bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes of inflammatory cytokines/chemokines during ravidasvir plus ritonavir‐boosted danoprevir and ribavirin therapy for patients with genotype 1b hepatitis C infection
Authors: Xiao Lanlan , Wu Xiaoxin , Zhang Fen , Wang Jie , Xu Xiaowei , Li Lanjuan
Published: June 2020

This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir‐boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment‐naïve non‐cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV‐host interactions during anti‐HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12‐weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12‐weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy‐five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment‐related serious AEs or AEs leading to discontinuation were reported. The serum HCV‐RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon‐inducible protein‐10 (IP‐10) decreased after anti‐HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP‐10 has the potential to be an indicator of innate immune viral recognition.
Dual contrast in computed tomography allows earlier characterization of articular cartilage over single contrast
Authors: Bhattarai Abhisek , Pouran Behdad , Mäkelä Janne T. A. , Shaikh Rubina , Honkanen Miitu K. M. , Prakash Mithilesh , Kröger Heikki , Grinstaff Mark W. , Weinans Harrie , Jurvelin Jukka S. , Töyräs Juha
Published: June 2020

Cationic computed tomography contrast agents are more sensitive for detecting cartilage degeneration than anionic or non‐ionic agents. However, osteoarthritis‐related loss of proteoglycans and increase in water content contrarily affect the diffusion of cationic contrast agents, limiting their sensitivity. The quantitative dual‐energy computed tomography technique allows the simultaneous determination of the partitions of iodine‐based cationic (CA4+) and gadolinium‐based non‐ionic (gadoteridol) agents in cartilage at diffusion equilibrium. Normalizing the cationic agent partition at diffusion equilibrium with that of the non‐ionic agent improves diagnostic sensitivity. We hypothesize that this sensitivity improvement is also prominent during early diffusion time points and that the technique is applicable during contrast agent diffusion. To investigate the validity of this hypothesis, osteochondral plugs (d = 8 mm, N = 33), extracted from human cadaver (n = 4) knee joints, were immersed in a contrast agent bath (a mixture of CA4+ and gadoteridol) and imaged using the technique at multiple time points until diffusion equilibrium. Biomechanical testing and histological analysis were conducted for reference. Quantitative dual‐energy computed tomography technique enabled earlier determination of cartilage proteoglycan content over single contrast. The correlation coefficient between human articular cartilage proteoglycan content and CA4+ partition increased with the contrast agent diffusion time. Gadoteridol normalized CA4+ partition correlated significantly (P < .05) with Mankin score at all time points and with proteoglycan content after 4 hours. The technique is applicable during diffusion, and normalization with gadoteridol partition improves the sensitivity of the CA4+ contrast agent.
Conditional survival analysis of hepatocellular carcinoma
Authors: Shah Mihir M. , Meyer Benjamin I. , Rhee Kevin , NeMoyer Rachel E. , Lin Yong , Tzeng Ching‐Wei D. , Jabbour Salma K. , Kennedy Timothy J. , Nosher John L. , Kooby David A. , Maithel Shishir K. , Carpizo Darren R.
Published: June 2020

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality worldwide with an approximate 5‐year survival of greater than 50% in patients after surgical resection. Survival estimates have limited utility for patients who have survived several years after initial treatment. We analyzed how conditional survival (CS) after curative‐intent surgery for HCC predicts survival estimates over time.

Methods

NCDB (2004‐2014) was queried for patients undergoing definitive surgical resection for HCC. Cumulative overall survival (OS) was calculated using the Kaplan‐Meier method, and CS at x years after diagnosis was calculated as CS1 = OS (X+5)/OS(X).

Results

The final analysis encompassed 11 357 patients. Age, negative margin status, grade severity and radiation before surgery were statistically significant predictors of cumulative overall conditional survival (P ≤ .0001). Overall unconditional 5‐year survival was 65.7%, but CS estimates were higher. A patient who has already survived 3 years has an additional 2‐year, or 5‐year CS, estimate of 86.96%.

Conclusion

Survival estimates following hepatic resection in HCC patients change according to survival time accrued since surgery. CS estimates are improved relative to unconditional OS. The impact of different variables influencing OS is likewise nonlinear over the course of time after surgery.
Photobiomodulation‐Induced Differentiation of Immortalized Adipose Stem Cells to Neuronal Cells
Authors: George Sajan , Hamblin Michael R. , Abrahamse Heidi
Published: June 2020

Background and Objectives

Transdermal differentiation of human adipose stem cells (ASCs) to other cell types is still a challenge in regenerative medicine. Studies using primary ASCs are also limited as they may undergo replicative senescence during repeated passages in vitro. However, ASCs immortalized (iASCs) with human telomerase enzyme expressing plasmid exhibits a uniform population suitable for differentiation in vitro. A right combination of biological and physical stimuli may induce transdermal differentiation of iASCs into neurons in vitro.

Study Design/Materials and Methods

iASCs were differentiated to free‐floating neural stem cell aggregates (neurospheres) using a combination of growth inducers. Cells in these spheres were induced to differentiate into neurons using low‐intensity lasers by a process called photobiomodulation (PBM).

Results

Laser at the near infrared (NIR) wavelength 825 nm and fluences 5, 10, and 15 J/cm2 was capable of increasing the differentiation of neurospheres to neurons. Precisely, there was a statistically significant increase in the early neuronal marker at 5 J/cm2 and a much appreciable increase at 15 J/cm2 in correlation with the biphasic dose response of PBM. However, these differentiated cells failed to express late neuronal markers in vitro. Comparison of these differentiating iASCs with the primary ASCs revealed a sharp distinction between the metabolic processes of the primary ASCs, neurospheres, and newly differentiated neurons.

Conclusion

We found that PBM increased the yield of neurons and effected stem cell differentiation through modulation of cellular metabolism and redox status. Our study also identifies that iASCs are an excellent model for analysis of stem cell biology and for performing transdermal differentiation.

Significance

This study demonstrates that a combination of biological and physical inducers can advance the differentiation of adipose stem cells to neurons. We were able to establish the optimal energy for the neuronal differentiation of iASCs in vitro. Lasers Surg. Med. © 2020 Wiley Periodicals LLC
Black Bass Growth Patterns in Relation to Hydrology in the Arkansas River, Arkansas
Authors: Eggleton Michael A. , Peacock Clint R.
Published: June 2020

Hydrology has been documented as affecting the recruitment of sport fishes. However, the potential cumulative effects of river hydrology on fish growth have not been intensively studied. In 2004, 2005, and 2010, annual growth increments were measured for Largemouth Bass Micropterus salmoides and Spotted Bass M. punctulatus populations from throughout the Arkansas portion of the Arkansas River. During three consecutive years (2007–2009), the lower Arkansas River experienced long durations of high water. Mean annual flows exceeded the 42-year average by 52%, with summer flows averaging 107% above normal and 29% of the days annually exceeding 2,830 m3/s. Using age-1–6 cohorts, we compared Largemouth Bass (n = 2,155) and Spotted Bass (n = 833) growth increments across hydrologic conditions occurring during the growth years experienced by these fish. Two-way ANOVAs using back-calculated age and growth year warm-season hydrology (classified as high, average, or low flow based on quartiles from historical April–September hydrographs) as main effects suggested significant hydrologic effects on the growth of both black bass species. A significant interaction between back-calculated age and growth year April–September hydrology for both black basses further suggested that flow affected growth differently across ages, with decreased annual growth increments detected for the age-1–3 cohorts. Decreased annual growth occurring during 2007–2009 also was consistent with a 0.5-year increase in the age at which Largemouth Bass attained 381 mm TL (i.e., the minimum length required for legal harvest) in 2010. Similarly, Spotted Bass required an extra 0.9 year to attain 304 mm TL (i.e., a common minimum length limit). Results suggested that the typically beneficial effects of high-flow years on black bass populations in large-river–floodplain systems may be dampened or non-existent in more highly regulated, impounded river systems, such as the modern-day Arkansas River.
Technology‐based management of neurourology patients in the COVID‐19 pandemic: Is this the future? A report from the International Continence Society (ICS) institute
Authors: Huri Emre , Hamid Rizwan
Published: June 2020

Coronavirus disease‐2019 (COVID‐19) pandemic significantly altered our daily life as well as our professional practice. COVID‐19 has disrupted our lives both professionally and personally. We know the urological management in a neurogenic patient needs to be tailored to the individual circumstances, this is even more pertinent during these uncertain times. International Continence Society is the premier international organization in functional urology. Lately, it has established an institute to facilitate teaching and training opportunities all over the world. The School of Neurourology teamed with the School of Modern Technology and set up a Webinar—“How to manage the neuro‐urological patients in the current pandemic.” This was set up as a case‐based discussion to deliberate the management of our patients in the present climate and examine the role of modern technology in overcoming the current barriers.
Improved methods to compare distance metrics in networks using uniform random spanning trees (DIMECOST)
Authors: Bourbour Sara , Mehta Dinesh P. , Navidi William C.
Published: June 2020

We consider the network analytics problem of comparing two distance metrics on the same set of n entities. The classical solution to this problem is the Mantel test, which uses permutation testing to accept or reject the null hypothesis that there is “no relationship between the two metrics.” Its computational complexity is n2 times the number of permutations (based on a user supplied parameter). This work makes two contributions: (1) DIMECOSTP, a more efficient hypothesis test based on uniform random spanning trees whose complexity is n times the number of permutations. (2) DIMECOSTCC, which uses the correlation coefficient between the two sets of edge weights in a random spanning tree as an indication of the strength of the relationship between the two distance metrics. Both methods utilize sound statistical principles. Experimental results confirm the efficacy of our methods.
An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data
Authors: James Alexander D. , Schiller Hilmar , Marvalin Cyrille , Jin Yi , Borell Hubert , Roffel Ad F. , Glaenzel Ulrike , Ji Yan , Camenisch Gian
Published: June 2020

Ribociclib (LEE011, Kisqali ®) is a highly selective small molecule inhibitor of cyclin‐dependent kinases 4 and 6 (CDK4/6), which has been approved for the treatment of advanced or metastatic breast cancer. A human ADME study was conducted in healthy male volunteers following a single oral dose of 600 mg [14C]‐ribociclib. Mass balance, blood and plasma radioactivity, and plasma ribociclib concentrations were measured. Metabolite profiling and identification was conducted in plasma, urine, and feces. An assessment integrating the human ADME results with relevant in vitro and in vivo non‐clinical data was conducted to provide an estimate of the relative contributions of various clearance pathways of the compound. Ribociclib is moderately to highly absorbed across species (approx. 59% in human), and is extensively metabolized in vivo, predominantly by oxidative pathways mediated by CYP3A4 (ultimately forming N‐demethylated metabolite M4) and, to a lesser extent, by FMO3 (N‐hydroxylated metabolite M13). It is extensively distributed in rats, based on QWBA data, and is eliminated rapidly from most tissues with the exception of melanin‐containing structures. Ribociclib passed the placental barrier in rats and rabbits and into milk of lactating rats. In human, 69.1% and 22.6% of the radiolabeled dose were excreted in feces and urine, respectively, with 17.3% and 6.75% of the 14C dose attributable to ribociclib, respectively. The remainder was attributed to numerous metabolites. Taking into account all available data, ribociclib is estimated to be eliminated by hepatic metabolism (approx. 84% of total), renal excretion (7%), intestinal excretion (8%), and biliary elimination (1%).
Bio‐actives of betel leaf (Piper betle L.): A comprehensive review on extraction, isolation, characterization, and biological activity
Authors: Madhumita Mitali , Guha Proshanta , Nag Ahnidra
Published: June 2020

Piper betle L., belonging to Piperaceae family, known as a traditional herbal medicinal plant and used for several health benefits in Asian countries. Currently, demand for its products such as herbal drugs, medicines, and natural herbal formulations has increased. The beneficial effects of betel leaves and its products have traditionally exploited for the treatment of several diseases like bad breath, cuts, injuries, inflammations, cold cough, indigestion, etc. Till now, a broad range of bioactive compounds including polyphenols, terpenes, etc., has been identified from the extracts and essential oil (EO) of betel leaves. The structural and functional characterization of the extract and EO bio‐actives has been derived by various advanced standard methods. Most of the health‐related benefits of betel leaves have been associated with their bioactive phenolic compounds. The extract of this highly perishable product can be used in organic synthesis, food, and beverage industry, pharmaceuticals, etc., to the environmental issues. The present review provides information on extraction techniques, identification of bioactive compounds, and their biological activities. That apart, information on processing, preservation, and health benefits along with their mechanisms has also been added.
Profile of herbal and dietary supplements induced liver injury in Latin America: A systematic review of published reports
Authors: Santos Genario , Gasca Jessica , Parana Raymundo , Nunes Vinicius , Schinnoni Maria , Medina‐Caliz Inmaculada , Cabello Maria Rosario , Lucena Maria Isabel , Andrade Raul J.
Published: June 2020

Hepatotoxicity related to HDS is a growing global health issue. We have undertaken a systematic review of published case reports and case series from LA from 1976 to 2020 to describe the clinical features of HDS related hepatotoxicity in this region. We search in PubMed, Web of Science, Scopus and specific LA databases according to PRISMA guidelines. Only HILI cases published in LA that met criteria for DILI definition were included. Duplicate records or reports that lacked relevant data that precluded establishing causality were excluded. Finally, 17 records (23 cases) were included in this review.Centella asiatica, Carthamus tinctorius, and Herbalife® were the most reported HDS culprit products, the main reason for HDS consumption was weight loss. The clinical characteristics of HDS hepatotoxicity in our study were compared to those of other studies in the USA, Europe and China showing a similar signature with predominance of young females, hepatocellular damage, a high rate of ALF and mortality, more frequent inadvertent re‐challenge and chronic damage. This study underscores the challenge in causality assessment when multi‐ingredients HDS are taken and the need for consistent publication practice when reporting hepatotoxicity cases due to HDS, to foster HDS liver safety particularly in LA.
Output feedback regulation of a class of high‐order feedforward nonlinear systems with unknown time‐varying delay in the input under measurement sensitivity
Authors: Koo Min‐Sung , Choi Ho‐Lim
Published: June 2020

An output feedback regulation problem is considered for a class of high‐order feedforward nonlinear systems with delay in the input under measurement sensitivity. The key features are that the considered systems have uncertain high‐order feedforward nonlinearity and unknown time‐varying delay in the input. Then, the controller is supposed to be engaged where the output feedback information is distorted by measurement sensitivity. Our proposed controller has two gains—fixed and adaptive gains. The fixed gain is first designed to compensate for measurement sensitivity, and the adaptive gain is next utilized to dominate both unknown input delay and uncertain high‐order feedforward nonlinearity. Simulation examples are given to highlight the advantage of our control scheme.
Wnt/β-catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema
Authors: Hu Yan , Ng-Blichfeldt John-Poul , Ota Chiharu , Ciminieri Chiara , Ren Wenhua , Hiemstra Pieter S. , Stolk Jan , Gosens Reinoud , Königshoff Melanie
Published: June 2020

Wnt/β-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β-catenin responsive progenitor cells and the potential impact of Wnt/β-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/β-catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wntlow epithelial progenitors. Further ectopic Wnt/β-catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/β-catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase-induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/β-catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema.
Stem cell homing: From physiology to therapeutics
Authors: Liesveld Jane L. , Sharma Naman , Aljitawi Omar S.
Published: June 2020

Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.
Digital sport entrepreneurial ecosystems
Authors: Ratten Vanessa , Thompson Ashleigh‐Jane
Published: June 2020

The entrepreneurial ecosystems literature has increasingly explored network relationships between different stakeholders, as well as the role of context. This article addresses the challenge of including a sport context in the entrepreneurial ecosystem literature thereby contributing to the sport entrepreneurship literature by bringing insights from entrepreneurship ecosystem research. In‐depth interviews of football stakeholders in the sport entrepreneurship ecosystem are conducted in terms of understanding the emergence of digital sport start‐ups. The issues raised help explore the changing nature of digital entrepreneurial ecosystems to take into account new sport technological advances. Mixed embeddedness theory is used as the conceptual foundation to understand sport digital entrepreneurial ecosystems. Key management practices are identified in terms of sport start‐ups participating in entrepreneurial ecosystems. The article concludes by making suggestions for future research.
Wildlife forensic science in Hong Kong
Authors: Hatten Chloe E. R. , Whitfort Amanda , Baker David M. , Dingle Caroline
Published: June 2020

In the past decade, Hong Kong has seen an increase in volume and diversity of endangered wildlife imported through its borders. Recent amendments to legislation concerning wildlife crimes in Hong Kong allow for increased sentencing and prosecution of the crimes. This calls for an increased forensic capacity to aid enforcement efforts. Wildlife forensic science in Hong Kong is generally performed ad hoc via a confidential tender‐application process. Additionally, minimal communication between forensic scientists, the prosecution and the judiciary on the use and production of wildlife forensic analyses has compounded the problem of wildlife crimes not being addressed as “serious” crimes. Improving communication and collaboration between relevant stakeholders, including the development of a wildlife forensic reference database, shared forensic practices, and shared information concerning expertise and analyses available within Hong Kong, would provide benefits to wildlife crime investigations. This article addresses some of these concerns in more detail and provides suggestions for improvements to the overall wildlife forensic capacity in Hong Kong. Increasing Hong Kong's capacity for wildlife forensic science will not only facilitate law enforcement efforts but also help to change Hong Kong's status as a regional hub for wildlife trade to one for excellence in wildlife crime deterrence.

This article is categorized under:

Jurisprudence and Regulatory Oversight > Expert Evidence and Narrative

Jurisprudence and Regulatory Oversight > Communication Across Science and Law

Jurisprudence and Regulatory Oversight > Interdisciplinary Collaboration

Forensic Biology > DNA Databases and Biometrics
Delinquent Development, Employment and Income in a Sample of Dutch Organized Crime Offenders: Shape, Content, and Correlates of Delinquent Trajectories from Age 12 to 65
Authors: van der Geest Victor , van Koppen M. Vere , Kleemans Edward R.
Published: June 2020

This chapter describes the shape and content of criminal careers of a large sample of Dutch organized crime offenders and relates these criminal careers to social economic factors such as employment and income. Other chapters in this volume provide systematic reviews of the literature regarding criminal careers of specific – largely understudied – groups, such as criminal careers of organized crime offenders (e.g. Savona et al. 2020). Reviews of the literature demonstrate that the vast majority of studies focuses on juveniles, adolescents, and high-volume crime. Therefore, we do not know whether or not ‘established facts’ about traditional criminal careers (e.g. Farrington, 2003; Blokland and Van der Geest, 2017) also hold for criminal careers in organized crime. Does a long and serious criminal career, for example, require an early onset of offending, as is the case for traditional forms of crime? And is employment an important preventive factor for involvement in crime, as is demonstrated by studies on employment and criminal careers (e.g. Van der Geest, 2011)? Since organized crime is in many ways different from traditional forms of crime (see below), it is important to focus more empirical research effort on this specific – seriously understudied – group of offenders.
Education and Training Needs, Methods, and Tools
Authors: Kotsampopoulos P. , Jensen T. V. , Babazadeh D. , Strasser T. I. , Rikos E. , Nguyen V. H. , Tran Q. T. , Bhandia R. , Guillo-Sansano E. , Heussen K. , Narayan A. , Nguyen T. L. , Burt G. M. , Hatziargyriou N.
Published: June 2020

The importance of education and training in the domain of power and energy systems targeting the topics of cyber-physical energy systems/smart grids is discussed in this chapter. State-of-the art laboratory-based and simulation-based tools are presented, aiming to address the new educational needs.
Massive spinning bosons on the celestial sphere
Authors: Law Y. T. Albert , Zlotnikov Michael
Published: June 2020

Abstract

A natural extension of the Pasterski-Shao-Strominger (PSS) prescription is described, enabling the map of Minkowski space amplitudes with massive spinning external legs to the celestial sphere to be performed. An integral representation for the conformal primary wave function (CPW) of massive spinning bosons on the celestial sphere is derived explicitly for spin-one and -two. By analogy with the spin-zero case, the spinning bulk-to-boundary propagator on Euclidean AdS is employed to extend the massive CPW integral representation to arbitrary integer spin, and to describe the appropriate inverse transform of massive spinning CPWs back to the plane wave basis in Minkowski space. Subsequently, a massive spin-s momentum operator representation on the celestial sphere is determined, and used in conjunction with known Lorentz generators to derive Poincaré symmetry constraints on generic massive spinning two-, three- and four-point celestial amplitude structures. Finally, as a consistency check, three-point Minkowski space amplitudes of two massless scalars and a spin-one or -two massive boson are explicitly mapped to the celestial sphere, and the resulting three-point function coefficients are confirmed to be in exact agreement with the results obtained from Poincaré symmetry constraints.
Horizon confidence sets
Authors: Fosten Jack , Gutknecht Daniel
Published: June 2020

This paper introduces a new statistical procedure to discriminate between competing forecasting models at different forecast horizons. Unlike existing tests, which eliminate a model fromallhorizons if dominated according to some loss measure, our methodology identifies an ‘optimal’ set of modelsat eachhorizon, retaining a model that performs well at a given horizon even if dominated at others. While our method is especially useful in applications to long-term forecasting as well as short-term nowcasting, it can also be applied in wider settings like the comparison of forecasting models across countries. We conduct a small Monte Carlo study to investigate the finite sample properties and apply our procedure to nowcasting US real GDP growth and its subcomponents, comparing a factor-based nowcasting method to a naïve benchmark. Unlike existing methods, ours can formally detect the point in the quarter at which the factor method beats the benchmark or vice versa.
Differences between fundamental solutions of general higher order elliptic operators and of products of second order operators
Authors: Grunau Hans-Christoph , Romani Giulio , Sweers Guido
Published: June 2020

We study fundamental solutions of elliptic operators of order $$2m\ge 4$$

2
m
≥
4

with constant coefficients in large dimensions $$n\ge 2m$$

n
≥
2
m

, where their singularities become unbounded. For compositions of second order operators these can be chosen as convolution products of positive singular functions, which are positive themselves. As soon as $$n\ge 3$$

n
≥
3

, the polyharmonic operator $$(-\Delta )^m$$

(
-
Δ
)

m

may no longer serve as a prototype for the general elliptic operator. It is known from examples of Maz’ya and Nazarov (Math. Notes 39:14–16, 1986; Transl. of Mat. Zametki 39, 24–28, 1986) and Davies (J Differ Equ 135:83–102, 1997) that in dimensions $$n\ge 2m+3$$

n
≥
2
m
+
3

fundamental solutions of specific operators of order $$2m\ge 4$$

2
m
≥
4

may change sign near their singularities: there are “positive” as well as “negative” directions along which the fundamental solution tends to $$+\infty $$

+
∞

and $$-\infty $$

-
∞

respectively, when approaching its pole. In order to understand this phenomenon systematically we first show that existence of a “positive” direction directly follows from the ellipticity of the operator. We establish an inductive argument by space dimension which shows that sign change in some dimension implies sign change in any larger dimension for suitably constructed operators. Moreover, we deduce for $$n=2m$$

n
=
2
m

, $$n=2m+2$$

n
=
2
m
+
2

and for all odd dimensions an explicit closed expression for the fundamental solution in terms of its symbol. From such formulae it becomes clear that the sign of the fundamental solution for such operators depends on the dimension. Indeed, we show that we have even sign change for a suitable operator of order 2m in dimension $$n=2m+2$$

n
=
2
m
+
2

. On the other hand we show that in the dimensions $$n=2m$$

n
=
2
m

and $$n=2m+1$$

n
=
2
m
+
1

the fundamental solution of any such elliptic operator is always positive around its singularity.
EasyDIVER: A Pipeline for Assembling and Counting High-Throughput Sequencing Data from In Vitro Evolution of Nucleic Acids or Peptides
Authors: Blanco Celia , Verbanic Samuel , Seelig Burckhard , Chen Irene A.
Published: June 2020

In vitro evolution is a well-established technique for the discovery of functional RNA and peptides. Increasingly, these experiments are analyzed by high-throughput sequencing (HTS) for both scientific and engineering objectives, but computational analysis of HTS data, particularly for peptide selections, can present a barrier to entry for experimentalists. We introduce EasyDIVER (Easy pre-processing and Dereplication of In Vitro Evolution Reads), a simple, user-friendly pipeline for processing high-throughput sequencing data from in vitro selections and directed evolution experiments. The pipeline takes as input raw, paired-end, demultiplexed Illumina read files. For each sample provided, EasyDIVER outputs a dereplicated list of unique nucleic acid and/or peptide sequences and their count reads.
Genetic control of non-genetic inheritance in mammals: state-of-the-art and perspectives
Authors: Tomar A. , Teperino R.
Published: June 2020

Thought to be directly and uniquely dependent from genotypes, the ontogeny of individual phenotypes is much more complicated. Individual genetics, environmental exposures, and their interaction are the three main determinants of individual’s phenotype. This picture has been further complicated a decade ago when the Lamarckian theory of acquired inheritance has been rekindled with the discovery of epigenetic inheritance, according to which acquired phenotypes can be transmitted through fertilization and affect phenotypes across generations. The results of Genome-Wide Association Studies have also highlighted a big degree of missing heritability in genetics and have provided hints that not only acquired phenotypes, but also individual’s genotypes affect phenotypes intergenerationally through indirect genetic effects. Here, we review available examples of indirect genetic effects in mammals, what is known of the underlying molecular mechanisms and their potential impact for our understanding of missing heritability, phenotypic variation. and individual disease risk.
Sporting activity after craniosynostosis surgery in children: a source of parental anxiety
Authors: Rotimi Oloruntobi , Jung Gu-Yun Paul , Ong Juling , Jeelani N. U. Owase , Dunaway David J. , James Greg
Published: June 2020

Purpose

Craniosynostosis correction involves major skull surgery in infancy—a potential source of worry for parents when their treated children begin involvement in sports.

Methods

Electronic multiple choice survey of parents of children who had undergone craniosynostosis surgery in infancy using 5-point Likert scales.

Results

Fifty-nine completed surveys were obtained from parents of children who had undergone previous craniosynostosis surgery. Mean age of children was 7.8 years (range 3 months to 22 years), with 36 non-syndromic and 23 syndromic cases. The most common surgery was fronto-orbital remodelling (18). Fifty-two of 59 were involved in athletic activity. The most intense sport type was non-contact in 23, light contact in 20, heavy contact in 4 and combat in 5. Participation level was school mandatory in 12, school club in 17, non-school sport club in 21 and regional representative in 2. One child had been advised to avoid sport by an external physician. Mean anxiety (1–5 Likert) increased with sport intensity: non-contact 1.7, light contact 2.2, heavy contact 3.5 and combat 3.6. Twenty-nine of 59 parents had been given specific advice by the Craniofacial Team regarding athletic activity, 28 of which found useful. Three sport-related head injuries were reported, none of which required hospitalisation.

Conclusion

Little information exists regarding sports for children after craniosynostosis surgery. This study suggests that parental anxiety remains high, particularly for high impact/combat sports, and that parents would like more information from clinicians about the safety of post-operative sporting activities.
Modern machine-learning can support diagnostic differentiation of central and peripheral acute vestibular disorders
Authors: Ahmadi Seyed-Ahmad , Vivar Gerome , Navab Nassir , Möhwald Ken , Maier Andreas , Hadzhikolev Hristo , Brandt Thomas , Grill Eva , Dieterich Marianne , Jahn Klaus , Zwergal Andreas
Published: June 2020

Background

Diagnostic classification of central vs. peripheral etiologies in acute vestibular disorders remains a challenge in the emergency setting. Novel machine-learning methods may help to support diagnostic decisions. In the current study, we tested the performance of standard and machine-learning approaches in the classification of consecutive patients with acute central or peripheral vestibular disorders.

Methods

40 Patients with vestibular stroke (19 with and 21 without acute vestibular syndrome (AVS), defined by the presence of spontaneous nystagmus) and 68 patients with peripheral AVS due to vestibular neuritis were recruited in the emergency department, in the context of the prospective EMVERT trial (EMergency VERTigo). All patients received a standardized neuro-otological examination including videooculography and posturography in the acute symptomatic stage and an MRI within 7 days after symptom onset. Diagnostic performance of state-of-the-art scores, such as HINTS (Head Impulse, gaze-evoked Nystagmus, Test of Skew) and ABCD2 (Age, Blood, Clinical features, Duration, Diabetes), for the differentiation of vestibular stroke vs. peripheral AVS was compared to various machine-learning approaches: (i) linear logistic regression (LR), (ii) non-linear random forest (RF), (iii) artificial neural network, and (iv) geometric deep learning (Single/MultiGMC). A prospective classification was simulated by ten-fold cross-validation. We analyzed whether machine-estimated feature importances correlate with clinical experience.

Results

Machine-learning methods (e.g., MultiGMC) outperform univariate scores, such as HINTS or ABCD2, for differentiation of all vestibular strokes vs. peripheral AVS (MultiGMC area-under-the-curve (AUC): 0.96 vs. HINTS/ABCD2 AUC: 0.71/0.58). HINTS performed similarly to MultiGMC for vestibular stroke with AVS (AUC: 0.86), but more poorly for vestibular stroke without AVS (AUC: 0.54). Machine-learning models learn to put different weights on particular features, each of which is relevant from a clinical viewpoint. Established non-linear machine-learning methods like RF and linear methods like LR are less powerful classification models (AUC: 0.89 vs. 0.62).

Conclusions

Established clinical scores (such as HINTS) provide a valuable baseline assessment for stroke detection in acute vestibular syndromes. In addition, machine-learning methods may have the potential to increase sensitivity and selectivity in the establishment of a correct diagnosis.
Modulatory effects of magnetic vestibular stimulation on resting-state networks can be explained by subject-specific orientation of inner-ear anatomy in the MR static magnetic field
Authors: Boegle R. , Kirsch V. , Gerb J. , Dieterich M.
Published: June 2020

Strong static magnetic fields, as used in magnetic resonance imaging (MRI), stimulate the vestibular inner ear leading to a state of imbalance within the vestibular system that causes nystagmus. This magnetic vestibular stimulation (MVS) also modulates fluctuations of resting-state functional MRI (RS-fMRI) networks. MVS can be explained by a Lorentz force model, indicating that MVS is the result of the interaction of the static magnetic field strength and direction (called “B0 magnetic field” in MRI) with the inner ear’s continuous endolymphatic ionic current. However, the high variability between subjects receiving MVS (measured as nystagmus slow-phase velocity and RS-fMRI amplitude modulations) despite matching head position, remains to be explained. Furthermore, within the imaging community, an “easy-to-acquire-and-use” proxy accounting for modulatory MVS effects in RS-fMRI fluctuations is needed. The present study uses MRI data of 60 healthy volunteers to examine the relationship between RS-fMRI fluctuations and the individual orientation of inner-ear anatomy within the static magnetic field of the MRI. The individual inner-ear anatomy and orientation were assessed via high-resolution anatomical CISS images and related to fluctuations of RS-fMRI networks previously associated with MVS. More specifically, we used a subject-specific proxy for MVS (pMVS) that corresponds to the orientation of the individual inner-ear anatomy within the static magnetic field direction (also called “z-direction” in MR imaging). We found that pMVS explained a considerable fraction of the total variance in RS-fMRI fluctuations (for instance, from 11% in the right cerebellum up to 36% in the cerebellar vermis). In addition to pMVS, we examined the angle of Reid’s plane, as determined from anatomical imaging as an alternative and found that this angle (with the same sinus transformation as for pMVS) explained considerably less variance, e.g., from 2 to 16%. In our opinion, an excess variability due to MVS should generally be addressed in fMRI research analogous to nuisance regression for movement, pulsation, and respiration effects. We suggest using the pMVS parameter to deal with modulations of RS-fMRI fluctuations due to MVS. MVS-induced variance can easily be accounted by using high-resolution anatomical imaging of the inner ear and including the proposed pMVS parameter in fMRI group-level analysis.
Smoking and multiple sclerosis risk: a Mendelian randomization study
Authors: Vandebergh Marijne , Goris An
Published: June 2020

Background

Striking changes in the demographic pattern of multiple sclerosis (MS) strongly indicate an influence of modifiable exposures, which lend themselves well to intervention. It is important to pinpoint which of the many environmental, lifestyle, and sociodemographic changes that have occurred over the past decades, such as higher smoking and obesity rates, are responsible. Mendelian randomization (MR) is an elegant tool to overcome limitations inherent to observational studies and leverage human genetics to inform prevention strategies in MS.

Methods

We use genetic variants from the largest genome-wide association study for smoking phenotypes (initiation: N = 378, heaviness: N = 55, lifetime smoking: N = 126) and body mass index (BMI, N = 656) and apply these as instrumental variables in a two-sample MR analysis to the most recent meta-analysis for MS. We adjust for the genetic correlation between smoking and BMI in a multivariable MR.

Results

In univariable and multivariable MR, smoking does not have an effect on MS risk nor explains part of the association between BMI and MS risk. In contrast, in both analyses each standard deviation increase in BMI, corresponding to roughly 5 kg/m2 units, confers a 30% increase in MS risk.

Conclusion

Despite observational studies repeatedly reporting an association between smoking and increased risk for MS, MR analyses on smoking phenotypes and MS risk could not confirm a causal relationship. This is in contrast with BMI, where observational studies and MR agree on a causal contribution. The reasons for the discrepancy between observational studies and our MR study concerning smoking and MS require further investigation.
Cav2.3 R-type calcium channels: from its discovery to pathogenic de novo CACNA1E variants: a historical perspective
Authors: Schneider T. , Neumaier F. , Hescheler J. , Alpdogan S.
Published: June 2020

So-called pharmacoresistant (R-type) voltage-gated Ca2+ channels are structurally only partially characterized. Most of them are encoded by the CACNA1E gene and are expressed as different Cav2.3 splice variants (variant Cav2.3a to Cav2.3e or f) as the ion conducting subunit. So far, no inherited disease is known for the CACNA1E gene but recently spontaneous mutations leading to early death were identified, which will be brought into focus. In addition, a short historical overview may highlight the development to understand that upregulation during aging, easier activation by spontaneous mutations or lack of bioavailable inorganic cations (Zn2+ and Cu2+) may lead to similar pathologies caused by cellular overexcitation.
Pedicle screw fixation of thoracolumbar fractures: conventional short segment versus short segment with intermediate screws at the fracture level—a systematic review and meta-analysis
Authors: Kapoen Carolijn , Liu Yang , Bloemers Frank W. , Deunk Jaap
Published: June 2020

Objective

Posterior short-segment fixation (4-screw construct = 4S) is the conventional surgical technique for thoracolumbar fractures. The effect of adding two intermediate pedicle screws at the fractured level (6-screw construct = 6S) is still a matter of debate. This review aims to compare the results between 4 and 6S pedicle screw fixation for thoracolumbar fractures.

Methods

A systematic review and meta-analysis were performed. The databases PubMed, Embase and Google Scholar were searched until January 2020. Inclusion criteria were studies comparing 4S and 6S techniques in patients with thoracolumbar fractures. Non-comparative studies and studies without full text were excluded. Cochrane risk of bias was assessed, and the GRADE approach was used to present the quality of evidence.

Results

Twenty-seven studies, of which 21 randomized controlled trials, with a total of 1890 patients (940 with 4S and 950 with 6S) were included. Meta-analysis showed that the 6S technique resulted in significantly lower pain scores, better short-term and long-term Cobb angles, less loss of correction and less implant failures. However, longer operation time and more blood loss were seen with the 6S technique. Length of hospital stay, Oswestry Disability Index scores and infections did not differ significantly between the 6S and 4S techniques. Quality of the evidence according to GRADE was moderate to low.

Conclusion

In the treatment of thoracolumbar fractures, adding intermediate screws at the fracture level (6S) results in less post-operative pain, better radiological outcomes and less implant failure at the cost of a longer operation time and higher blood loss.
Embodying the past, designing the future: technological determinism reconsidered in technology education
Authors: Hallström Jonas
Published: June 2020

From a philosophical viewpoint, technological design is about connecting what is desirable with what is technically possible. Technology itself plays a major role in design processes, not only because technology development is what designing is all about, but also since the existing technology at any given point in time frames what is possible to achieve in terms of new outcomes. A limiting role of technology in design, education and other societal activities goes under the concept oftechnological determinismand has arguably been one of the most significant points of debate in the social sciences in the last decades. The aim of this article is to investigate how philosophical, sociological and historical research, as well as design and innovation research about technological determinism, could be fruitfully reconsidered in technology education. The analysis yielded three novel findings about the nature of technological determinism. First of all, technological determinism can take the form of an idea, theory or a way of explaining technology development in history or the present, but it can also take the form of actual material structures that—implicitly or explicitly—permeate and influence society, or, at least, this is what some researchers claim. Secondly, technological determinism is not just something that is the result of a bird’s eye view of technology and society or when we study technology as part of the macro level of society. Determinism can appear on all levels, even the micro level. Thirdly, like its counterpart social/societal determinism, technological determinism is not necessarily a “bad” thing, but a natural result of design being a balance between what is societally desirable and technically possible. The most critical issue from the point of view of technological literacy is to promote the idea that it is humans that design and retain control over technology.