bluuebunny/crossref_metadata_2025 huggingface dataset:
No need to hesitate: immune‐related neutropenia and thrombocytopenia that improved by corticosteroids
Authors: Kanai Osamu , Nakatani Koichi , Fujita Kohei , Okamura Misato , Mio Tadashi
Published: June 2021

Unlike cytotoxicity, haematological toxicity is a rare immune‐related adverse event that is occasionally irreversible and refractory. A 67‐year‐old man was diagnosed with advanced lung squamous cell carcinoma. After 41 cycles of nivolumab as third‐line chemotherapy, the patient developed severe neutropenia and thrombocytopenia. The bone marrow biopsy and serum immunological tests indicated no evidence of bone marrow failure and suggested autoimmune mature blood cell destruction. After initiating treatment with prednisolone 50 mg orally and filgrastim 75 μg subcutaneously once daily, neutropenia and thrombocytopenia recovered within four and nine days, respectively. The filgrastim was discontinued four days later, and the corticosteroid was discontinued three months later; there has been no haemocytopenia recurrence since then. The patient has remained untreated for more than two years without progression of lung cancer. In conclusion, corticosteroids should be considered for the treatment of autoimmune haemocytopenia if refractory bone marrow dysplasia can be ruled out.
Frequency delay‐dependent stability criterion for time‐delay systems thanks to Fourier–Legendre remainders
Authors: Bajodek Mathieu , Gouaisbaut Frédéric , Seuret Alexandre
Published: June 2021

This paper investigates the stability of a linear finite‐dimensional system interconnected to a single delay operator. From robust approaches, to derive delay‐dependent frequency tests, a characterization of the delay behavior is required. Based on approximation methods, one describes the transported signal by lumped parameters. More precisely, by the use of the first Fourier–Legendre polynomials coefficients, we split the delay block into a finite‐dimensional part interconnected to a specific infinite‐dimensional residual part. Two models are investigated with residuals related to two Fourier–Legendre remainders of the delayed transfer function. The main contribution is to highlight that the finite‐dimensional models based on the first Legendre coefficients are proven to be related to Padé approximations and are recognized to be more and more accurate as the dimension increases. Interestingly, this modeling allows computing in an accurate manner the root locus of time‐delay systems. Furthermore, as a by‐product of this result, taking into account the infinite‐dimensional remainders to keep track of the initial time‐delay system, stability criteria are proposed by analysis. Considering both infinite‐dimensional remainders as bounded delay‐free uncertainties, the small‐gain theorem provides a new sufficient condition of stability for retarded time‐delay systems, which can be implemented as a delay‐dependent frequency‐sweeping test. Our results are illustrated on several academic examples.
Qualitatively different ways of unpacking visual representations when teaching intermolecular forces in upper secondary school
Authors: Patron Emelie , Linder Cedric , Wikman Susanne
Published: June 2021

Since visual representations play a particularly important role in the teaching and learning of chemistry, the exploration described in this article focuses on them. This is an explorative study of the qualitatively different ways that visual representations can be unpacked by Swedish upper secondary school chemistry teachers dealing with intermolecular forces. Unpacking is characterized as the ways that visual representations get used to open up the possibility of having the critical aspects and features of an intended object of learning being brought into focal awareness, initially on their own and then simultaneously. The analysis, which combines a phenomenographic and a social semiotic approach, leads to the characterizations of five qualitatively different ways that visual representations may be unpacked. These outcome categories are presented in terms of a conceptual hierarchy, where two of these ways of unpacking are characterized as being teacher‐centered and the other three as student‐centered. This leads to a case being made that if teachers use student‐centered ways of unpacking visual representations, then their students will be more likely to gain greater access to critical aspects and features of the enacted object of learning. We argue that in terms of making theoretical and practical contributions to the phenomenographic perspective on learning, the results can be used as a tool for researchers wishing to explore how visual representations can be used effectively in science education and also provide a useful basis for discussion in teacher education and in teacher professional development programs.
Learning to teach science during the clinical experience: Agency, opportunity, and struggle
Authors: Windschitl Mark , Lohwasser Karin , Tasker Tammy , Shim Soo‐Yean , Long Caroline
Published: June 2021

Agency has been used as a lens to focus on how educators learn through pedagogical risk‐taking, advocacy for curricular reform, and resisting policies that are not focused on the needs of students. We explored the role of agency as 65 preservice science teachers created learning opportunities for themselves during their clinical placements. Specifically, we investigated whether the types of agentive episodes varied by the level of congruence novices perceived between the vision of science teaching supported in their university coursework and the prevailing practices and culture of their host classrooms. Interview and survey data of participants from three preparation programs indicate that those in highly congruent placements experienced earlier and more mentor‐scaffolded opportunities to take on active roles in teaching, and exercised agency to extend research‐informed practices or tools they observed their mentors using. This resulted in participants seeing the richness of students' thinking and how capable they were of challenging work, given strategic supports. Those in low congruence placements had fewer chances to play active roles in teaching, were more likely to draw upon agency to make minor adjustments as they emulated their mentors' instructionally conservative lessons, and expressed concern they were “getting better” at aspects of teaching they viewed as inequitable or less responsive to students. Regardless of congruence, however, even simple acts of agency such as asking mentors to explain their instructional decisions were remarkably rare.
Sibling Umbilical Cord Blood Infusion is Safe in Young Children with Cerebral Palsy
Authors: Sun Jessica M. , Case Laura E. , Mikati Mohamad A. , Jasien Joan M. , McLaughlin Colleen , Waters-Pick Barbara , Worley Gordon , Troy Jesse , Kurtzberg Joanne
Published: June 2021

Preclinical and early phase clinical studies suggest that an appropriately dosed umbilical cord blood (CB) infusion has the potential to help improve motor function in young children with cerebral palsy (CP). As many children with CP do not have their own CB available, use of allogeneic cells would extend access to this potentially beneficial therapy to more children. In this phase I, open-label study, 15 children, aged 1 to 6 years, with moderate to severe spastic CP were treated with a single intravenous infusion of allogeneic human leukocyte antigen (HLA) matched or partially matched sibling CB with a cell dose of ≥2.5 × 107 cells/kg based on the pre-cryopreservation count (median infused cell dose, 3.3 × 107; range, 1.8-5.2 × 107). There were a total of 49 adverse events (AEs) over a 2-year time period, but there were no AEs related to the CB infusions. Specifically, there were no acute infusion reactions and no antibody formation against platelets, red blood cells, or donor-specific HLA antigens. Donor cells were not detected in peripheral blood 6 months later. Six months after infusion, participants were assessed for response and experienced a mean ± SD increase of 4.7 ± 2.5 points on the Gross Motor Function Measure-66 and 1 ± 2.9 points on the Peabody Gross Motor Quotient. Appropriately dosed, allogeneic partially or fully HLA-matched sibling CB infusion is well tolerated and potentially beneficial in young children with CP.
Interferometric 4D‐STEM for Lattice Distortion and Interlayer Spacing Measurements of Bilayer and Trilayer 2D Materials
Authors: Zachman Michael J. , Madsen Jacob , Zhang Xiang , Ajayan Pulickel M. , Susi Toma , Chi Miaofang
Published: June 2021

Van der Waals materials composed of stacks of individual atomic layers have attracted considerable attention due to their exotic electronic properties that can be altered by, e.g., manipulating the twist angle of bilayer materials or the stacking sequence of trilayer materials. To fully understand and control the unique properties of these few‐layer materials, a technique that can provide information about their local in‐plane structural deformations, twist direction, and out‐of‐plane structure is needed. In principle, interference in overlap regions of Bragg disks originating from separate layers of a material encodes 3D information about the relative positions of atoms in the corresponding layers. Here, an interferometric 4D scanning transmission electron microscopy technique is described that utilizes this phenomenon to extract precise structural information from few‐layer materials with nm‐scale resolution. It is demonstrated how this technique enables measurement of local pm‐scale in‐plane lattice distortions as well as twist direction and average interlayer spacings in bilayer and trilayer graphene, and therefore provides a means to better understand the interplay between electronic properties and precise structural arrangements of few‐layer 2D materials.
A Polarization Boosted Strategy for the Modification of Transition Metal Dichalcogenides as Electrocatalysts for Water‐Splitting
Authors: Chen Guanyu , Zhang Chang , Xue Shuyan , Liu Jiwei , Wang Yizhe , Zhao Yunhao , Pei Ke , Yu Xuefeng , Che Renchao
Published: June 2021

The design and fabrication of transition metal dichalcogenides (TMDs) are of paramount significance for water‐splitting process. However, the limited active sites and restricted conductivity prevent their further application. Herein, a polarization boosted strategy is put forward for the modification of TMDs to promote the absorption of the intermediates, leading to the improved catalytic performance. By the forced assembly of TMDs (WS2 as the example) and carbon nanotubes (CNTs) via spray‐drying method, such frameworks can remarkably achieve low overpotentials and superior durability in alkaline media, which is superior to most of the TMDs‐based catalysts. The two‐electrode cell for water‐splitting also exhibits perfect activity and stability. The enhanced catalytic performance of WS2/CNTs composite is mainly owing to the strong polarized coupling between CNTs and WS2 nanosheets, which significantly promotes the charge redistribution on the interface of CNTs and WS2. Density functional theory (DFT) calculations show that the CNTs enrich the electron content of WS2, which favors electron transportation and accelerates the catalysis. Moreover, the size of WS2 is restricted caused by the confinement of CNTs, leading to the increased numbers of active sites, further improving the catalysis. This work opens a feasible route to achieve the optimized assembling of TMDs and CNTs for efficient water‐splitting process.
High‐Efficiency Anion‐Exchange Membrane Water Electrolyzer Enabled by Ternary Layered Double Hydroxide Anode
Authors: Lee Jooyoung , Jung Hyeonjung , Park Yoo Sei , Woo Seongwon , Yang Juchan , Jang Myeong Je , Jeong Jaehoon , Kwon Nayoung , Lim Byungkwon , Han Jeong Woo , Choi Sung Mook
Published: June 2021

Developing high‐efficiency and low‐cost oxygen‐evolving electrodes in anion exchange membrane (AEM) water electrolysis technology is one of the major challenges. Herein, it is demonstrated that the surface corrosion of a conventional Ni foam electrode in the presence of Fe3+ and V3+ cations can transform it into an electrode with a high catalytic performance for oxygen evolution reaction (OER). The corroded electrode consists of a ternary NiFeV layered double hydroxide (LDH) nanosheet array supported on the Ni foam surface. This NiFeV LDH electrode achieves an OER current density of 100 mA cm−2 at an overpotential of 272 mV in 1 m KOH, outperforming the IrO2 catalyst by 180 mV. Density functional theory calculations reveal that the unique structure and the presence of vanadium in NiFeV LDH play a key role in achieving improved OER activity. When coupled with a commercial Pt/C cathode catalyst, the resulting AEM water electrolyzer achieves a cell current density as high as 2.1 A cm−2 at a voltage of only 1.8 Vcell in 1 m KOH, which is similar to the performance of the proton exchange membrane water electrolyzer obtained from the IrO2 and Pt/C catalysts pair.
A framework for modeling structural association among De‐Motivators of scaling agile
Authors: Abrar Muhammad Faisal , Ali Sikandar , Majeed Muhammad Faran , Khan Sohail , Khan Muzamil , Ullah Hamid , Khan Mushtaq Ahmad , Baseer Samad , Asshad Muhammad
Published: June 2021

Usage of agile methods for software development has increased in recent times. Rapid delivery of software products is ensured by these methods with less expense and high user gratification. Application of these methods on a large scale causes many De‐Motivators or challenges as initially these methods were aimed at those developmental teams that worked on small scale. However, no effort has been made yet to hand out the various correlations among the challenges. To fill the space, the Interpretive Structural Model (ISM) approach is used to reconnoiter the correlations among the De‐Motivators regarding Scaling Agile Software Development Methodologies (ASDM) from the management perspective. Creation of a framework for structural modeling association among the De‐Motivators is the aim of this study. To attain the goal, a hybrid methodology was applied based on a Systematic literature review (SLR), empirical survey, and ISM. First, we pointed out 15 De‐Motivators of Scaling ASDM from management perspectives through SLR study. Second, with the help of 59 experts from different countries, a questionnaire survey was conducted to empirically examine the correlations among the detected De‐Motivators. Further, correlations among the challenges are discovered with the usage of ISM through review of the panel, and they accomplish the categorization through CrossImpact Matrix Multiplication Applied Approach.
Regio‐ and Stereoselective Functionalization Enabled by Bidentate Directing Groups
Authors: Jeon Jinwon , Lee Changseok , Park Inyoung , Hong Sungwoo
Published: June 2021

Chelation‐assisted C−H bond and alkene functionalization using bidentate directing groups offers an elegant and versatile approach to overcome regiocontrol issues by allowing the catalyst to come into close proximity with the targeted sites. In this personal account, we highlight our recent works in developing regio‐ and stereocontrolled functionalizations through transition‐metal catalysis enabled by bidentate directing groups. We classify our results into two categories: (1) regioselective alkene functionalization using bidentate directing groups, and (2) asymmetric C–H functionalization using chiral bidentate directing groups. Furthermore, density functional theory studies to elucidate the origin of the regio‐ and stereoselectivity exerted by bidentate directing groups are discussed.
Vets celebrate World Environment Day
Authors: Raynsford Charlotte
Published: June 2021

BVA media officer Charlotte Raynsford explains how BVA showed its support for #WorldEnvironmentDay 2021.
Leaving vet nursing for a short‐term sales role was a risk that paid off
Authors: Covell Charlotte
Published: June 2021

Charlotte Covell took over as managing director of Virbac UK and Ireland in January. She joined the company as a territory manager, before advancing through various roles to get to where she is today.
Arthropods as potential vectors of African swine fever virus outbreaks in pig farms in the Republic of Korea
Authors: Yoon Hachung , Hong Seong‐Keun , Lee Ilseob , Choi Deuk‐Soo , Lee Jong‐Ho , Lee Eunesub , Wee Sung‐Hwan
Published: June 2021

The seasonality of African swine fever (ASF) in the summers and outbreaks in farms with high biosecurity levels suggest that the ASF virus (ASFV) may be transmitted by arthropod vectors. Arthropods were collected in this study from 14 pig farms with ASF outbreaks in Korea in 2019 to explore the role of arthropods as potential ASFV vectors. A total of 28,729 arthropods, including 28,508 (99.2%) Diptera, were collected using blacklight traps, insect nets and yellow sticky strips. All arthropod samples were negative for ASFV genomic DNA according to laboratory tests using real‐time polymerase chain reaction. This result may reflect the effects of immediate control measures following the detection of farms with ASF outbreaks in the early phase of infection in Korea.
Long‐term trends of Nordic power market: A review
Authors: Chen Yi‐kuang , Hexeberg Anne , Rosendahl Knut Einar , Bolkesjø Torjus F.
Published: June 2021

The Nordic power system will play an important role in a future carbon‐neutral European power market. In this study, 43 scenarios in 15 Nordic power market outlooks published between 2016 and 2019 are reviewed. Most scenarios see high future power prices with substantial correlation with assumed gas and emission quota prices. The underlying uncertainties in gas and emission quota prices are passed on to future power prices. The power prices are well above the cost of wind power, indicating that the wind deployment is either underestimated or might be largely dependent on non‐market factors. The models used for the outlooks have limited sector coverage and trade‐offs are made between computational resources and complexity. A set of recommendations for future outlook publications are proposed based on this review experience. Moving towards a low‐carbon future, more attention should be put to the demand side, especially with increasing importance of sector coupling and electrification. Also, to assess the profound uncertainties in the energy transition period, techniques besides scenario analysis can be applied. Explicit assessments on impacts of emerging topics, such as social oppositions to particular technologies and increased awareness of sustainability indicators besides clean energy, will add values for long‐term decision making in the power markets. Last but not the least, best efforts of clarity and transparency should always be ensured.

This article is categorized under:

Energy Systems Economics > Economics and Policy

Energy Systems Analysis > Economics and Policy

Energy Policy and Planning > Economics and Policy
Community detection in complex networks: From statistical foundations to data science applications
Authors: Dey Asim K. , Tian Yahui , Gel Yulia R.
Published: June 2021

Identifying and tracking community structures in complex networks are one of the cornerstones of network studies, spanning multiple disciplines, from statistics to machine learning to social sciences, and involving even a broader range of application areas, from biology to politics to blockchain. This survey paper aims to provide an overview of some most popular approaches in statistical network community detection as well as the newly emerging research directions such as community extraction with higher‐order features and community discovery in multilayer and multiscale networks. Our goal is to offer a unified view at methodological interconnections and the wide spectrum of interdisciplinary data science applications of network community analysis.

This article is categorized under:

Data: Types and Structure > Graph and Network Data

Statistical Learning and Exploratory Methods of the Data Sciences > Clustering and Classification
Probing small-scale power spectra with pulsar timing arrays
Authors: Lee Vincent S. H. , Mitridate Andrea , Trickle Tanner , Zurek Kathryn M.
Published: June 2021

Abstract

Models of Dark Matter (DM) can leave unique imprints on the Universe’s small scale structure by boosting density perturbations on small scales. We study the capability of Pulsar Timing Arrays to search for, and constrain, subhalos from such models. The models of DM we consider are ordinary adiabatic perturbations in ΛCDM, QCD axion miniclusters, models with early matter domination, and vector DM produced during inflation. We show that ΛCDM, largely due to tidal stripping effects in the Milky Way, is out of reach for PTAs. Axion miniclusters may be within reach, although this depends crucially on whether the axion relic density is dominated by the misalignment or string contribution. Models where there is matter domination with a reheat temperature below 1 GeV may be observed with future PTAs. Lastly, vector DM produced during inflation can be detected if it is lighter than 10−16 GeV. We also make publicly available a Python Monte Carlo tool for generating the PTA time delay signal from any model of DM substructure.
EFT diagrammatica: UV roots of the CP-conserving SMEFT
Authors: Bakshi Supratim Das , Chakrabortty Joydeep , Prakash Suraj , Rahaman Shakeel Ur , Spannowsky Michael
Published: June 2021

Abstract

The Standard Model Effective Field Theory (SMEFT) is an established theoretical framework that parametrises the impact a UV theory has on low-energy observables. Such parametrization is achieved by studying the interactions of SM fields encapsulated within higher mass dimensional (≥5) operators. Through judicious employment of the tools of EFTs, SMEFT has become a source of new predictions as well as a platform for conducting a coherent comparison of new physics (beyond Standard Model) scenarios. We, for the first time, are proposing a diagrammatic approach to establish selection criteria for the allowed heavy field representations corresponding to each SMEFT operator. We have elucidated the links of a chain connecting specific CP conserving dimension-6 SMEFT operators with unique sets of heavy field representations. The contact interactions representing each effective operator have been unfolded into tree- and (or) one-loop-level diagrams to reveal unique embeddings of heavy fields within them. For each case, the renormalizable vertices of a UV model serve as the building blocks for all possible unfolded diagrams. Based on this, we have laid the groundwork to construct observable-driven new physics models. This in turn also prevents us from making redundant analyses of similar models. While we have taken a predominantly minimalistic approach, we have also highlighted the necessity for non-minimal interactions for certain operators.
One-loop impact factor for the emission of two gluons
Authors: Canay Marc , Del Duca Vittorio
Published: June 2021

Abstract

We consider one-loop five-point QCD amplitudes in next-to-multi-Regge kinematics, and evaluate the one-loop impact factor for the emission of two gluons. This is the last ingredient which is necessary to evaluate the gluon-jet impact factor at NNLO accuracy in αs. It is also the first instance in which loop-level QCD amplitudes are evaluated in next-to-multi-Regge kinematics, which requires to apply a different Reggeisation ansatz to each colour-ordered amplitude.
The norm attainment problem for functions of projections
Authors: Böttcher Albrecht , Spitkovsky Ilya M.
Published: June 2021

The paper is concerned with the problem of identifying the norm attaining operators in the von Neumann algebra generated by two orthogonal projections on a Hilbert space. Every skew projection on that Hilbert space is contained in such an algebra and hence the results of the paper also describe functions of skew projections and their adjoints that attain the norm.
An existence result for the fractional Kelvin–Voigt’s model on time-dependent cracked domains
Authors: Caponi Maicol , Sapio Francesco
Published: June 2021

We prove an existence result for the fractional Kelvin–Voigt’s model involving Caputo’s derivative on time-dependent cracked domains. We first show the existence of a solution to a regularized version of this problem. Then, we use a compactness argument to derive that the fractional Kelvin–Voigt’s model admits a solution which satisfies an energy-dissipation inequality. Finally, we prove that when the crack is not moving, the solution is unique.
On the Tight Security of TLS 1.3: Theoretically Sound Cryptographic Parameters for Real-World Deployments
Authors: Diemert Denis , Jager Tibor
Published: June 2021

We consider thetheoretically soundselection of cryptographic parameters, such as the size of algebraic groups or RSA keys, for TLS 1.3 in practice. While prior works gave security proofs for TLS 1.3, their security loss isquadraticin the total number of sessions across all users, which due to the pervasive use of TLS is huge. Therefore, in order to deploy TLS 1.3 in a theoretically sound way, it would be necessary to compensate this loss with unreasonably large parameters that would be infeasible for practical use at large scale. Hence, while these previous works show that in principle the design of TLS 1.3 is secure in an asymptotic sense, they do not yet provide any usefulconcretesecurity guarantees for real-world parameters used in practice. In this work, we provide a new security proof for the cryptographic core of TLS 1.3 in the random oracle model, which reduces the security of TLS 1.3tightly(that is, with constant security loss) to the (multi-user) security of its building blocks. For some building blocks, such as the symmetric record layer encryption scheme, we can then rely on prior work to establish tight security. For others, such as the RSA-PSS digital signature scheme currently used in TLS 1.3, we obtain at least alinearloss in the number of users, independent of the number of sessions, which is much easier to compensate with reasonable parameters. Our work also shows that by replacing the RSA-PSS scheme with a tightly secure scheme (e.g., in a future TLS version), one can obtain the first fully tightly secure TLS protocol. Our results enable a theoretically sound selection of parameters for TLS 1.3, even in large-scale settings with many users and sessions per user.
In silico biomechanical design of the metal frame of transcatheter aortic valves: multi-objective shape and cross-sectional size optimization
Authors: Carbonaro Dario , Gallo Diego , Morbiducci Umberto , Audenino Alberto , Chiastra Claudio
Published: June 2021

Transcatheter aortic valve (TAV) implantation has become an established alternative to open-hearth surgical valve replacement. Current research aims to improve the treatment safety and extend the range of eligible patients. In this regard, computational modeling is a valuable tool to address these challenges, supporting the design phase by evaluating and optimizing the mechanical performance of the implanted device. In this study, a computational framework is presented for the shape and cross-sectional size optimization of TAV frames. Finite element analyses of TAV implantation were performed in idealized aortic root models with and without calcifications, implementing a mesh-morphing procedure to parametrize the TAV frame. The pullout force magnitude, peak maximum principal stress within the aortic wall, and contact pressure in the left ventricular outflow tract were defined as objectives of the optimization problem to evaluate the device mechanical performance. Design of experiment coupled with surrogate modeling was used to define an approximate relationship between the objectives and the TAV frame parameters. Surrogate models were interrogated within a fixed design space and multi-objective design optimization was conducted. The investigation of the parameter combinations within the design space allowed the successful identification of optimized TAV frame geometries, suited to either a single or groups of aortic root anatomies. The optimization framework was efficient, resulting in TAV frame designs with improved mechanical performance, ultimately leading to enhanced procedural outcomes and reduced costs associated with the device iterative development cycle.
A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers
Authors: Zhu Xiaoxue , Qian Hongjie , Sun Jixuan , Wu Min , Yu Chen , Ding Yanhua , Zhang Xiaodi , Chai Katherine , Li Xiaojiao
Published: June 2021

Purpose

To compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males.

Methods

In this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration–time profile (AUC) from time zero extrapolated to infinity (AUC0–inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study.

Results

Pharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0–inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0–inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80–125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study.

Conclusion

HLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963).

Clinical trial registration

The study was registered with Clinicaltrials.gov, NCT03483649.
Analysis of an inventory system with emergency ordering option at the time of supply disruption
Authors: Poormoaied Saeed , Demirci Ece Zeliha
Published: June 2021

This paper studies a continuous-review stochastic inventory problem for a firm facing random demand and random supply disruptions. The supplier experiences operational (on) and disrupted (off) periods with exponentially distributed durations. The firm adopts an order-up-to level policy during the on period and additionally can release an emergency order based on the inventory level just before disruption. This inventory policy is described by a continuous-time Markov chain model. We analyze the model for two different lead time scenarios and suggest solution approaches yielding the optimal policy parameters. In a numerical study, we explore the value of exercising such a policy and show that an emergency ordering opportunity at the disruption time brings substantial cost savings in cases with high lost sales cost, long off period, and low percentage of supplier’s availability.
Gabra2 is a genetic modifier of Dravet syndrome in mice
Authors: Hawkins Nicole A. , Nomura Toshihiro , Duarte Samantha , Barse Levi , Williams Robert W. , Homanics Gregg E. , Mulligan Megan K. , Contractor Anis , Kearney Jennifer A.
Published: June 2021

Pathogenic variants in epilepsy genes result in a spectrum of clinical severity. One source of phenotypic heterogeneity is modifier genes that affect expressivity of a primary pathogenic variant. Mouse epilepsy models also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a+/−) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a+/− mice recapitulate features of Dravet syndrome, including spontaneous seizures, sudden death, and cognitive/behavioral deficits. Scn1a+/− mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no spontaneous seizures. In contrast, admixture with C57BL/6J (B6) results in epilepsy and premature lethality. We previously mapped Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for strain-dependent differences in survival. Gabra2, encoding the GABAA α2 subunit, was nominated as a candidate modifier at Dsm1. Direct measurement of GABAA receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this deletion reestablished normal levels of Gabra2 expression. In this study, we used B6 mice with a repaired Gabra2 allele to evaluate Gabra2 as a genetic modifier of severity in Scn1a+/− mice. Gabra2 repair restored transcript and protein expression, increased abundance of α2-containing GABAA receptors in hippocampal synapses, and rescued epilepsy phenotypes of Scn1a+/− mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome, and support enhancing function of α2-containing GABAA receptors as treatment strategy for Dravet syndrome.
Patients with acute myocarditis and preserved systolic left ventricular function: comparison of global and regional longitudinal strain imaging by echocardiography with quantification of late gadolinium enhancement by CMR
Authors: Meindl Christine , Paulus Michael , Poschenrieder Florian , Zeman Florian , Maier Lars S. , Debl Kurt
Published: June 2021

Background

Conventional transthoracic echocardiography (TTE) does often not accurately reveal pathologies in patients with acute myocarditis and preserved left ventricular ejection fraction (LVEEF). Therefore, we investigated the diagnostic value of two-dimensional (2D) speckle tracking echocardiography compared to late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) imaging in patients with acute myocarditis and normal global LVEF.

Methods and results

31 patients (group 1) with the diagnosis of acute myocarditis confirmed by CMR according to the Lake Louise criteria and 20 healthy controls (group 2) were analyzed including global longitudinal strain (GLS) and regional longitudinal strain (RLS) derived by the bull’s eye plot. Although preserved LVEF was present in both groups, GLS was significantly lower in patients with acute myocarditis (group 1: GLS − 19.1 ± 1.8% vs. group 2: GLS − 22.1 ± 1.7%, p < 0.001). Compared to controls, lower RLS values were detected predominantly in the lateral, inferolateral, and inferior segments in patients with acute myocarditis. Additionally RLS values were significantly lower in segments without LGE.

Conclusion

In patients with acute myocarditis and preserved LVEF, a significant reduction of GLS compared to healthy subjects was detected. Further RLS adds important information to the localization and extent of myocardial injury.

Graphic abstract
AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure
Authors: Remes Anca , Wagner Andreas H. , Schmiedel Nesrin , Heckmann Markus , Ruf Theresa , Ding Lin , Jungmann Andreas , Senger Frauke , Katus Hugo A. , Ullrich Nina D. , Frey Norbert , Hecker Markus , Müller Oliver J.
Published: June 2021

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.
Intermediate to long-term clinical outcomes and survival analysis of the Salto Mobile Bearing total ankle prothesis
Authors: Stadler C. , Stöbich M. , Ruhs B. , Kaufmann C. , Pisecky L. , Stevoska S. , Gotterbarm T. , Klotz M. C.
Published: June 2021

Introduction

Osteoarthritis of the ankle is a major burden to affected patients. While tibio-talar arthrodesis has been the gold-standard regarding the treatment of osteoarthritis of the ankle joint for many years, at present total ankle arthroplasty (TAA) provides appealing clinical outcomes and is continually gaining popularity.

The aim of this study was to evaluate the intermediate- to long-term clinical outcome including the survival rate of Salto Mobile Bearing TAA (Tonier SA, Saint Ismier, France).

Material and methods

In this retrospective study intermediate- to long-term outcomes measures [Ankle Range of Motion (ROM), American Orthopaedic Foot and Ankle Score (AOFAS score) and survival rate] of 171 consecutive TAA were analysed and compared before and after surgery. Revision was defined as secondary surgery with prothesis component removal, while reoperation was defined as a non-revisional secondary surgery involving the ankle.

Results

At a mean follow-up (FU) period of 7.2 ± 2.7 years (range 2.0 to 14.1 years) there was a significant improvement in ankle ROM (total ROM improved from 25.0° ± 15.0° to 28.7° ± 11.3°, p = 0.015; plantarflexion improved from 18.4° ± 11.7° to 20.6° ± 8.2°, p = 0.044; dorsiflexion improved from 6.6° ± 5.7° to 8.1° ± 4.9°, p = 0.011). AOFAS score increased significantly by 41 ± 15 points after surgery (43.3 ± 11.1 before and 84.3 ± 12.0 after surgery, p < 0.001). Overall survival rate within the FU was 81.3% (95% CI 75.3% to 87.3%) with any secondary surgery, 89.9% (95% CI 84.1% to 93.6%) with revision and 93.6% (95% CI 89.8% to 97.3%) with reoperation as endpoint.

Conclusion

This study endorses the previously reported appealing intermediate- to long-term outcomes of the Salto Mobile Bearing TAA. There was a significant increase in ROM and AOFAS score as well as decent implant survival at final FU.
Two-stage mental health survey of first-line medical staff after ending COVID-19 epidemic assistance and isolation
Authors: Xu Li , You Dingyun , Li Chengyu , Zhang Xiyu , Yang Runxu , Kang Chuanyuan , Wang Nianshi , Jin Yuxiong , Yuan Jing , Li Chao , Wei Yujun , Li Ye , Yang Jianzhong
Published: June 2021

Facing with COVID-19 epidemic such a catastrophic health emergency, the mental health status of medical staff deserves attention. We conducted a two-stage of psychological status monitoring after the end of the assistance and 14 days of isolation, further targeted the vulnerable groups in need of intervention. The study is a cross-sectional survey on 1156 Yunnan medical staff aid to Hubei. Used Cluster sampling method to collect data at 2 time points (at the end of returning from Wuhan and the 14th day of isolation), from March 18, 2020 to April 6, 2020. Female and nurse had higher rates of depressive symptoms than male and doctors and other occupations. The proportion of female with mild and above moderate anxiety levels (22.91%, 2.61%) was higher than male (17.35%, 1.03%) (p < 0.05). Female had a better impaired sleep quality (45.06%, 17.49%) more than male (28.57%, 7.94%). Medical staff supported in Wuhan and with junior professional titles reported a higher proportion of sleep quality impairment. At the 14th isolation day stage, the proportion of nurses changed from depression to health (9.15%) and from health to depression (6.1%) better than doctors. The front-line medical staffs had suffered greater psychological pressure in the treatment process of major public health emergency. Researches on the dynamic monitor for the change of psychological status after aiding epidemic areas were still in relatively blank stage. Targeting the vulnerable characteristics of aiding medical staff is significant for effective psychological intervention and sustainable operation of health system.
A questionnaire survey on evaluation for penetration and compliance of the Japanese Guideline on Febrile Neutropenia among hematology-oncology physicians and surgeons
Authors: Akiyama Nobu , Okamura Takuho , Yoshida Minoru , Kimura Shun-ichi , Yano Shingo , Yoshida Isao , Kusaba Hiroyuki , Takahashi Kosuke , Fujita Hiroyuki , Fukushima Keitaro , Iwasaki Hiromichi , Tamura Kazuo , Saeki Toshiaki , Takamatsu Yasushi , Zenda Sadamoto
Published: June 2021

Purpose

The Japanese Society of Medical Oncology published a guideline (GL) on febrile neutropenia (FN) in 2017. The study’s purpose is to reveal how widely GL penetrated among physicians and surgeons providing chemotherapy.

Methods

A questionnaire survey was conducted with SurveyMonkey™ for members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed with statistical text-analytics.

Result

A total of 800 responses were retrieved. Major respondents were experts with more than 10-year experience, physicians 54%, and surgeons 46%. Eighty-seven percent of respondents knew and used GL. Forty-eight percent assessed FN with Multinational Association of Supportive Care in Cancer (MASCC) score “always” or “more than half.” Eighty-one percent chose beta-lactam monotherapy as primary treatment in high-risk patients. Seventy-seven percent did oral antibacterial therapy in low-risk patients ambulatorily. Seventy-eight percent administered primary prophylactic G-CSF (ppG-CSF) in FN frequency ≥ 20% regimen. Fifty-nine percent did ppG-CSF for high-risk patients in FN frequency 10–20% regimen. Ninety-seven percent did not use ppG-CSF in FN frequency < 10% regimen. The medians of complete and complete plus partial compliance rates were 46.4% (range 7.0–92.8) and 77.8% (range 35.4–98.7). The complete compliance rates were less than 30% in seven recommendations, including the MASCC score assessment.

Conclusion

GL is estimated to be widely utilized, but some recommendations were not followed, presumably due to a mismatch with actual clinical practices in Japan.
Prediction of chemical compounds properties using a deep learning model
Authors: Galushka Mykola , Swain Chris , Browne Fiona , Mulvenna Maurice D. , Bond Raymond , Gray Darren
Published: June 2021

The discovery of new medications in a cost-effective manner has become the top priority for many pharmaceutical companies. Despite decades of innovation, many of their processes arguably remain relatively inefficient. One such process is the prediction of biological activity. This paper describes a new deep learning model, capable of conducting a preliminary screening of chemical compounds in-silico. The model has been constructed using a variation autoencoder to generate chemical compound fingerprints, which have been used to create a regression model to predict their LogD property and a classification model to predict binding in selected assays from the ChEMBL dataset. The conducted experiments demonstrate accurate prediction of the properties of chemical compounds only using structural definitions and also provide several opportunities to improve upon this model in the future.
Anpassung an Überschwemmungen in südostasiatischen Megastädten – Was kann der Privatsektor leisten?
Authors: Neise Thomas , Leitold Roxana
Published: June 2021

Die fortschreitende Urbanisierung und erste Auswirkungen des Klimawandels verstärken das Überschwemmungsrisiko in küstennahen südostasiatischen Megastädten. Lokale Industriebetriebe sind insbesondere in ihrer Funktions- und Wettbewerbsfähigkeit betroffen. Gleichzeitig wird in den Debatten zu Klimawandelanpassung und Katastrophenrisikominderung die Beteiligung des Privatsektors an Flutschutzmaßnahmen diskutiert, da die lokalen Behörden in Südostasien das Flutrisiko häufig nicht eigenständig substanziell reduzieren können. Vor diesem Hintergrund wird untersucht, wie Industriebetriebe in Ho Chi Minh City (Vietnam) und Jakarta (Indonesien) auf Überschwemmungen reagieren, welche Anpassungsmaßnahmen sie durchführen und inwiefern ihr Engagement einen Beitrag zur kollektiven Anpassungen leistet. Die Analyse von 63 Tiefeninterviews mit Industriebetrieben und 30 Hintergrundgesprächen mit lokalen Behörden, Wirtschaftsverbänden und Wissenschaftler*innen zeigt, dass insbesondere klein- und mittelständische Betriebe Schwierigkeiten haben, effektive Maßnahmen zu ergreifen. Kollektive Anpassungsmaßnahmen vom Privatsektor und lokalen Behörden sind bislang wenig implementiert. Basierend auf den Ergebnissen werden abschließend politische Handlungsempfehlungen skizziert, wie das Engagement des Privatsektors gestärkt und besser integriert werden kann.
Stress-Dependent Deformation and Permeability of a Fractured Coal Subject to Excavation-Related Loading Paths
Authors: Cao Wenzhuo , Lei Qinghua , Cai Wu
Published: June 2021

The deformation and permeability of coal are largely affected by the presence and distribution of natural fractures such as cleats and bedding planes with orthogonal and abutting characteristics, resulting in distinct hydromechanical responses to stress loading during coal mining processes. In this research, a two-dimensional (2D) fracture network is constructed based on a real coal cleat trace data collected from the Fukang mine area, China. Realistic multi-stage stress loading is designed to sequentially mimic an initial equilibrium phase and a mining-induced perturbation phase involving an increase of axial stress and a decrease of confining stress. The geomechanical and hydrological behaviour of the fractured coal under various stress loading conditions is modelled using a finite element model, which can simulate the deformation of coal matrix, the shearing and dilatancy of coal cleats, the variation of cleat aperture induced by combined effects of closure/opening, and shear and tensile-induced damage. The influence of different excavation stress paths and directions of mining is further investigated. The simulation results illustrate correlated variations among the shear-induced cleat dilation, damage in coal matrix, and equivalent permeability of the fractured coal. Model results are compared with results of previous work based on conventional approaches in which natural fracture networks are not explicitly represented. In particular, the numerical model reproduces the evolution of equivalent permeability under the competing influence of the effective stress perpendicular to cleats and shear-induced cleat dilation and associated damage. Model results also indicate that coal mining at low stress rates is conducive to the stability of surrounding coal seams, and that coal mining in parallel to cleat directions is desirable. The research findings of this paper have important implications for efficient and safe exploitation of coal and coalbed methane resources.