
Published: April 2021

Purpose of review

Commercial availability of virtual reality headsets and software has exponentially grown over the last decade as it has become more sophisticated, less expensive, and portable. Although primarily used by the general public for entertainment, virtual reality has been adopted by periprocedural clinicians to improve patient experiences and treatments. The purpose of this review is to explore recently reported evidence for virtual reality effectiveness for pediatric periprocedural care and discuss considerations for clinical implementation.

Recent findings

In the preprocedure setting, practitioners use virtual reality to introduce children to periprocedural environments, distract attention from preprocedural vascular access, and increase cooperation with anesthesia induction. Intraprocedure, virtual reality decreases sedation requirements, and in some instances, eliminates anesthesia for minor procedures. Virtual reality also augments pain reduction therapies in the acute and extended rehabilitation periods, resulting in faster recovery and improved outcomes. Virtual reality seems to be well treated for pediatric use, given close clinical care and carefully curated content.

Given the multiple clinical applications of virtual reality to supplement pediatric periprocedural care, practitioners should consider developing clinical programs that reliably provide access to virtual reality. Future research should focus on identification of patient characteristics and types of software that yield optimal patient outcomes.
Peripartum considerations in sickle cell disease
Authors: Ezihe-Ejiofor Ada , Jackson Jaleesa
Published: April 2021

Purpose of review

Pregnancy exacerbates sickle cell disease (SCD) and is associated with increased frequency and severity of complications resulting in high levels of maternal and fetal morbidity and mortality. We review recent recommendations for managing SCD in pregnancy.

Recent findings

An updated pathobiological model of SCD now attributes the clinical picture to a vicious cycle of four major cellular disturbances. Management decisions should be guided by an understanding of this upgraded model. Red cell transfusions are a key therapeutic intervention used in managing several acute and chronic complications. Transfusion however has significant drawbacks. The American Society of Hematology recently published transfusion guidelines to support care providers.

Patients should be managed by a multidisciplinary and experienced team. The perioperative episode is a recognized period of disease exacerbation and informed anesthetic management can contribute to improved patient outcomes.
Perioperative frailty: lessons learned and future directions
Authors: Adeleke Ibukunoluwa , Blitz Jeanna
Published: April 2021

Purpose of review

As the surgical population ages, preoperative diagnosis and optimization of frailty becomes increasingly important. Various concepts are used to define frailty, and several tools have been validated for use in the perioperative period. This article reviews current conceptual frameworks of frailty, references current literature and provides a practical approach to the preoperative frailty assessment with a focus on potential interventions.

Recent findings

A multipronged approach toward preoperative optimization should be used in patients with frailty syndrome. Oral protein supplementation and immunonutrition therapy can reduce complications in patients with malnutrition. Initiating a preoperative physical exercise regimen may mitigate frailty. Nonpharmacologic interventions to reduce preoperative anxiety and improve mood are effective, low-cost adjuncts associated with improvement in postoperative outcomes. Engaging in shared decision making is a critical component of the preoperative evaluation of frail patients.

Emerging evidence suggests that frailty may be mitigated with patient-specific, multidimensional preoperative interventions, thus potentially improving postoperative outcomes in this vulnerable patient population.
Changes in Assessment of and Satisfaction With Discharge Preparation From the Neonatal Intensive Care Unit
Authors: Smith Vincent C. , Mao Wenyang , McCormick Marie C.
Published: April 2021

Background:

A successful transition from the neonatal intensive care unit (NICU) to home is aided by a comprehensive discharge planning program that keeps families involved and engaged with the discharge preparation process.

Purpose:

To compare the assessment of parental NICU discharge preparedness with parental satisfaction with the NICU discharge preparation.

Methods:

Families were surveyed 4 to 6 weeks after NICU discharge, and those selecting “very prepared” were considered “satisfied” with their discharge preparation. On discharge day, families were considered “prepared” for discharge based on their overall level of preparedness and their nurse's rating of them on a discharge readiness assessment tool.

Results:

In total, 1104 families (60%) reported being both “satisfied” and “prepared”; 293 families (16%) were “satisfied” but not “prepared”; 297 families (16%) were not “satisfied” but were “prepared”; and 134 families (7%) were neither “satisfied” nor “prepared.” Compared with families that were both “satisfied” and “prepared,” families that were neither “satisfied” nor “prepared” were more likely to be raising the infant alone, of Black race, and to have sicker infants.

Implications for Practice:

Some families are at a higher risk and merit more consideration during NICU discharge planning. Assess the discharge readiness of all families prior to discharge. Those at an increased risk may benefit from more discharge education and training, specifically for single mothers, those with limited resources, or others considered at high risk.
Cardiovascular, Brain, and Lung Involvement in a Newborn With a Novel FLNA Mutation
Authors: Meliota Giovanni , Vairo Ugo , Ficarella Romina , Milella Leonardo , Faienza Maria Felicia , D'Amato Gabriele
Published: April 2021

Background:

Filamin A (FLNA) is an intracellular actin-binding protein, encoded by the FLNA gene, with a wide tissue expression. It is involved in several cellular functions, and extracellular matrix structuring. FLNA gene alterations lead to diseases with a wide phenotypic spectrum, such as brain periventricular nodular heterotopia (PVNH), cardiovascular abnormalities, skeletal dysplasia, and lung involvement.

Clinical Findings:

We present the case of a female infant who showed at birth aortic valve stenosis and PVNH, and subsequently developed interstitial lung disease with severe pulmonary hypertension.

Primary Diagnosis:

The association of aortic valve dysplasia, left ventricular outflow obstruction, persistent patent ductus arteriosus, and brain heterotopic gray matter suggested a possible FLNA gene alteration. A novel heterozygous intronic variant in the FLNA gene (NM_001110556.1), c.4304-1G >A, was detected.

Interventions:

In consideration of valve morphology and severity of stenosis, the neonate was scheduled for a transcatheter aortic valvuloplasty. At 3 months of life, she developed hypoxemic respiratory failure with evidence of severe pulmonary hypertension. Inhaled nitric oxide (iNO) and milrinone on continuous infusion were started. Because of a partial response to iNO, an intravenous continuous infusion of sildenafil was introduced.

Outcomes:

In consideration of severe clinical course and fatal outcome, the new FLNA gene mutation described in our patient seems to be associated with a loss of function of FLNA.

Practice Recommendations:

Lung and brain involvement, in association with left ventricular outflow obstruction and persistent patency of ductus arteriosus, should be considered highly suggestive of FLNA gene alterations, in a female newborn.
Selection of Mediastinal Lymphoma Patients for Proton Therapy Within the Proton Collaborative Group Registry
Authors: Tseng Yolanda D. , Pankuch Mark , Mohindra Pranshu , McGee Lisa , Rossi Carl , Flampouri Stella , Hajj Carla , Molitoris Jason K. , Chang John H. , Tsai Henry , Stevens Craig , Rosen Lane , Vargas Carlos , Hartsell William
Published: April 2021

Purpose:

As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG).

Methods:

Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8).

Results:

Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease.

Conclusions:

Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.