bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline
Authors: Gordan John D. , Kennedy Erin B. , Abou-Alfa Ghassan K. , Beg Muhammad Shaalan , Brower Steven T. , Gade Terence P. , Goff Laura , Gupta Shilpi , Guy Jennifer , Harris William P. , Iyer Renuka , Jaiyesimi Ishmael , Jhawer Minaxi , Karippot Asha , Kaseb Ahmed O. , Kelley R. Kate , Knox Jennifer J. , Kortmansky Jeremy , Leaf Andrea , Remak William M. , Shroff Rachna T. , Sohal Davendra P.S. , Taddei Tamar H. , Venepalli Neeta K. , Wilson Andrea , Zhu Andrew X. , Rose Michal G.
Published: November 2020

PURPOSE

To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC).

METHODS

ASCO convened an Expert Panel to conduct a systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population.

RESULTS

Nine phase III randomized controlled trials met the inclusion criteria.

RECOMMENDATIONS

Atezolizumab + bevacizumab (atezo + bev) may be offered as first-line treatment of most patients with advanced HCC, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines. Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1. Following first-line treatment with atezo + bev, and until better data are available, second-line therapy with a tyrosine kinase inhibitor may be recommended for appropriate candidates. Following first-line therapy with sorafenib or lenvatinib, second-line therapy options for appropriate candidates include cabozantinib, regorafenib for patients who previously tolerated sorafenib, or ramucirumab (for patients with α-fetoprotein ≥ 400 ng/mL), or atezo + bev where patients did not have access to this option as first-line therapy. Pembrolizumab or nivolumab are also reasonable options for appropriate patients following sorafenib or lenvatinib. Consideration of nivolumab + ipilimumab as an option for second-line therapy and third-line therapy is discussed. Further guidance on choosing between therapy options is included within the guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .
On Borges’s B/baroque
Authors: Johnson Christopher D.
Published: November 2020

This article examines Jorge Luis Borges’s ingenious, largely dehistoricized interpretations and imitations of seventeenth-century writers typically called Baroque. It contends that the aesthetic, epistemological, and metaphysical values Borges assigns to works by Cervantes, Góngora, Quevedo, Gracián, Marino, Browne, Pascal, Leibniz, Angelus Silesius, and Spinoza depend largely on his conservative notions of how style and, specifically, metaphor should work. While writers from the historical Baroque often require readers to embrace hermeneutic difficulty, Borges, despite the ingenious difficulty of his own writings, refuses to countenance this stance. This refusal turns also on Borges’s distinction between writing he fervently praises as “classic” and writing he ambiguously blames as “baroque.” The former serves as the explicit model for his own invention; but the latter implicitly, agonistically, informs much of his thinking and writing as well. Borges’s unwillingness to distinguish the historical Baroque from a recurring, eternal baroque is understandable, given his philosophy of art and history; however, it ignores how periodization can have the heuristic and conceptual function of finding unity in multiplicity, a unity that includes divergent styles and ideologies.
American Politics in the Era of Zombie Neoliberalism
Authors: Kotsko Adam
Published: November 2020

Adam Kotsko analyzes the current political conjuncture in the United States through the lens of political theology, which he understands as fundamentally a study of systems of legitimacy. From this perspective, the neoliberal order is not merely an economic or political order but also a theological one, centered on the axiomatic value of free choice and imbued with a faith in the market’s judgment of our free choices. The system-wide effects of the global financial crisis, which did not correlate with any good or bad choices, shattered the legitimacy of the neoliberal order, but so far both major US political parties have been focused on somehow rehabilitating neoliberalism rather than breaking with it. In the wake of Trump’s inauguration, this attempt to restore neoliberalism has reached farcical levels, as both parties are seduced by conspiracy theories that implicitly concede that the current order is illegitimate, yet fail to promote a real alternative.
Neo-homesteading
Authors: Shonkwiler Alison
Published: November 2020

This essay examines the growing interest in home-based labor in light of the changing structures of conventional work. Neo-homesteading, particularly in its part-time and casual modes, reveals the conflicted middle-class desire to achieve freedom from the wage economy without abandoning the advantages and benefits of modern, high-tech capitalism. Recent narratives about the value of home production affirm the effort to assert greater control over work lives and to recuperate satisfying, sustainable, and less alienated forms of production. At the same time, these narratives expose troubling contradictions in the “postwork” landscape, such as a deeper investment in private and individualized labor, an unstable relationship to land ownership, and a neoliberal retrenchment into a family-based organization of labor. Neo-homesteading, it is argued, makes visible both the radical and the reactionary possibilities that emerge from the effort to reconceive work.
Strange Intimacies
Authors: Nash Jennifer C. , Pinto Samantha
Published: November 2020

This paper sits with the understudied subgenre of the contemporary black maternal memoir in the Black Lives Matter era. We read Sybrina Fulton and Tracy Martin’s Rest in Power: The Enduring Life of Trayvon Martin and Lezley McSpadden’s Tell the Truth and Shame the Devil: The Life, Legacy, and Love of My Son Michael Brown not only as performances of grief and of the birth of political subjectivity—even as they emphatically stage how respectable black maternal political subjectivity is born through loss. These black maternal memoirs also offer what we call strange intimacies, which strain the predictable scripts of the maternal memoir. We read the embeddedness of strange intimacies in these memoirs as a way of refusing the gendered logics of the reception of the black maternal, and as performances of intimacy that refuse and undo normative conceptions of familial intimacy and black maternal loss.
Turkish Delights with an Aftertaste
Authors: Landry Olivia
Published: November 2020

Hop-Çiki-Yaya Polisiyesi is a Turkish crime novel series by Mehmet Murat Somer that appeared between 2003 and 2004. The series is set in the trans world of Istanbul, and the hero/heroine is a gender-nonbinary sleuth. The present essay explores the paradox at the heart of this series, which on the one hand offers an affirmative portrait of a sex-positive and sociopolitically mobile trans world, and on the other hand exposes the reality of trans murders and the necropolitics as well as bare life politics in practice against the trans community in Turkey. The publication of these novels coincided with the emergence of an LGBTQ+ politics in Turkey but also with the rise to power of the Islamist Adalet ve Kalkınma Partisi (Justice and Development Party). Drawing on crime fiction theories, trans studies, and recent Turkish history, this essay draws out the significance of this series and its place in the trajectory of LGBTQ+ life in Turkey.
Spatiotemporal sequence of mesoderm and endoderm lineage segregation during mouse gastrulation
Authors: Probst Simone , Sagar  , Tosic Jelena , Schwan Carsten , Grün Dominic , Arnold Sebastian J.
Published: November 2020

Anterior mesoderm (AM) and definitive endoderm (DE) progenitors represent the earliest embryonic cell types that are specified during germ layer formation at the primitive streak (PS) of the mouse embryo. Genetic experiments indicate that both lineages segregate from Eomes-expressing progenitors in response to different Nodal signaling levels. However, the precise spatiotemporal pattern of the emergence of these cell types and molecular details of lineage segregation remain unexplored. We combined genetic fate labeling and imaging approaches with single-cell RNA sequencing (scRNA-seq) to follow the transcriptional identities and define lineage trajectories of Eomes-dependent cell types. Accordingly, all cells moving through the PS during the first day of gastrulation express Eomes. AM and DE specification occurs before cells leave the PS from Eomes-positive progenitors in a distinct spatiotemporal pattern. ScRNA-seq analysis further suggested the immediate and complete separation of AM and DE lineages from Eomes-expressing cells as last common bipotential progenitor.
Building neuromuscular junctions in vitro
Authors: Barbeau Susie , Tahraoui-Bories Julie , Legay Claire , Martinat Cécile
Published: November 2020

The neuromuscular junction (NMJ) has been the model of choice to understand the principles of communication at chemical synapses. Following groundbreaking experiments carried out over 60 years ago, many studies have focused on the molecular mechanisms underlying the development and physiology of these synapses. This Review summarizes the progress made to date towards obtaining faithful models of NMJs in vitro. We provide a historical approach discussing initial experiments investigating NMJ development and function from Xenopus to mice, the creation of chimeric co-cultures, in vivo approaches and co-culture methods from ex vivo and in vitro derived cells, as well as the most recent developments to generate human NMJs. We discuss the benefits of these techniques and the challenges to be addressed in the future for promoting our understanding of development and human disease.
Sequential peripheral enrichment of H2A.Zac and H3K9me2 during trophoblast differentiation in human embryonic stem cells
Authors: Kafer Georgia Rose , Tanaka Yoshihisa , Rillo-Bohn Regina , Shimizu Eiko , Hasegawa Kouichi , Carlton Peter M.
Published: November 2020

During the transition from pluripotency to a lineage-committed state, chromatin undergoes large-scale changes in structure, involving covalent modification of histone tails, use of histone variants and gene position changes with respect to the nuclear periphery. Here, using high-resolution microscopy and quantitative image analysis, we surveyed a panel of histone modifications for changes in nuclear peripheral enrichment during differentiation of human embryonic stem cells to a trophoblast-like lineage. We found two dynamic modifications at the nuclear periphery, acetylation of histone H2A.Z (H2A.Zac), and dimethylation of histone H3 at lysine 9 (H3K9me2). We demonstrate successive peripheral enrichment of these markers, with H2A.Zac followed by H3K9me2, over the course of 4 days. We find that H3K9me2 increases concomitantly with, but independently of, expression of lamin A, since deletion of lamin A did not affect H3K9me2 enrichment. We further show that inhibition of histone deacetylases causes persistent and increased H2A.Z acetylation at the periphery, delayed H3K9me2 enrichment and failure to differentiate. Our results show a concerted change in the nature of peripheral chromatin occurs upon differentiation into the trophoblast state.
Trackosome: a computational toolbox to study the spatiotemporal dynamics of centrosomes, nuclear envelope and cellular membrane
Authors: Castro Domingos , Nunes Vanessa , Lima Joana T. , Ferreira Jorge G. , Aguiar Paulo
Published: November 2020

During the initial stages of mitosis, multiple mechanisms drive centrosome separation and positioning. How they are coordinated to promote centrosome migration to opposite sides of the nucleus remains unclear. Here, we present Trackosome, an open-source image analysis software for tracking centrosomes and reconstructing nuclear and cellular membranes, based on volumetric live-imaging data. The toolbox runs in MATLAB and provides a graphical user interface for easy access to the tracking and analysis algorithms. It provides detailed quantification of the spatiotemporal relationships between centrosomes, nuclear envelope and cellular membrane, and can also be used to measure the dynamic fluctuations of the nuclear envelope. These fluctuations are important because they are related to the mechanical forces exerted on the nucleus by its adjacent cytoskeletal structures. Unlike previous algorithms based on circular or elliptical approximations, Trackosome measures membrane movement in a model-free condition, making it viable for irregularly shaped nuclei. Using Trackosome, we demonstrate significant correlations between the movements of the centrosomes, and identify specific oscillation modes of the nuclear envelope. Overall, Trackosome is a powerful tool that can be used to help unravel new elements in the spatiotemporal dynamics of subcellular structures.
Multipoint Recognition of Molecular Conformations with Organocatalysts for Asymmetric Synthetic Reactions
Authors: Asano Keisuke
Published: November 2020

Organocatalysts activate substrates through mild noncovalent and covalent interactions, and their cooperative actions at multiple catalytic sites are essential even in intrinsically rapid organic reactions such as intramolecular cyclizations. The enzyme-like catalytic system is effective for recognizing specific molecular conformations of substrates, which continually change under reaction conditions, through multipoint interactions, thereby leading to high stereoselectivity. On the basis of this concept, we developed a range of organocatalytic asymmetric synthetic reactions, which are challenging using other categories of catalysts. The proposed catalysis was applied to various manners of asymmetric induction including those accompanied by not only facial selectivity but also by kinetic resolution (KR), dynamic kinetic resolution (DKR), desymmetrization, and dynamic kinetic asymmetric transformation (DYKAT). They enabled various asymmetric transformations through intramolecular hetero-Michael addition, construction of axial chirality, and α,β-unsaturated acylammonium catalysis, which advanced the methods for asymmetric heterocycle synthesis, construction of tetrasubstituted chiral carbons, enantioselective synthesis of axially chiral compounds, and asymmetric library synthesis of pharmaceutically potential compounds. This study also expanded the chemistry of bifunctional organocatalysis. This review provides a comprehensive account of our achievements regarding multipoint recognition of molecular conformations with organocatalysts for asymmetric synthetic reactions.
Can diagnostic changes caused by cone beam computed tomography alter the clinical decision in impacted lower third molar treatment plan?
Authors: Mendonça Lucas Moreira , Gaêta-Araujo Hugo , Cruvinel Pedro Bastos , Tosin Ingrid Wenzel , Azenha Marcelo Rodrigues , Ferraz Emanuela Prado , Oliveira-Santos Christiano , Tirapelli Camila
Published: November 2020

Objectives:

This study observed whether changes in diagnosis caused by analysis of three-dimensional images can lead to alterations in the treatment plans of impacted lower third molars (ILTMs).

Methods:

Sets of panoramic (PAN) – cone beam computed tomography (CBCT) of 218 patients were assessed for ILTM classification, contact with mandibular canal, contact and resorption of the lower second molar (LSM), intraoperative planning and post-operative expectations.

Results:

Percentage agreement and McNemar test compared PAN vs CBCT assessments. Logistic regression analyzed the dependency of change in surgical planning considering the changes in diagnostic features; descriptive statistics was used to observe the expectation of post-operative complications and paresthesia. Differences were found between PAN vs CBCT for classification of impaction and positioning, LSM relationship, choice for crown and root sectioning and expectation of post-operative complications (all with p < 0.001). Logistic regression indicated that the change in diagnosis caused by CBCT examination did not change the clinical decision to extract ILTM but altered the planning of intraoperative steps such as osteotomy, crown sectioning and relaxing incision. The expectation of post-operative complications decreased when professionals planned the ILTM removal using tri-dimensional images.

Conclusions:

We concluded that changes in the diagnosis after CBCT examination can lead to alterations in the treatment plan of impacted lower third molar.
Predictors of Choosing Business Analytics Concentration and Consequent Academic Performance
Authors: Mitra Sinjini , Goldstein Zvi , Kapoor Bhushan L.
Published: November 2020

Choosing a major field of study is important, and so is the selection of a specialized concentration that is aligned with an individual’s career aspirations. In this paper, we explore a relatively newer concentration in the area of business, namely business analytics. The field of analytics has seen a rapid growth in recent years and enrollment in college degree programs in this area has also skyrocketed. The goal of this study is to understand the primary reasons that influence a student’s decision to self-select a concentration of business analytics at a large public university. Moreover, we determine which factors are likely to have a significant effect on the performance of students enrolled in this concentration. The primary factors considered are individuals’ bright and dark personality traits, self-perceived satisfaction in related courses, along with several background control factors. The major insights obtained from analyzing our data revealed a significant effect of certain personality characteristics on both students’ concentration choice (extraversion, narcissism) and on performance (conscientiousness, emotional stability, narcissism). On the other hand, students’ performance in foundational courses in the concentration and self-perceived satisfaction in the chosen concentration had no statistically significant effect on their performance.
Blood: this life-saving fluid
Authors: Peate Ian
Published: November 2020

The key function of blood is to deliver oxygen and nutrients to, and remove waste from, the cells; the blood also has a number of other functions to perform. This article in the anatomy and physiology (A&P) series offers an overview of this life-saving fluid. It emphasises the need for those who provide care and support to develop an understating of blood and its various functions in illness and health. Understanding the function of blood can help offer people care that is safe, effective and informed.

The article considers the various components of blood. The various functions of blood, including its role in transportation, regulation and protection, are described. Understanding these issues can help in ensuring care is safe and appropriate.

The article offers a glossary of terms that can help in understanding some of the terms used. A short quiz is provided so as to reinforce learning.
Pharmacotherapy in arrhythmias: an overview of anti-arrhythmic drug therapy
Authors: Eftekhari Helen
Published: November 2020

The article aims to give an overview of the principles in anti-arrhythmic drug prescribing. Practitioners assessing cardiac patients are highly likely to review anti-arrhythmic drug therapies and need an understanding of the principles of therapy. The cardiac action potential is explained, followed by general principles involved in treating arrhythmias and prescribing decisions. An overview of the five classifications of anti-arrhythmic drugs is given, with examples of the main drugs in the classification and principles to consider within each. Finally anticoagulation is reviewed being a cornerstone prescribing decision in the most common arrhythmia, atrial fibrillation.
Dermatology prescribing update: eczema
Authors: Van Onselen Julie
Published: November 2020

Eczema is a common skin condition, which for the majority is managed in primary care. Nurse prescribers should be aware of evidence–based guidelines in eczema treatment, on which they need to base prescribing decisions and work with the patient on individual skin care plans. Education and support in managing eczema is essential for patients of all ages (and carers of children and older people). Eczema has a huge impact on quality of life but a good management plan can make a big difference to controlling eczema, which is a chronic condition. This article explains the principles of eczema treatments, in acute, sub-acute and chronic stages of eczema with emollients, topical corticosteroids, antibiotics, antimicrobials and antivirals, topical calcineurin inhibitors and antihistamines.
Exit, Voice or Loyalty? VET Stakeholders’ Response to Large Scale Skilled Emigration From Poland
Authors: Reegård Kaja , Debowski Horacy
Published: November 2020

Context: The topic of this paper is how mass emigration of skilled workers affects national policies, and employers’ willingness to invest in Vocational Education and Training (VET) in Poland. In the wake of EU enlargement in 2004, Poland became one of the biggest sending countries for skilled labour to Western European countries. These massive outflows of skilled labour, not compensated by adequate inflows of equally skilled workers, have led to serious skills shortages, especially in the construction sector. The paper investigates whether emigration and immigration constitute a driving force for institutional change of the Polish VET system, by analysing policy development and the attitudes of VET stakeholders towards contributing to VET.Approach: The paper focuses on the emigration of skilled construction workers in Poland. Drawing on Hirschman’s (1970) framework, when faced with massive skills deficits construction companies are confronted with different options: i) withdraw from the VET system and find other training and recruitment options (exit), ii) attempt to improve conditions by turning to policy makers (voice), and/or iii) remain loyal to the VET system. The analysis is based on an interview study of decision makers responsible for VET policies, employers, chamber of Craft and trade unions, principals of vocational schools, teachers and representatives of regional examination boards.Findings: After years of inattention, VET has been regaining a strong position in national policies. We find that construction companies are mostly more willing now, compared to 5 years ago, to take on learners for practical training and to contribute to improving school equipment. The study showed that one of the most significant obstacles to employers investing in the training of VET learners is the fear of losing a young skilled employee through emigration. Yet, dependent on skilled labour, employers of big construction companies saw no other option than to continue investing in training young learners. However, smaller companies seeking the short-term benefits of employing low-cost labour are less interested in investing in VET.Conclusion: Despite a range of recent policy actions and legislative efforts, several major challenges in the Polish VET system remain unresolved. Continued effort to institutionalise and enhance dialogue between the education system and the labour market appears as the most pressing need. It is currently too early to determine the degree of "institutional stickiness" of the activities observed on the policy level and among employers regarding their increased interest in VET as a response to mass skilled emigration.
The sticky steps of the career ladder for engineers: the case of first-generation students in Germany
Authors: Huesmann Monika , Calveley Moira , Smith Paul , Forson Cynthia , Rosenbaum Lisa
Published: November 2020

Although governments and higher education institutions across Europe are promoting agendas for widening the educational participation and increasing the social mobility of young people from lower socio-economic groups, very little has been written about the experiences of these individuals when seeking and entering employment. We aim to address this gap. Using a qualitative research approach, we explore the career expectations, experiences and limitations of first-generation university engineering students and graduates in Germany. The article draws upon the work of Pierre Bourdieu to demonstrate how social and cultural capitals instilled by parents and social peers are invaluable in developing personal and professional networks and eventual entry into the engineering professions. A lack of, or underdeveloped, capitals can inhibit career opportunities and ultimately the social mobility and professional choices of graduate engineers. Our research discovered that university graduates from less advantaged backgrounds face a ‘class ceiling’ at university, in obtaining an internship and then when gaining entry to and working in the engineering profession; they encounter ‘sticky steps’ at each stage of their career ladder.
Intrinsic spectrally-dependent background in spectroscopic visible-light optical coherence tomography
Authors: Rubinoff Ian , Kuranov Roman V. , Zhang Hao F.
Published: November 2020

Visible-light optical coherence tomography (vis-OCT) has enabled new spectroscopic applications, such as retinal oximetry, as a result of increased optical absorption and scattering contacts in biological tissue and improved axial resolution. Besides extracting tissue properties from back-scattered light, spectroscopic analyses must consider spectral alterations induced by image reconstruction itself. We investigated an intrinsic spectral bias in the background noise floor, which is hereby referred to as the spectrally-dependent background (SDBG). We developed an analytical model to predict the SDBG-induced bias and validated this model using numerically simulated and experimentally acquired data. We found that SDBG systemically altered the measured spectra of blood in human retinal vessels in vis-OCT, as compared to literature data. We provided solutions to quantify and compensate for SDBG in retinal oximetry. This work is particularly significant for clinical applications of vis-OCT.
Programmable VCSEL-based photonic system architecture for future agile Tb/s metro networks
Authors: Moreolo M. Svaluto , Fabrega J. M. , Nadal L. , Martínez R. , Casellas R. , Vílchez J. , Muñoz R. , Vilalta R. , Gatto A. , Parolari P. , Boffi P. , Neumeyr C. , Larrabeiti D. , Otero G. , Fernández-Palacios J. P.
Published: November 2020

To deal with the challenging requirements of metropolitan area networks (MANs), it is essential to design cost-effective systems that can support high capacity and dynamic adaptation, as well as a synergy of programmability and efficient photonic technologies. This becomes crucial for very large MANs that support 5G, where multihop connections will need to be dynamically established at target capacities beyond Tb/s. Programmability, automation, and modularity of network elements are key desired features. In this work, a modular photonic system, programmable via a software-defined networking platform, designed for dynamic 5G-supportive MANs, is described and analyzed. We consider modular sliceable bandwidth/bit rate variable transceivers (S-BVTs) based on vertical-cavity surface-emitting laser (VCSEL) technology and dense photonic integration. The proposed system and its programmability are experimentally assessed using a VCSEL with 10 GHz bandwidth. The experiments are performed over connections as long as six-hop and 160 km, from low-level aggregation nodes to metro-core nodes, thereby enabling IP off-loading. Furthermore, a numerical model is derived to estimate the performance when adopting higher bandwidth VCSELs (

≥

18

G
H
z

) and integrated coherent receivers, as targeted in the proposed system. The analysis is performed for both 50 GHz and 25 GHz granularities. In the former case, 50 Gb/s capacity per flow can be supported over the targeted connections, for optical signal-to-noise ratio values above 26 dB. When the granularity is 25 GHz, the filter narrowing effect severely impacts the performance. Nevertheless, 1.2 Tb/s capacity (scalable to higher values if spectral/spatial dimensions are exploited) can be achieved when configuring the S-BVT to enable 40 VCSEL flows. This confirms that the system is promising to support Tb/s connections in future agile MANs.
Realization of general first-order optical systems using thin lenses of arbitrary focal length and fixed free propagation distance
Authors: Yasir P. A. Ameen
Published: November 2020

Any general first-order optical system can be represented using

S

∈
S
p
(
4
,

R

)

, where

S
p
(
4
,

R

)

is the symplectic group with real entries in four dimensions. We prove that any

S

∈
S
p
(
4
,

R

)

can be realized using not more than 18 thin lenses of arbitrary focal length and seven unit distance. New identities that realize

S

=

S
1

⊕

S
2

, where

S
1

,

S
2

∈
S
p
(
2
,

R

)

, are obtained. Also, it is proved any

S

of the form

S
1

⊕

S
2

can be realized using a maximum of eight thin lenses of arbitrary focal length and three unit distance. Moreover, decompositions for examples such as differential magnifier, partial Fourier transform, and inverse partial Fourier transform are also provided. A “gadget” is proposed that can realize any

S

∈
S
p
(
4
,

R

)

using thin lens transformations—which can be realized through the use of eight spatial light modulators (SLMs) and seven unit distance. Experimental limitation imposed by SLMs while realizing thin lens transformations is also outlined. The justification for the choice of unit distance according to the availability of thin lenses in a lab is given too.
Adjustable and stable beam profile generation in a Yb:YAG thin-disk laser
Authors: Song Enmao , Dai Tianrui , Zhu Guangzhi , Wang Hailin , Aleksei Kozlov , Zhu Xiao
Published: November 2020

We present a Yb:YAG thin-disk laser with an adjustable and stable beam profile. A double-cavity geometry with an acousto-optic modulator (AOM) makes the spatial separation of the gain area, in which the central and external parts are used for

L
G

00

and

L
G

01

mode generation, respectively. By changing the loss of the AOM, the beam profile of the primary cavity is adjustable from annularity to flat-top continuously. At input pump power of 44 W, 8.5 W annular, 11.1 W shallow crater-shaped, and 12.1 W flat-topped modes were obtained. Moreover, the thin-disk laser with a multi-pass pumping scheme not only improves thermal management, but also minimizes depolarization loss, allowing the optimization of mode stability and laser performances. This Letter implies that a high-power laser with an adjustable and stable beam profile can be implemented via this scheme.
Spectral broadening of ultraviolet dispersive waves in gas-filled hollow-core fiber using pump pulse modulation
Authors: Smith Callum R. , Adamu Abubakar I. , Michieletto Mattia , Bang Ole
Published: November 2020

UV supercontinuum laser sources based on resonant dispersive wave (RDW) generation in gas-filled hollow-core (HC) fibers offer an attractive architecture for numerous applications. However, the narrow UV spectral peak inherent to RDW generation limits the suitability for applications that require broad spectral coverage within the UV region such as spectroscopic scatterometry. In this Letter, we demonstrate how the UV spectrum can be shaped by modulating the peak power of the pump pulses driving the RDW generation, thereby creating a broadened and flattened UV spectrum. Using an argon-filled anti-resonant HC fiber, we generate a UV spectrum with a center wavelength of 323.6 nm with an FWHM of 51.7 nm, corresponding to a relative bandwidth of 16.1%.
A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar
Authors: Watson James A. , Lamb Thomas , Holmes Jane , Warrell David A. , Thwin Khin Thida , Aung Zaw Lynn , Oo Min Zaw , Nwe Myat Thet , Smithuis Frank , Ashley Elizabeth A.
Published: November 2020

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined ‘optimal dose’. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell’s viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified ‘3+3’ design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.
Long-read RNA sequencing of human and animal filarial parasites improves gene models and discovers operons
Authors: Wheeler Nicolas J , Airs Paul M. , Zamanian Mostafa
Published: November 2020

Filarial parasitic nematodes (Filarioidea) cause substantial disease burden to humans and animals around the world. Recently there has been a coordinated global effort to generate, annotate, and curate genomic data from nematode species of medical and veterinary importance. This has resulted in two chromosome-level assemblies (Brugia malayi and Onchocerca volvulus) and 11 additional draft genomes from Filarioidea. These reference assemblies facilitate comparative genomics to explore basic helminth biology and prioritize new drug and vaccine targets. While the continual improvement of genome contiguity and completeness advances these goals, experimental functional annotation of genes is often hindered by poor gene models. Short-read RNA sequencing data and expressed sequence tags, in cooperation with ab initio prediction algorithms, are employed for gene prediction, but these can result in missing clade-specific genes, fragmented models, imperfect mapping of gene ends, and lack of isoform resolution. Long-read RNA sequencing can overcome these drawbacks and greatly improve gene model quality. Here, we present Iso-Seq data for B. malayi and Dirofilaria immitis, etiological agents of lymphatic filariasis and canine heartworm disease, respectively. These data cover approximately half of the known coding genomes and substantially improve gene models by extending untranslated regions, cataloging novel splice junctions from novel isoforms, and correcting mispredicted junctions. Furthermore, we validated computationally predicted operons, manually curated new operons, and merged fragmented gene models. We carried out analyses of poly(A) tails in both species, leading to the identification of non-canonical poly(A) signals. Finally, we prioritized and assessed known and putative anthelmintic targets, correcting or validating gene models for molecular cloning and target-based anthelmintic screening efforts. Overall, these data significantly improve the catalog of gene models for two important parasites, and they demonstrate how long-read RNA sequencing should be prioritized for ongoing improvement of parasitic nematode genome assemblies.
Improving five-year survival prediction via multitask learning across HPV-related cancers
Authors: Goncalves Andre , Soper Braden , Nygård Mari , Nygård Jan F. , Ray Priyadip , Widemann David , Sales Ana Paula
Published: November 2020

Oncology is a highly siloed field of research in which sub-disciplinary specialization has limited the amount of information shared between researchers of distinct cancer types. This can be attributed to legitimate differences in the physiology and carcinogenesis of cancers affecting distinct anatomical sites. However, underlying processes that are shared across seemingly disparate cancers probably affect prognosis. The objective of the current study is to investigate whether multitask learning improves 5-year survival cancer patient survival prediction by leveraging information across anatomically distinct HPV related cancers. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program database. The study cohort consisted of 29,768 primary cancer cases diagnosed in the United States between 2004 and 2015. Ten different cancer diagnoses were selected, all with a known association with HPV risk. In the analysis, the cancer diagnoses were categorized into three distinct topography groups of varying specificity. The most specific topography grouping consisted of 10 original cancer diagnoses differentiated by the first two digits of the ICD-O-3 topography code. The second topography grouping consisted of cancer diagnoses categorized into six distinct organ groups. Finally, the third topography grouping consisted of just two groups, head-neck cancers and ano-genital cancers. The tasks were to predict 5-year survival for patients within the different topography groups using 14 predictive features which were selected among descriptive variables available in the SEER database. The information from the predictive features was shared between tasks in three different ways, resulting in three distinct predictive models: 1) Information was not shared between patients assigned to different tasks (single task learning); 2) Information was shared between all patients, regardless of task (pooled model); 3) Only relevant information was shared between patients grouped to different tasks (multitask learning). Prediction performance was evaluated with Brier scores. All three models were evaluated against one another on each of the three distinct topography-defined tasks. The results showed that multitask classifiers achieved relative improvement for the majority of the scenarios studied compared to single task learning and pooled baseline methods. In this study, we have demonstrated that sharing information among anatomically distinct cancer types can lead to improved predictive survival models.
Can the use of older-generation beta-lactam antibiotics in livestock production over-select for beta-lactamases of greatest consequence for human medicine? An in vitro experimental model
Authors: Ogunrinu Olanrewaju J. , Norman Keri N. , Vinasco Javier , Levent Gizem , Lawhon Sara D. , Fajt Virginia R. , Volkova Victoria V. , Gaire Tara , Poole Toni L. , Genovese Kenneth J. , Wittum Thomas E. , Scott H. Morgan
Published: November 2020

Though carbapenems are not licensed for use in food animals in the U.S., carbapenem resistance among Enterobacteriaceae has been identified in farm animals and their environments. The objective of our study was to determine the extent to which older-generation β-lactam antibiotics approved for use in food animals in the U.S. might differentially select for resistance to antibiotics of critical importance to human health, such as carbapenems.Escherichia coli (E.coli)strains from humans, food animals, or the environment bearing a single β-lactamase gene (n = 20 each) forblaTEM-1,blaCMY-2, andblaCTX-M-*or elseblaKPC/IMP/NDM(due to limited availability, often in combination with otherblagenes), were identified, along with 20E.colistrains lacking any known beta-lactamase genes. Baseline estimates of intrinsic bacterial fitness were derived from the population growth curves. Effects of ampicillin (32 μg/mL), ceftriaxone (4 μg/mL) and meropenem (4 μg/mL) on each strain and resistance-group also were assessed. Further,in vitrobatch cultures were prepared by mixing equal concentrations of 10 representativeE.colistrains (two from each resistance gene group), and each mixture was incubated at 37°C for 24 hours in non-antibiotic cation-adjusted Mueller-Hinton II (CAMH-2) broth, ampicillin + CAMH-2 broth (at 2, 4, 8, 16, and 32 μg/mL) and ceftiofur + CAMH-2 broth (at 0.5, 1, 2, 4, and 8μg/mL). Relative and absolute abundance of resistance-groups were estimated phenotypically. Line plots of the raw data were generated, and non-linear Gompertz models and multilevel mixed-effect linear regression models were fitted to the data. The observed strain growth rate distributions were significantly different across the groups. AmpC strains (i.e.,blaCMY-2) had distinctly less robust (p < 0.05) growth in ceftriaxone (4 μg/mL) compared to extended-spectrum beta-lactamase (ESBL) producers harboringblaCTX-M-*variants. With increasing beta-lactam antibiotic concentrations, relative proportions of ESBLs and CREs were over-represented in the mixed bacterial communities; importantly, this was more pronounced with ceftiofur than with ampicillin. These results indicate that aminopenicillins and extended-spectrum cephalosporins would be expected to propagate carbapenemase-producing Enterobacteriaceae in food animals if and when Enterobacteriaceae from human health care settings enter the food animal environment.
Selection signatures in two oldest Russian native cattle breeds revealed using high-density single nucleotide polymorphism analysis
Authors: Zinovieva Natalia Anatolievna , Dotsev Arsen Vladimirovich , Sermyagin Alexander Alexandrovich , Deniskova Tatiana Evgenievna , Abdelmanova Alexandra Sergeevna , Kharzinova Veronika Ruslanovna , Sölkner Johann , Reyer Henry , Wimmers Klaus , Brem Gottfried
Published: November 2020

Native cattle breeds can carry specific signatures of selection reflecting their adaptation to the local environmental conditions and response to the breeding strategy used. In this study, we comprehensively analysed high-density single nucleotide polymorphism (SNP) genotypes to characterise the population structure and detect the selection signatures in Russian native Yaroslavl and Kholmogor dairy cattle breeds, which have been little influenced by introgression with transboundary breeds. Fifty-six samples of pedigree-recorded purebred animals, originating from different breeding farms and representing different sire lines, of the two studied breeds were genotyped using a genome-wide bovine genotyping array (Bovine HD BeadChip). Three statistical analyses—calculation of fixation index (FST) for each SNP for the comparison of the pairs of breeds, hapFLK analysis, and estimation of the runs of homozygosity (ROH) islands shared in more than 50% of animals—were combined for detecting the selection signatures in the genome of the studied cattle breeds. We confirmed nine and six known regions under putative selection in the genomes of Yaroslavl and Kholmogor cattle, respectively; the flanking positions of most of these regions were elucidated. Only two of the selected regions (localised on BTA 14 at 24.4–25.1 Mbp and on BTA 16 at 42.5–43.5 Mb) overlapped in Yaroslavl, Kholmogor and Holstein breeds. In addition, we detected three novel selection sweeps in the genome of Yaroslavl (BTA 4 at 4.74–5.36 Mbp, BTA 15 at 17.80–18.77 Mbp, and BTA 17 at 45.59–45.61 Mbp) and Kholmogor breeds (BTA 12 at 82.40–81.69 Mbp, BTA 15 at 16.04–16.62 Mbp, and BTA 18 at 0.19–1.46 Mbp) by using at least two of the above-mentioned methods. We expanded the list of candidate genes associated with the selected genomic regions and performed their functional annotation. We discussed the possible involvement of the identified candidate genes in artificial selection in connection with the origin and development of the breeds. Our findings on the Yaroslavl and Kholmogor breeds obtained using high-density SNP genotyping and three different statistical methods allowed the detection of novel putative genomic regions and candidate genes that might be under selection. These results might be useful for the sustainable development and conservation of these two oldest Russian native cattle breeds.
A systematic review of risk communication in clinical trials: How does it influence decisions to participate and what are the best methods to improve understanding in a trial context?
Authors: Coyle Maeve , Gillies Katie
Published: November 2020

Background

Effective risk communication is challenging. Ensuring potential trial participants’ understand ‘risk’ information presented to them is a key aspect of the informed consent process within clinical trials, yet minimal research has looked specifically at how to communicate probabilities to support decisions about trial participation. This study reports a systematic review of the literature focusing on presentation of probabilistic information or understanding of risk by potential trial participants.

Methods

A search strategy for risk communication in clinical trials was designed and informed by systematic reviews of risk communication in treatment and screening contexts and supplemented with trial participation terms. Extracted data included study characteristics and the main interventions/findings of each study. Explanatory studies that investigated the methods for presenting probabilistic information within participant information leaflets for a clinical trial were included, as were interventions that focused on optimising understanding of probabilistic information within the context of a clinical trial.

Results

The search strategy identified a total of 4931 studies. Nineteen papers were selected for full text screening, and seven studies included. All reported results from risk communication studies that aimed to support potential trial participants’ decision making set within hypothetical trials. Five of these were randomised comparisons of risk communication interventions, and two were prospectively designed, non-randomised studies. Study interventions focused on probability presentation, risk framing and risk interpretation with a wide variety of interventions being evaluated and considerable heterogeneity in terms of outcomes assessed. Studies show conflicting findings when it comes to how best to present information, although numerical, particularly frequency formats and some visual aids appear to have promise.

Conclusions

The evidence base surrounding risk communication in clinical trials indicates that there is as yet no clear optimal method for improving participant understanding, or clear consensus on how it affects their willingness to participate. Further research into risk communication within trials is needed to help illuminate the mechanisms underlying risk perception and understanding and provide appropriate ways to present and communicate risk in a trial context so as to further promote informed choices about participation. A key focus for future research should be to investigate the potential for learning in the evidence on risk communication from treatment and screening decisions when applied to decisions about trial participation.