bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing public support for welfare sanctioning in Britain and the Netherlands: A persuasion experiment
Authors: Kootstra Anouk , Roosma Femke
Published: April 2018

During the last few decades, welfare sanctioning has come to play an increasingly central role in the institutional design of, and the philosophical and political approach to, most welfare states. Although much attention has been given to the morality and effectiveness of such policies, there is limited research that examines their social legitimacy. In this article we map public support for welfare sanctioning for unemployed people who do not want to accept jobs with wages or skill levels lower than their previous jobs. Our main contribution to the literature lies in the aim to discover how the social legitimacy of this policy can be increased or reduced by providing moral and economic counterarguments in a persuasion experiment. We use five waves of panel data administered in 2014–15 among approximately 9,000 respondents in Britain and the Netherlands. We show that support for welfare sanctioning is high in the two countries. Findings indicate that arguments opposing the policy reduce support to a greater extent than arguments in favor of the policy are able to improve its social legitimacy. We found moral arguments, considering the well‐being of unemployed people, to be more effective than economic arguments focusing on the effects of the policy on welfare spending. In Britain, people are more persistent in their support than in the Netherlands, which could be because the debate on this topic is more polarized in Britain. Also, people with higher political interests, higher education, and men are less likely to change opinions after being confronted with counterarguments.
Statistical inference for moving‐average Lévy‐driven processes: Fourier‐based approach
Authors: Belomestny Denis , Orlova Tatiana , Panov Vladimir
Published: April 2018

We consider a new method of semiparametric statistical estimation for the continuous‐time moving‐average Lévy processes. We derive the convergence rates of the proposed estimators and show that these rates are optimal in minimax sense.
Characterization of the novel HLA‐B*40:01:51 allele by sequencing‐based typing
Authors: Zhang L.‐Q. , Xiao Y. , Zhou X.‐Y. , Cai J.‐P.
Published: April 2018

HLA‐B*40:01:51 differs from HLA‐B*40:01:01 by 2 nucleotide substitutions at position 72 and 126.
Characterization of the novel HLA‐C*03:02:17 allele by sequencing‐based typing
Authors: Zhang L.‐Q. , Xiao Y. , Zhou X.‐Y. , Cai J.‐P.
Published: April 2018

HLA‐C*03:02:17 differs from HLA‐C*03:02:02:01 by one nucleotide substitution at position 393.
Prevalence and risk factors for HBV and HCV in prisoners in Iran: a national bio‐behavioural surveillance survey in 2015
Authors: Moradi Ghobad , Gouya Mohammad‐Mehdi , Azimizan Zavareh Fatemeh , Mohamadi Bolbanabad Amjad , Darvishi Sonia , Aghasadeghi Mohammad Reza , Nabavi Mahmood , Alasvand Ramin , Tashakorian Mehrzad , Nouri Bijan , Rahmani Khaled , Molaei Leila
Published: April 2018

Objectives

To provide more accurate estimates of the prevalence of Hepatitis B (HBV) and Hepatitis C (HCV) and their contributing factors among prisoners in Iran.

Methods

Cross‐sectional study of 6200 Iranian prisoners in 2015. Data were collected through questionnaires and interviews. HBV infection and HCV exposure status of the participants was determined by HBsAg and HCV antibodies blood tests using enzyme‐linked immunosorbent assay (ELISA). Data were analysed in STATA‐12.

Result

Prevalence of HCV exposure was 9.48% (95% CI: 8.73–10.27), and prevalence of HBV was 2.48% (95% CI: 2.07–2.89) in the general prison population. In multivariate analysis, the most important risk factor for HBV was a history of drug use in lifetime (adjusted odds ratio, AOR: 1.8, 95% CI: 1.17–3.02). The main risk factors for HCV exposure were a history of drug use in lifetime (AOR: 4.08, CI: 2.56–6.27), age over 30 (AOR: 2.68, CI: 2.01–3.56), and having tattoos (AOR = 1.67, CI: 1.35–2.07).

Conclusion

Although vaccination is used to control HBV among prisoners, prevalence of HCV exposure is alarming in the prison population of Iran, especially among people who inject drugs. Eliminating viral hepatitis in Iran by 2030 requires a national commitment and rapid measures for targeting this high‐risk group. Given the increased efficiency of HCV treatment in recent years, prisons provide an opportunity to access patients for treatment.
Red blood cell specifications for patients with hemoglobinopathies: a systematic review and guideline
Authors: Compernolle Veerle , Chou Stella T. , Tanael Susano , Savage William , Howard Jo , Josephson Cassandra D. , Odame Isaac , Hogan Christopher , Denomme Gregory , Shehata Nadine ,   for the International Collaboration for Transfusion Medicine Guidelines
Published: April 2018

BACKGROUND

Red blood cell (RBC) transfusions remain essential in the treatment of patients with sickle cell disease (SCD) and β‐thalassemia. Alloimmunization, a well‐documented complication of transfusion, increases the risk of delayed hemolytic transfusion reactions, complicates crossmatching and identifying compatible units, and delays provision of transfusions. Guidance is required to optimize the RBC product administered to these patients.

STUDY DESIGN AND METHODS

An international, multidisciplinary team conducted a systematic review and developed, following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, recommendations to assist treating physicians and transfusion specialists in their decision to select RBCs for these patients.

RESULTS

Eighteen studies (17 clinical studies and one cost‐effectiveness study) were included in the systematic review. The overall quality of the studies was very low. In total, 3696 patients were included: 1680 with β‐thalassemia and 2016 with SCD.

CONCLUSION

The panel recommends that ABO D CcEe K–matched RBCs are selected for individuals with SCD and β‐thalassemia, even in the absence of alloantibodies, to reduce the risk of alloimmunization. In patients with SCD and β‐thalassemia who have developed clinically significant alloantibodies, selection of RBCs antigen negative to the alloantibody is recommended, if feasible. In these patients, selection of more extended phenotype‐matched RBCs will likely reduce the risk of further alloimmunization. However, given the limited availability of extended phenotype‐matched units, attention should be given to ensure that a delay in transfusion does not adversely affect patient care.
Identity in the London Indian diaspora: Towards the quantification of qualitative data
Authors: Hundt Marianne , Staicov Adina
Published: April 2018

For second‐generation members of a diaspora community, ethnic and cultural affiliation are less straightforward than for the first generation. We compare information on identity construction in London's Indian Diaspora with the participants’ linguistic integration into the host community. Our study is novel and exploratory in that it combines quantitative, variationist methodology with a qualitative approach. We employ two standard sociolinguistic instruments to model subjects’ ethnic identity: a questionnaire and sociolinguistic interviews with a focus on discursive identity construction. In a second step we investigate possible connections between morphosyntactic variation and ethnic identity in language use data from three different communicative contexts. The results show that, while interview data on ethnic identity are amenable to quantification, clear correlations between the resulting identity scores and vernacular morphosyntactic features are difficult to find. In particular, patterns of style‐shifting between the different communicative contexts are not as expected.
Controlling the B/Ti ratio of TiBx thin films grown by high-power impulse magnetron sputtering
Authors: Bakhit Babak , Petrov Ivan , Greene J. E. , Hultman Lars , Rosén Johanna , Greczynski Grzegorz
Published: April 2018

TiBx thin films grown from compound TiB2 targets by magnetron sputter deposition are typically highly over-stoichiometric, with x ranging from 3.5 to 2.4, due to differences in Ti and B preferential-ejection angles and gas-phase scattering during transport from the target to the substrate. Here, the authors demonstrate that stoichiometric TiB2 films can be obtained using high-power impulse magnetron sputtering (HiPIMS) operated in power-controlled mode. The B/Ti ratio x of films sputter-deposited in Ar is controllably varied from 2.08 to 1.83 by adjusting the length of HiPIMS pulses ton between 100 and 30 μs, while maintaining average power and pulse frequency constant. This results in peak current densities JT,peak ranging from 0.27 to 0.88 A/cm2. Energy- and time-resolved mass spectrometry analyses of the ion fluxes incident at the substrate position show that the density of metal ions increases with decreasing ton due to a dramatic increase in JT,peak resulting in the strong gas rarefaction. With ton < 60 μs (JT,peak > 0.4 A/cm2), film growth is increasingly controlled by ions incident at the substrate, rather than neutrals, as a result of the higher plasma dencity and, hence, electron-impact ionization probablity. Thus, since sputter-ejected Ti atoms have a higher probability of being ionized than B atoms, due to their lower first-ionization potential and larger ionization cross-section, the Ti concentration in as-deposited films increases with decreasing ton (increasing JT,peak) as ionized sputtered species are steered to the substrate by the plasma in order to maintain charge neutrality.
In situ infrared spectroscopy during La2O3 atomic layer deposition using La(iPrCp)3 and H2O
Authors: Sperling Brent A. , Maslar James E. , Ivanov Sergei V.
Published: April 2018

Infrared spectra of surface species have been obtained during atomic layer deposition using tris(isopropylcyclopentadienyl)lanthanum, La(iPrCp)3, and water as precursors at 160 and 350 °C. Gas-phase spectra of La(iPrCp)3 are obtained for comparison. At low temperature, ligand exchange is seen to occur, and carbonate formation is found. With extended purging, the organic ligands are found to be stable on the surface, and carbonates are not formed. These observations indicate that carbonate formation is occurring during exposure to the precursors. At high temperature, the La precursor is observed to decompose leaving an opaque deposit containing relatively little hydrogen.
Linear and nonlinear ultrasound simulations using the discontinuous Galerkin method
Authors: Kelly James F. , Marras Simone , Zhao Xiaofeng , McGough Robert J.
Published: April 2018

A nodal discontinuous Galerkin (DG) code based on the nonlinear wave equation is developed to simulate transient ultrasound propagation. The DG method has high-order accuracy, geometric flexibility, low dispersion error, and excellent scalability, so DG is an ideal choice for solving this problem. A nonlinear acoustic wave equation is written in a first-order flux form and discretized using nodal DG. A dynamic sub-grid scale stabilization method for reducing Gibbs oscillations in acoustic shock waves is then established. Linear and nonlinear numerical results from a two-dimensional axisymmetric DG code are presented and compared to numerical solutions obtained from linear and Khokhlov-Zabolotskaya-Kuznetsov-based simulations in FOCUS. The numerical results indicate that these nodal DG simulations capture nonlinearity, thermoviscous absorption, and diffraction for both flat and focused pistons in homogeneous media.
A finite element approach for the calculation of self and mutual radiation impedances of resonators
Authors: Rucz Péter
Published: April 2018

A simulation method relying on the finite and infinite element techniques and a post-processing routine is introduced in this paper for the calculation of self and mutual radiation impedances of horns and acoustical resonators. The proposed procedure can be applied for the evaluation of the frequency dependent coupling impedance matrix of an arbitrary number of ducts in an arbitrary geometrical arrangement. The resulting impedance matrix can be utilized in a one-dimensional low-frequency waveguide model in order to calculate the input impedance or admittance function of the system. The applicability and usefulness of the proposed methodology is demonstrated by multiple simulation cases.
Multi-watt, multi-octave, mid-infrared femtosecond source
Authors: Seidel Marcus , Xiao Xiao , Hussain Syed A. , Arisholm Gunnar , Hartung Alexander , Zawilski Kevin T. , Schunemann Peter G. , Habel Florian , Trubetskov Michael , Pervak Vladimir , Pronin Oleg , Krausz Ferenc
Published: April 2018

One-micrometer wavelength ultrafast laser emission is transformed to a powerful tool for ultrabroadband mid-infrared spectroscopy.
Flexible active-matrix organic light-emitting diode display enabled by MoS
2
thin-film transistor
Authors: Choi Minwoo , Park Yong Ju , Sharma Bhupendra K. , Bae Sa-Rang , Kim Soo Young , Ahn Jong-Hyun
Published: April 2018

Highly flexible organic light-emitting diode display was demonstrated using MoS
2
TFTs as an active-matrix backplane.
Chronicling embryos, cell by cell, gene by gene
Authors: Pennisi Elizabeth
Published: April 2018

Single-cell sequencing tracks cells' gene activity during zebrafish and frog embryogenesis.
Cleaning up the killing fields
Authors: Wade Lizzie
Published: April 2018

Colombia has promised to be free of land mines by 2021. Researchers are testing new methods to speed up the process.
The principles of cascading power limits in small, fast biological and engineered systems
Authors: Ilton Mark , Bhamla M. Saad , Ma Xiaotian , Cox Suzanne M. , Fitchett Leah L. , Kim Yongjin , Koh Je-sung , Krishnamurthy Deepak , Kuo Chi-Yun , Temel Fatma Zeynep , Crosby Alfred J. , Prakash Manu , Sutton Gregory P. , Wood Robert J. , Azizi Emanuel , Bergbreiter Sarah , Patek S. N.
Published: April 2018

Hop, skip, jump, or massive leap

In biological and engineered systems, an inherent trade-off exists between the force and velocity that can be delivered by a muscle, spring, or combination of the two. However, one can amplify the maximum throwing power of an arm by storing the energy in a bow or sling shot with a latch mechanism for sudden release. Ilton
et al.
used modeling to explore the performance of motor-driven versus spring-latch systems in engineering and biology across size scales. They found a range of general principles that are common to animals, plants, fungi, and machines that use elastic structures to maximize kinetic energy.

Science
, this issue p.
eaao1082
Spatial entanglement patterns and Einstein-Podolsky-Rosen steering in Bose-Einstein condensates
Authors: Fadel Matteo , Zibold Tilman , Décamps Boris , Treutlein Philipp
Published: April 2018

Splitting the entanglement

When particles in a quantum mechanical system are entangled, a measurement performed on one part of the system can affect the results of the same type of measurement performed on another part—even if these subsystems are physically separated. Kunkel
et al.
, Fadel
et al.
, and Lange
et al.
achieved this so-called distributed entanglement in a particularly challenging setting: an ensemble of many cold atoms (see the Perspective by Cavalcanti). In all three studies, the entanglement was first created within an atomic cloud, which was then allowed to expand. Local measurements on the different, spatially separated parts of the cloud confirmed that the entanglement survived the expansion.

Science
, this issue p.
413
, p.
409
, p.
416
; see also p.
376
Advancing the ethics of paleogenomics
Authors: Bardill Jessica , Bader Alyssa C. , Garrison Nanibaa' A. , Bolnick Deborah A. , Raff Jennifer A. , Walker Alexa , Malhi Ripan S. ,   the Summer internship for INdigenous peoples in Genomics (SING) Consortium
Published: April 2018

Ancestral remains should be regarded not as “artifacts” but as human relatives who deserve respect
Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis
Authors: Farrell Jeffrey A. , Wang Yiqun , Riesenfeld Samantha J. , Shekhar Karthik , Regev Aviv , Schier Alexander F.
Published: April 2018

Mapping the vertebrate developmental landscape

As embryos develop, numerous cell types with distinct functions and morphologies arise from pluripotent cells. Three research groups have used single-cell RNA sequencing to analyze the transcriptional changes accompanying development of vertebrate embryos (see the Perspective by Harland). Wagner
et al.
sequenced the transcriptomes of more than 90,000 cells throughout zebrafish development to reveal how cells differentiate during axis patterning, germ layer formation, and early organogenesis. Farrell
et al.
profiled the transcriptomes of tens of thousands of embryonic cells and applied a computational approach to construct a branching tree describing the transcriptional trajectories that lead to 25 distinct zebrafish cell types. The branching tree revealed how cells change their gene expression as they become more and more specialized. Briggs
et al.
examined whole frog embryos, spanning zygotic genome activation through early organogenesis, to map cell states and differentiation across all cell lineages over time. These data and approaches pave the way for the comprehensive reconstruction of transcriptional trajectories during development.

Science
, this issue p.
981
, p.
eaar3131
, p.
eaar5780
; see also p.
967
A synthetic polymer system with repeatable chemical recyclability
Authors: Zhu Jian-Bo , Watson Eli M. , Tang Jing , Chen Eugene Y.-X.
Published: April 2018

Recycle, recycle, recycle

Some polymers, such as polyethylene terephthalate in soft drink bottles, can be depolymerized back to the starting monomers. This makes it possible to repolymerize true virgin material for repeated use. Zhu
et al.
developed a polymer based on a five-membered ring cyclic monomer derived from γ-butyrolactone that could be produced at ambient temperature and mild conditions (see the Perspective by Sardon and Dove). The high-molecular-weight polymer exhibited high crystallinity and thermal stability. However, at hot enough conditions, or at lower temperatures in the presence of a zinc chloride catalyst, the polymer could be returned to its starting monomers and thus recycled into new material.

Science
, this issue p.
398
; see also p.
380
Quantitative mass imaging of single biological macromolecules
Authors: Young Gavin , Hundt Nikolas , Cole Daniel , Fineberg Adam , Andrecka Joanna , Tyler Andrew , Olerinyova Anna , Ansari Ayla , Marklund Erik G. , Collier Miranda P. , Chandler Shane A. , Tkachenko Olga , Allen Joel , Crispin Max , Billington Neil , Takagi Yasuharu , Sellers James R. , Eichmann Cédric , Selenko Philipp , Frey Lukas , Riek Roland , Galpin Martin R. , Struwe Weston B. , Benesch Justin L. P. , Kukura Philipp
Published: April 2018

Watching proteins' weight

Careful measurements of light scattering can provide information on individual macromolecules and complexes. Young
et al.
used a light-scattering approach for accurate mass determination of proteins as small as 20 kDa (see the Perspective by Lee and Klenerman). Movies of protein complex association and dissociation were analyzed to extract biophysical parameters from single molecules and assemblies without labeling. Using this approach, the authors determined in vitro kinetics of fibril and aggregate growth and association constants for a complex protein-glycoprotein assembly.

Science
, this issue p.
423
; see also p.
378
Field-deployable viral diagnostics using CRISPR-Cas13
Authors: Myhrvold Cameron , Freije Catherine A. , Gootenberg Jonathan S. , Abudayyeh Omar O. , Metsky Hayden C. , Durbin Ann F. , Kellner Max J. , Tan Amanda L. , Paul Lauren M. , Parham Leda A. , Garcia Kimberly F. , Barnes Kayla G. , Chak Bridget , Mondini Adriano , Nogueira Mauricio L. , Isern Sharon , Michael Scott F. , Lorenzana Ivette , Yozwiak Nathan L. , MacInnis Bronwyn L. , Bosch Irene , Gehrke Lee , Zhang Feng , Sabeti Pardis C.
Published: April 2018

Taking CRISPR technology further

CRISPR techniques are allowing the development of technologies for nucleic acid detection (see the Perspective by Chertow). Taking advantages of the distinctive enzymatic properties of CRISPR enzymes, Gootenberg
et al.
developed an improved nucleic acid detection technology for multiplexed quantitative and highly sensitive detection, combined with lateral flow for visual readout. Myhrvold
et al.
added a sample preparation protocol to create a field-deployable viral diagnostic platform for rapid detection of specific strains of pathogens in clinical samples. Cas12a (also known as Cpf1), a type V CRISPR protein, cleaves double-stranded DNA and has been adapted for genome editing. Chen
et al.
discovered that Cas12a also processes single-stranded DNA threading activity. A technology platform based on this activity detected human papillomavirus in patient samples with high sensitivity.

Science
, this issue p.
439
, p.
444
, p.
436
; see also p.
381
Split, but still attached
Authors: Cavalcanti Daniel
Published: April 2018

Entanglement survives between spatially separated atoms of an atomic cloud after it expands
Genetic and Functional Characterization of an MCR-3-Like Enzyme-Producing Escherichia coli Isolate Recovered from Swine in Brazil
Authors: Kieffer Nicolas , Nordmann Patrice , Moreno Andrea Micke , Zanolli Moreno Luisa , Chaby Richard , Breton Aude , Tissières Pierre , Poirel Laurent
Published: April 2018

A collection of 126 pigs was screened for carriage of colistin-resistant
Enterobacteriaceae
in a farm in Minas Gerais, Brazil. Out of this collection, eight colistin-resistant
Escherichia coli
isolates were recovered, including one from Minas Gerais State producing a new MCR-3 variant (MCR-3.12). Analysis of the lipopolysaccharide revealed that MCR-3.12 had a function similar to that of MCR-1 and MCR-2 as a result of the addition of a phosphoethanolamine group to the lipid A moiety. Genetic analysis showed that the
mcr-3.12
gene was carried by an IncA/C
2
plasmid and was embedded in an original genetic environment. This study reports the occurrence of the MCR-3-like determinant in South America and is the first to demonstrate the functionality of this group of enzymes as a phosphoethanolamine transferase.
Setup, Validation, and Quality Control of a Centralized Whole-Genome-Sequencing Laboratory: Lessons Learned
Authors: Arnold Cath , Edwards Kirstin , Desai Meeta , Platt Steve , Green Jonathan , Conway David
Published: April 2018

Routine use of whole-genome analysis for infectious diseases can be used to enlighten various scenarios pertaining to public health, including identification of microbial pathogens, relating individual cases to an outbreak of infectious disease, establishing an association between an outbreak of food poisoning and a specific food vehicle, inferring drug susceptibility, source tracing of contaminants, and study of variations in the genome that affect pathogenicity/virulence. We describe the setup, validation, and ongoing verification of a centralized whole-genome-sequencing (WGS) laboratory to carry out sequencing for these public health functions for the National Infection Services, Public Health England, in the United Kingdom.
Timeliness of Proteolytic Events Is Prerequisite for Efficient Functioning of the Alphaviral Replicase
Authors: Lulla Valeria , Karo-Astover Liis , Rausalu Kai , Saul Sirle , Merits Andres , Lulla Aleksei
Published: April 2018

Polyprotein processing has an important regulatory role in the life cycle of positive-strand RNA viruses. In the case of alphaviruses, sequential cleavage of the nonstructural polyprotein (ns-polyprotein) at three sites eventually yields four mature nonstructural proteins (nsPs) that continue working in complex to replicate viral genomic RNA and transcribe subgenomic RNA. Recognition of cleavage sites by viral nsP2 protease is guided by short sequences upstream of the scissile bond and, more importantly, by the spatial organization of the replication complex. In this study, we analyzed the consequences of the artificially accelerated processing of the Semliki Forest virus ns-polyprotein. It was found that in mammalian cells, not only the order but also the correct timing of the cleavage events is essential for the success of viral replication. Analysis of the effects of compensatory mutations in rescued viruses as well as
in vitro
translation and
trans
-replicase assays corroborated our findings and revealed the importance of the V515 residue in nsP2 for recognizing the P4 position in the nsP1/nsP2 cleavage site. We also extended our conclusions to Sindbis virus by analyzing the properties of the hyperprocessive variant carrying the N614D mutation in nsP2. We conclude that the sequence of the nsP1/nsP2 site in alphaviruses is under selective pressure to avoid the presence of sequences that are recognized too efficiently and would otherwise lead to premature cleavage at this site before completion of essential tasks of RNA synthesis or virus-induced replication complex formation. Even subtle changes in the ns-polyprotein processing pattern appear to lead to virus attenuation.

IMPORTANCE
The polyprotein expression strategy is a cornerstone of alphavirus replication. Three sites within the ns-polyprotein are recognized by the viral nsP2 protease and cleaved in a defined order. Specific substrate targeting is achieved by the recognition of the short sequence upstream of the scissile bond and a correct macromolecular assembly of ns-polyprotein. Here, we highlighted the importance of the timeliness of proteolytic events, as an additional layer of regulation of efficient virus replication. We conclude that, somewhat counterintuitively, the cleavage site sequences at the nsP1/nsP2 and nsP2/nsP3 junctions are evolutionarily selected to be recognized by protease inefficiently, to avoid premature cleavages that would be detrimental for the assembly and functionality of the replication complex. Understanding the causes and consequences of viral polyprotein processing events is important for predicting the properties of mutant viruses and should be helpful for the development of better vaccine candidates and understanding potential mechanisms of resistance to protease inhibitors.
KRAB-ZFP Repressors Enforce Quiescence of Oncogenic Human Herpesviruses
Authors: Li Xiaofan , Burton Eric M. , Koganti Siva , Zhi Jizu , Doyle Francis , Tenenbaum Scott A. , Horn Biljana , Bhaduri-McIntosh Sumita
Published: April 2018

Cancer-causing herpesviruses infect nearly every human and persist indefinitely in B lymphocytes in a quiescent state known as latency. A hallmark of this quiescence or latency is the presence of extrachromosomal viral genomes with highly restricted expression of viral genes. Silencing of viral genes ensures both immune evasion by the virus and limited pathology to the host, yet how multiple genes on multiple copies of viral genomes are simultaneously silenced is a mystery. In a unifying theme, we report that both cancer-causing human herpesviruses, despite having evolved independently, are silenced through the activities of two members of the Krüppel-associated box (KRAB) domain–zinc finger protein (ZFP) (KRAB-ZFP) epigenetic silencing family, revealing a novel STAT3-KRAB-ZFP axis of virus latency. This dual-edged antiviral strategy restricts the destructive ability of the lytic phase while promoting the cancer-causing latent phase. These findings also unveil roles for KRAB-ZFPs in silencing of multicopy foreign genomes with the promise of evicting herpesviruses to kill viral cancers bearing clonal viral episomes.

IMPORTANCE
Despite robust immune responses, cancer-causing viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) persist for life. This persistence is accomplished partly through a stealth mechanism that keeps extrachromosomal viral genomes quiescent. Quiescence, or latency, ensures that not every cell harboring viral genomes is killed directly through lytic activation or indirectly via the immune response, thereby evicting virus from host. For the host, quiescence limits pathology. Thus, both virus and host benefit from quiescence, yet how quiescence is maintained through silencing of a large set of viral genes on multiple viral genomes is not well understood. Our studies reveal that members of a gene-silencing family, the KRAB-ZFPs, promote quiescence of both cancer-causing human viruses through simultaneous silencing of multiple genes on multicopy extrachromosomal viral genomes.
Changes in retinal ischaemic index correlate with recalcitrant macular oedema in retinal vein occlusion: WAVE study
Authors: Kwon Soonil , Wykoff Charles Clifton , Brown David M , van Hemert Jano , Fan Wenying , Sadda SriniVas R
Published: April 2018

Aim

To evaluate changes in the ischaemic index (ISI) after targeted retinal photocoagulation (TRP) and to investigate the correlation between these changes and macular oedema (ME).

Method

Twenty-four eyes of 24 patients with retinal vein occlusion (RVO) with recurrent ME were included. Ultra-widefield fluorescein angiography (UWFFA; Optos 200Tx) was obtained at baseline and every 4 months. The regions of retinal non-perfusion and the total gradable retina were manually segmented on UWFFA images for calculating the global ISI. ISI was also computed for specific regions defined by a standardised grid: perimacular area (PMA), near-peripheral area (NPA), mid-peripheral area (MPA) and far-peripheral area (FPA). Global and regional ISIs and change in ISI over time were correlated with central macular thickness (CMT).

Results

The ISIs of entire retina, PMA, NPA, MPA and FPA at baseline were 30.5%±23.3, 17.7%±20.6, 21.9%±19.0, 33.0%±27.9 and 48.0%±32.9, respectively. The ISIs at final follow-up were 23.5%±19.9, 15.7%±22.2, 16.5%±16.7, 24.7%±24.7 and 24.7%±24.7, respectively. A significant correlation was found between CMT and global ISI during follow-up (r=0.22, p=0.03). Among the different retinal zones, PMA showed a correlation with CMT (r=0.27, p=0.007). The change in ISI for the total retina (Δtotal), PMA (ΔPMA) and NPA (ΔNPA) retinal regions was positively correlated with the change in CMT (ΔCMT) (r=0.45, 0.42 and 0.50, respectively, p=0.006, 0.009 and 0.002, respectively).

Conclusion

The severity of ME was correlated with the ISIs of the entire retina and the PMA. The reduction in ME was correlated with the reduction in ISI of the entire retina as well as the ISIs for the NPA and PMA following TRP. The role of TRP, particularly to these regions (NPA, PMA), warrants further investigation in recalcitrant RVO-associated ME.
Decreased expression of A20 is associated with ocular Behcet’s disease (BD) but not with Vogt-Koyanagi-Harada (VKH) disease
Authors: He Yue , Wang Chaokui , Su Guannan , Deng Bolin , Ye Zi , Huang Yang , Yuan Gangxiang , Kijlstra Aize , Li Hong , Yang Peizeng
Published: April 2018

Purpose

A20 is a ubiquitously expressed and inducible cytosolic protein, which plays an important role in the negative regulation of inflammation and immunity. In this study, we investigated the role of A20 in Behcet’s disease (BD) and Vogt-Koyanagi-Harada (VKH) disease.

Methods

The levels of A20 in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) were detected in BD patients with active and inactive uveitis, VKH patients with active and inactive uveitis, and normal subjects, respectively, by real-time PCR. The effect of A20 silencing was performed by transduction of DCs with adenovirus containing an A20 shRNA vector. The effect of A20 silencing on the maturation of DCs was measured by flow cytometry. The effect of A20 silencing of DCs on cytokine production by DCs and CD4+ T cells was analysed by ELISA. The phosphorylation levels of JNK, p38 and ERK1/2 were detected by flow cytometry.

Results

The expression of A20 was markedly decreased in PBMCs and DCs obtained from BD patients with active uveitis, but not in patients with VKH disease as compared with normal controls. Silencing of A20 significantly increased the levels of interleukin (IL)-1β and IL-6 and suppressed the expression of the anti-inflammatory cytokines IL-10 and IL-27. Downregulation of A20 also led to an increase in IL-17 production by CD4+ T cells. However, downregulation of A20 in DCs did not have an effect on cell surface markers such as CD40, CD80, CD83, CD86 and HLA-DR. Silencing of A20 caused an increased expression of phospho-JNK and phospho-MAPK p38 but not phospho-ERK1/2.

Conclusions

This study showed that the expression of A20 was decreased in BD patients with active uveitis but not in VKH disease. Decreased expression of A20 may lead to an enhanced activation of proinflammatory Th17 cells, causing a reactivation of BD.
Atypical epiretinal tissue in full-thickness macular holes: pathogenic and prognostic significance
Authors: Bae Kunho , Lee Soo Min , Kang Se Woong , Kim Eung Suk , Yu Seung-Young , Kim Kyung Tae
Published: April 2018

Background

To elucidate the clinical characteristics of a full-thickness macular hole (FTMH) with atypical epiretinal tissue (AET), and expand the spectrum of pathogenesis of MH.

Methods

This study involved 225 consecutive eyes of 211 patients who underwent surgery for an idiopathic FTMH. Eyes were divided into two groups according to the presence of AET. Tomographic features at baseline, closure rate of the MH and visual outcomes were compared between the two groups.

Results

AET was detected in 26 (11.6%) among 225 eyes. Overall closure of the MH was noted in 92.3% of eyes with AET and 99.5% of eyes without AET at 12 months postoperatively (p=0.003). At 12 months postoperatively, the mean logarithm of the minimum angle of resolution visual acuity in eyes with and without AET was 0.38 and 0.21, respectively (p=0.046). At baseline, eyes with AET more frequently had splitting of the inner retina but fewer intact photoreceptors compared with eyes without AET (19.2% vs 2.5%, and 57.7% vs 89.9%, p<0.001, respectively).

Conclusions

The presence of AET in an FTMH was related to poorer anatomical success and less visual recovery after surgery, suggesting that AET reflects a chronic pathogenic process involving more severe damage to the foveal tissue.
Microaneurysm turnover is a predictor of diabetic retinopathy progression
Authors: Pappuru Rajeev K R , Ribeiro Luísa , Lobo Conceição , Alves Dalila , Cunha-Vaz José
Published: April 2018

Aim

To analyse retinopathy phenotypes and microaneurysm (MA) turnover in mild non-proliferative diabetic retinopathy (NPDR) as predictors of progression to diabetic central-involved macular oedema (CIMO) in patients with type 2 diabetes mellitus (DM) in two different ethnic populations.

Methods

205 patients with type 2 DM and mild NPDR were followed in a prospective observational study for 2 years or until development of CIMO, in two centres from different regions of the world. Ophthalmological examinations, including best-corrected visual acuity (BCVA), fundus photography with RetmarkerDR analysis, and optical coherence tomography (OCT), were performed at baseline and 6 12 and 24 months.

Results

158 eyes/patients reached either the study endpoint, CIMO (24) or performed the last study visit (24-month visit) without developing CIMO (134). From the eyes/patients in analysis, 27 eyes (17.1%) progressed to more advanced ETDRS (Early Treatment Diabetic Retinopathy Study) levels: 6 progressed to mild NPDR (level 35), 15 progressed to moderate NPDR (level 43), 5 progressed to moderately severe NPDR (level 47) and 1 progressed to high risk PDR (level 71). Worsening in ETDRS level is associated with phenotype C (p=0.005). From the 130 eyes/patients with a low MA turnover, 18 (13.8%) eyes/patients had an increase in ETDRS level, and from the 19 eyes/patients with a high MA turnover, 9 (47.4%) had an increase in ETDRS level (p<0.001).

Conclusion

Eyes in the initial stages of diabetic retinopathy show different phenotypes with different risks for progression to CIMO. In phenotype C, MA turnover correlates with ETDRS grading worsening and development of CIMO.
Diagnostic value of ganglion cell-inner plexiform layer for early detection of ethambutol-induced optic neuropathy
Authors: Lee Ju-Yeun , Han Jinu , Seo Jeong Gi , Park Kyung-Ah , Oh Sei Yeul
Published: April 2018

Aim

To evaluate the diagnostic value of macular ganglion cell-inner plexiform layer (mGCIPL) thickness versus peripapillary retinal nerve fibre layer (pRNFL) thickness for the early detection of ethambutol-induced optic neuropathy (EON).

Methods

Twenty-eight eyes of 15 patients in the EON group and 100 eyes of 53 healthy subjects in the control group were included. All patients with EON demonstrated the onset of visual symptoms within 3 weeks. Diagnostic power for pRNFL and mGCIPL thicknesses measured by Cirrus spectral-domain optical coherence tomography was assessed by area under the receiver operating characteristic (AUROC) curves and sensitivity.

Results

All of the mGCIPL thickness measurements were thinner in the EON group than in the control group in early EON (p<0.001). All of pRNFL thicknesses except inferior RNFL showed AUROC curves above 0.5, and all of the mGCIPL thicknesses showed AUROC curves above 0.5. The AUROC of the average mGCIPL (0.812) thickness was significantly greater than that of the average pRNFL (0.507) thickness (p<0.001). Of all the mGCIPL-related parameters considered, the minimum thickness showed the greatest AUROC value (0.863). The average mGCIPL thickness showed a weak correlation with visual field pattern standard deviations (r
2
=0.158, p<0.001).

Conclusions

In challenging cases of EON, the mGCIPL thickness has better diagnostic performance in detecting early-onset EON as compared with using pRNFL thickness. Among the early detection ability of mGCIPL thickness, minimum GCIPL thickness has high diagnostic ability.
Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial
Authors: Shickh Salma , Clausen Marc , Mighton Chloe , Casalino Selina , Joshi Esha , Glogowski Emily , Schrader Kasmintan A , Scheer Adena , Elser Christine , Panchal Seema , Eisen Andrea , Graham Tracy , Aronson Melyssa , Semotiuk Kara M , Winter-Paquette Laura , Evans Michael , Lerner-Ellis Jordan , Carroll June C , Hamilton Jada G , Offit Kenneth , Robson Mark , Thorpe Kevin E , Laupacis Andreas , Bombard Yvonne
Published: April 2018

Introduction

Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results.

Methods and analysis

We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results.

Ethics and dissemination

This study has been approved by research ethics boards of St. Michael’s Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice.

Trial registration number

NCT03244202; Pre-results.
Impact of periodontitis as representative of chronic inflammation on long-term clinical outcomes in patients with atrial fibrillation
Authors: Im Sung Il , Heo Jinho , Kim Bong Joon , Cho Kyoung-Im , Kim Hyun Su , Heo Jung Ho , Hwang Jin Yong
Published: April 2018

Objectives

Relationship between atrial fibrillation (AF) and inflammation was shown in previous studies. However, there was limited data about the association between the periodontitis and AF in the long-term follow-up. The aim of this study was to evaluate the impact of periodontitis on long-term clinical outcomes in patients with AF.

Methods

The Kosin University echocardiography, ECG and periodontitis database were reviewed from 2013 to 2015 to identify patients with AF. Those patients were divided into two groups according to the presence of periodontitis and clinical events including any arrhythmic attack, thromboembolic and bleeding and death were collected during a median of 18 months.

Results

Among 227 patients with AF, 47 (20.7%) patients had periodontitis. Major adverse cardiac events (MACE) were significantly higher in patients with periodontitis compared with those without periodontitis (p<0.001). Arrhythmias including AF, atrial tachycardia, atrial premature beat, ventricular tachycardia and ventricular premature beat also occurred in 44 (93.6%) patients, which was higher significantly higher incidence in patients with periodontitis than in those without periodontitis (p<0.001). In univariate analysis, age, CHA2DS2-VASc, left atrial volume index (LAVi) and periodontitis were significantly associated with arrhythmic events and MACE including bleeding events, thromboembolic events, arrhythmic events and mortality. In multivariate analysis, LAVi (p=0.005) and periodontitis (p<0.001) were independent risk factors for arrhythmic events and periodontitis (p<0.001) for MACE at the long-term follow-up.

Conclusions

The periodontitis as representative of chronic inflammation was an independent predictor of arrhythmic events and MACE in patients with AF.
Risk prediction in stable cardiovascular disease using a high-sensitivity cardiac troponin T single biomarker strategy compared to the ESC-SCORE
Authors: Biener Moritz , Giannitsis Evangelos , Kuhner Manuel , Zelniker Thomas , Mueller-Hennessen Matthias , Vafaie Mehrshad , Stoyanov Kiril M , Neumann Franz-Josef , Katus Hugo A , Hochholzer Willibald , Valina Christian Marc
Published: April 2018

Objective

To evaluate the prognostic performance of high-sensitivity cardiac troponin T (hs-cTnT) compared with the ESC-SCORE.

Methods

We included low-risk outpatients with stable cardiovascular (CV) disease categorised into need for non-secondary and secondary prevention. The prognostication of hs-cTnT at index visit was compared with the European Society of Cardiology-Systematic COronary Risk Evaluation (ESC-SCORE) with respect to all-cause mortality (ACM) and two composite endpoints (ACM, acute myocardial infarction (AMI) and stroke and ACM, AMI, stroke and rehospitalisation for acute coronary syndrome (ACS) and decompensated heart failure (DHF)).

Results

Within a median follow-up of 796 days, a total of 16 deaths, 32 composite endpoints of ACM, AMI and stroke and 83 composite endpoints of ACM, AMI, stroke, rehospitalisation for ACS and DHF were observed among 693 stable low-risk outpatients. Using C-statistics, measurement of hs-cTnT alone outperformed the ESC-SCORE for the prediction of ACM in the entire study population (Δarea under the curve (AUC) 0.221, p=0.0039) and both prevention groups (non-secondary: ΔAUC 0.164, p=0.0208; secondary: ΔAUC 0.264, p=0.0134). For the prediction of all other secondary endpoints, hs-cTnT was at least as effective as the ESC-SCORE, both in secondary and non-secondary prevention. Using continuous and categorical net reclassification improvement and integrated discrimination improvement, hs-cTnT significantly improved reclassification regarding all endpoints in the entire population and in the secondary prevention cohort. In non-secondary prevention, hs-cTnT improved reclassification only for ACM. The results were confirmed in an independent external cohort on 2046 patients.

Conclusions

Hs-cTnT is superior to the multivariable ESC-SCORE for the prediction of ACM and a composite endpoint in stable outpatients with and without relevant CV disease.

Trial registration number

NCT01954303; Pre-results.
Changes in recreational drug use, drug use associated with chemsex, and HIV-related behaviours, among HIV-negative men who have sex with men in London and Brighton, 2013–2016
Authors: Sewell Janey , Cambiano Valentina , Miltz Ada , Speakman Andrew , Lampe Fiona C , Phillips Andrew , Stuart David , Gilson Richard , Asboe David , Nwokolo Nneka , Clarke Amanda , Hart Graham , Rodger Alison
Published: April 2018

Objectives

The objective of this study was to compare the prevalence of polydrug use, use of drugs associated with chemsex, specific drug use, and HIV-related behaviours, between two time periods, using two groups of HIV-negative men who have sex with men (MSM) attending the same sexual health clinics in London and Brighton, in two consecutive periods of time from 2013 to 2016.

Methods

Data from MSM in the cross-sectional Attitudes to and Understanding Risk of Acquisition of HIV (AURAH) study (June 2013 to September 2014) were compared with baseline data from different MSM in the prospective cohort study Attitudes to and Understanding Risk of Acquisition of HIV over Time (AURAH2) (November 2014 to April 2016). Prevalence of polydrug use, drug use associated with chemsex and specific drug use, and 10 measures of HIV-related behaviours including condomless sex, post-exposure prophylaxis (PEP) use, pre-exposure prophylaxis (PrEP) use, and HIV testing, were compared. Prevalence ratios (PRs) for the association of the study (time period) with drug use and HIV-related behaviour measures were estimated using modified Poisson regression analysis, unadjusted and adjusted for sociodemographic factors.

Results

In total, 991 MSM were included from AURAH and 1031 MSM from AURAH2. After adjustment for sociodemographic factors, use of drugs associated with chemsex had increased (adjusted PR (aPR) 1.30, 95% CI 1.11 to 1.53) and there were prominent increases in specific drug use; in particular, mephedrone (aPR 1.32, 95% CI 1.10 to 1.57), γ-hydroxybutyric/γ-butryolactone (aPR 1.47, 95% CI 1.15 to 1.87) and methamphetamine (aPR 1.42, 95% CI 1.01 to 2.01). Use of ketamine had decreased (aPR 0.54, 95% CI 0.38 to 0.78). Certain measures of HIV-related behaviours had also increased, most notably PEP use (aPR 1.50, 95% CI 1.21 to 1.88) and number of self-reported bacterial STI diagnoses (aPR 1.24, 95% CI 1.08 to 1.43).

Conclusions

There have been significant increases in drug use associated with chemsex and some measures of HIV-related behaviours among HIV-negative MSM in the last few years. Changing patterns of drug use and associated behaviours should be monitored to enable sexual health services to plan for the increasingly complex needs of some clients.