bluuebunny/crossref_metadata_2025 huggingface dataset:
Geometric flux formula for the gravitational Wilson loop
Authors: Klitgaard N , Loll R , Reitz M , Toriumi R
Published: September 2020

Finding diffeomorphism-invariant observables to characterize the properties of gravity and spacetime at the Planck scale is essential for making progress in quantum gravity. The holonomy and Wilson loop of the Levi-Civita connection are potentially interesting ingredients in the construction of quantum curvature observables. Motivated by recent developments in nonperturbative quantum gravity, we establish new relations in three and four dimensions between the holonomy of a finite loop and certain curvature integrals over the surface spanned by the loop. They are much simpler than a gravitational version of the nonabelian Stokes’ theorem, but require the presence of totally geodesic surfaces in the manifold, which follows from the existence of suitable Killing vectors. We show that the relations are invariant under smooth surface deformations, due to the presence of a conserved geometric flux.
A robust all-inorganic hybrid energy harvester for synergistic energy collection from sunlight and raindrops
Authors: Liu Xiaolan , Cui Peng , Wang Jingjing , Shang Wanyu , Zhang Song , Guo Junmeng , Gu Guangqin , Zhang Bao , Cheng Gang , Du Zuliang
Published: September 2020

As a new concept of the device, a hybrid energy harvester integrated with a water droplet triboelectric nanogenerator (WD-TENG) and a solar cell has been reported to convert raindrop energy and solar energy into electricity. However, organic triboelectric layers are usually utilized in previous studies that might be decomposed under long-term UV irradiation, resulting in degradation of the hybrid energy harvester. In this work, a fully inorganic hybrid energy harvester is demonstrated. Superhydrophobic SiO2 film is introduced to the system as both the triboelectric layer of the WD-TENG and the anti-reflective layer of the solar cell, which could increase the power conversion efficiency (PCE) of the solar cell from 15.17% to 15.71%. Meanwhile, WD-TENG with the SiO2 triboelectric layer could collect energies from rain droplets. This superhydrophobic SiO2 film could effectively reduce the dependence of the tilt angle for the WD-TENG and bring up self-cleaning performance for the hybrid energy harvester. Moreover, this fully inorganic architecture could enhance the stability of the hybrid energy harvester, making it a promising strategy in practical applications.
Experiment with syringe and U-tube to determine the atmospheric pressure
Authors: Santosa I E
Published: September 2020

A simple apparatus consisting of a plastic syringe coupled with a U-tube has been constructed. This setup is filled with water to trap air in one arm of the U-tube. A change in the volume of the enclosed air causes a change in its pressure that is indicated by the difference in the water levels. Boyle’s law is shown by a linear relation between the pressure and the invers of the volume observed in the experimental result. Using the best linear fit we obtain the atmospheric pressure to be (108.7 ± 4.5) kPa.
Terahertz pulse generation by two-color laser fields with circular
polarization
Authors: Tailliez C , Stathopulos A , Skupin S , Buožius D , Babushkin I , Vaičaitis V , Bergé L
Published: September 2020

We study the influence of the polarization states of ionizing femtosecond
two-color pulses on the emitted terahertz radiation in gases. A local-current
model and plane-wave evaluations justify the previously-reported impact on the
THz energy yield and a (almost) linearly-polarized THz field when using
circularly-polarized laser harmonics. For such pump pulses, the THz yield is
independent of the relative phase between the two colors. When the pump pulses
have same helicity, the increase in the THz yield is associated with longer
ionization sequences and higher electron transverse momenta acquired in the
driving field. Reversely, for two color pulses with opposite helicity, the
dramatic loss of THz power comes from destructive interferences driven by the
highly symmetric response of the photocurrents lined up on the third harmonic of
the fundamental pulse. While our experiments confirm an increased THz yield for
circularly-polarized pumps of same helicity, surprisingly, the emitted THz
radiation is not linearly-polarized. This effect is explained by means of
comprehensive 3D numerical simulations highlighting the role of the spatial
alignment and non-collinear propagation of the two colors.
Chaotic dynamics of the hydrogen atom in a space-dependent electric field
Authors: Wang De-Hua , Chu Bin-Hua , Zhao Gang
Published: September 2020

We study the chaotic dynamics of the hydrogen atom in a space-dependent gradient electric field. We use the Poincaré surface of section (PSS) and the Lyapunov exponents to characterize chaotic dynamics. The dynamical character of this system is studied and the regular-chaos transition is found when the system passes from the non-integrable case to the integrable one. It is found that for a given gradient electric field, this system has a critical scaled energy

ε

s

.

When the scaled energy

ε
≤

ε

s

,

the structure of the whole phase space is nearly regular. However, as the scaled energy

ε
>

ε

s

,

chaotic structures appear in the PSS. As the scaled energy is very large, the whole PSS is chaotic. The chaotic property of this system is further verified by the positive value of the maximum Lyapunov exponent. In addition, we show that with increasing electric field gradient the dynamics of this system becomes increasingly chaotic. Our work provides an example to study the chaotic dynamics of the hydrogen atom by using the space-dependent electric field. We hope that our results can guide the future experimental researches about the dynamical property of the atoms or molecules in the non-uniform external fields.
Methods and applications of RNA contact prediction*
Authors: Wang Huiwen , Zhao Yunjie
Published: September 2020

The RNA tertiary structure is essential to understanding the function and biological processes. Unfortunately, it is still challenging to determine the large RNA structure from direct experimentation or computational modeling. One promising approach is first to predict the tertiary contacts and then use the contacts as constraints to model the structure. The RNA structure modeling depends on the contact prediction accuracy. Although many contact prediction methods have been developed in the protein field, there are only several contact prediction methods in the RNA field at present. Here, we first review the theoretical basis and test the performances of recent RNA contact prediction methods for tertiary structure and complex modeling problems. Then, we summarize the advantages and limitations of these RNA contact prediction methods. We suggest some future directions for this rapidly expanding field in the last.
Performance analysis of GaN-based high-electron-mobility transistors with postpassivation plasma treatment*
Authors: Zhou Xing-Ye , Tan Xin , Lv Yuan-Jie , Gu Guo-Dong , Zhang Zhi-Rong , Guo Yan-Min , Feng Zhi-Hong , Cai Shu-Jun
Published: September 2020

AlGaN/GaN high-electron-mobility transistors (HEMTs) with postpassivation plasma treatment are demonstrated and investigated for the first time. The results show that postpassivation plasma treatment can reduce the gate leakage and enhance the drain current. Comparing with the conventional devices, the gate leakage of AlGaN/GaN HEMTs with postpassivation plasma decreases greatly while the drain current increases. Capacitance–voltage measurement and frequency-dependent conductance method are used to study the surface and interface traps. The mechanism analysis indicates that the surface traps in the access region can be reduced by postpassivation plasma treatment and thus suppress the effect of virtual gate, which can explain the improvement of DC characteristics of devices. Moreover, the density and time constant of interface traps under the gate are extracted and analyzed.
Development of a primary measurement standard for trace moisture in Ar
Authors: Amano Minami , Abe Hisashi
Published: September 2020

We have developed a primary measurement standard for trace moisture in Ar in the range of 10 nmol mol−1 to 1 μmol mol−1 in the amount-of-substance fraction (mole fraction) using the previously developed multi-gas trace-moisture generator. The relative expanded uncertainty (k = 2) of the primary standard in Ar was between 2.7 % and 1.5 %. The performance of a moisture analyzer (MA) based on cavity ring-down spectroscopy (CRDS), which is considered to be the best existing device thus far for trace-moisture measurement, was tested through a comparison with the primary standard in Ar. The readings of the CRDS-based MA were approximately 10 % lower than the numerical values of the primary standard. The relative standard deviation of the readings became approximately 15 %, which was 15 times as large as that for N2. These were caused by a failure in the default setting of the MA for Ar and could be improved by optimizing the setting.
Constructional design of echinoid endoskeleton: main structural components and their potential for biomimetic applications
Authors: Perricone Valentina , Grun Tobias B , Marmo Francesco , Langella Carla , Candia Carnevali Maria Daniela
Published: September 2020

The endoskeleton of echinoderms (Deuterostomia: Echinodermata) is of mesodermal origin and consists of cells, organic components, as well as an inorganic mineral matrix. The echinoderm skeleton forms a complex lattice-system, which represents a model structure for naturally inspired engineering in terms of construction, mechanical behaviour and functional design. The sea urchin (Echinodermata: Echinoidea) endoskeleton consists of three main structural components: test, dental apparatus and accessory appendages. Although, all parts of the echinoid skeleton consist of the same basic material, their microstructure displays a great potential in meeting several mechanical needs according to a direct and clear structure–function relationship. This versatility has allowed the echinoid skeleton to adapt to different activities such as structural support, defence, feeding, burrowing and cleaning. Although, constrained by energy and resource efficiency, many of the structures found in the echinoid skeleton are optimized in terms of functional performances. Therefore, these structures can be used as role models for bio-inspired solutions in various industrial sectors such as building constructions, robotics, biomedical and material engineering. The present review provides an overview of previous mechanical and biomimetic research on the echinoid endoskeleton, describing the current state of knowledge and providing a reference for future studies.
Biomanufacturing organized collagen-based microfibers as a Tissue ENgineered Device (TEND) for tendon regeneration
Authors: Maghdouri-White Yas , Sori Nardos , Petrova Stella , Wriggers Hilary , Kemper Nathan , Dasgupta Amrita , Coughenour Kelly , Polk Seth , Thayer Nick , Mario Rodriguez DVM , Simon DPM Bill , Bulysheva Anna , Bonner Kevin , Arnoczky DVM Steven , Adams MD Samuel , Francis Michael P.
Published: September 2020

Approximately 800, 000 surgical repairs are performed annually in the U.S. for debilitating injuries to ligaments and tendons of the foot, ankle, knee, wrist, elbow and shoulder, presenting a significant healthcare burden. To overcome current treatment shortcomings and advance the treatment of tendon and ligament injuries, we have developed a novel electrospun Tissue ENgineered Device (TEND), comprised of type I collagen and poly(D,L-lactide) (PDLLA) solubilized in a benign solvent, dimethyl sulfoxide (DMSO). TEND fiber alignment, diameter and porosity were engineered to enhance cell infiltration leading to promote tissue integration and functional remodeling while providing biomechanical stability. TEND rapidly adsorbs blood and platelet-rich-plasma (PRP), and gradually releases growth factors over two weeks. TEND further supported cellular alignment and upregulation of tenogenic genes from clinically relevant human stem cells within three days of culture. TEND implanted in a rabbit Achilles tendon injury model showed new in situ tissue generation, maturation, and remodeling of dense, regularly oriented connective tissue in vivo. In all, TEND’s organized microfibers, biological fluid and cell compatibility, strength and biocompatiblility make significant progress towards clinically translating electrospun collagen-based medical devices for improving the clinical outcomes of tendon injuries.
From the perspective of material science: a review of flexible electrodes for brain-computer interface
Authors: He Guangwei , Dong Xufeng , Qi Min
Published: September 2020

As an important branch of man-machine interaction, Brain-Computer Interface (BCI) has the potential to be widely used in various fields, such as health-care, physical efficiency, aerospace, intelligence traffic system, entertainment and so on. The flexible electrode is the crucial component of the BCI, and is the key for the development of the BCI technology. Recently, with the increasing demands on Brain-Computer Interface, plenty of flexible electrode materials and the structural design for applications in BCI technology have been developed. In this study, we review the development of the three kinds of flexible electrodes material selection and structural design in BCI, including non-intrusive electrodes, intrusive electrodes and semi-intrusive electrodes. The challenge and the problems that hinder the development of the flexible electrode are analyzed. Besides, from the perspective of material science, the future applications of the flexible electrode in the BCI field is prospected.
Tensile and compression behaviour, microstructural characterization on Mg-3Zn-3Sn-0.7Mn alloy reinforced with SiCp prepared through powder metallurgy method
Authors: Singh G Robert , Christopher Ezhil Singh S , Sivapragash M , Anselm Lenin , Kumar R Sanjeev , Lenin A Haiter
Published: September 2020

In this research paper, Mg-3Zn-3Sn-0.7Mn/SiC composite is developed by reinforcing various weight fractions of SiCp in Mg-3Zn-3Sn-0.7Mn alloy through powder metallurgy route. The weight fraction of SiCpusage is varied from 3% to 15% in Mg-3Zn-3Sn-0.7Mn alloy (i.e., in Mg-3Zn-3Sn-0.7Mn/xSiC; the sample values are varies for x is 3, 6, 9, 12 and 15%). The effect of SiCp addition got tested against its tensile strength, compression behavior, hardness, microstructure, alloying nature and porosity. This study shows better grain refinement with improved properties while reinforcing Mg-3Zn-3Sn-0.7Mn alloy with 6 wt% SiC composites. It was observed that the grain refinement occurred while adding up to 6 wt% of SiC particles in the composite and thereafter increase in SiC caused little grain refinement effect. Hardness is getting increased with the increase of SiC weight fraction and reached maximum to 133 HV at 12SiC/ Mg-3Zn-3Sn-0.7Mn. Higher UTS of 293 MPa obtained from the sample prepared with 12%SiC for 0.0533 s−1 strain rate. The highest UCS of 341 MPa is obtained from the sample made with 15%SiC inclusion for 0.0.0533 s−1strain rate. From the SEM fracture analysis, the Mg-3Zn-3Sn-0.7Mn alloy and Mg-3Zn-3Sn-0.7Mn/SiC composite exhibit the almost same type of fracture called quasi-cleavage regardless of the % addition of SiC reinforcement. It was observed that the increase of SiC weight fraction increases the UCS because of its increased load-bearing capacity and reduction in cleavage facets.
Using longitudinal survey and sensor data to understand the social and ecological determinants of clean fuels use and discontinuance in rural Ghana
Authors: Carrión D , Prah R , Gould C F , Agbokey F , Mujtaba M , Pillarisetti A , Tumasi M , Agyei O , Chillrud S , Tawiah T , Jack D , Asante K P
Published: September 2020

Efforts to reduce the health and ecological burdens of household biomass combustion are underway in Ghana, principally by promoting clean cookstoves and fuels. Recent studies have focused on the sustained use of clean cookstoves, but sometimes household adopt a new cookstove and then end use of that stove. In this study, we introduce a novel framework for understanding and encouraging household transitions to cleaner cooking: clean fuel discontinuance. We leveraged data from the Ghana Randomized Air Pollution and Health Study (GRAPHS) (N = 1412) where pregnant women received either improved biomass (BioLite) or dual burner LPG stoves for free. LPG users were given free LPG refills during GRAPHS. Weekly questionnaires were administered. Stove use monitors tracked a sub-cohort (n = 220) 6 months before and after the fuel subsidy. We examined social and ecological determinants of stove use and discontinuance. Overall intervention stove use adherence was high throughout GRAPHS, with self-reported use at 69% and 86% of participant-weeks for BioLite and LPG arms respectively. Participants used intervention stoves less for meals requiring vigorous stirring. Burns from intervention stoves decreased use among BioLite (RR: 0.96, p = 0.009), but not LPG users. Device breakage was mentioned as an impediment in 18% of free-text responses for LPG users and 1% for BioLite. Tree canopy within a spatial buffer—a plausible proxy for biomass fuels access—was the only variable explaining LPG discontinued stove use in adjusted Cox time-to-event analyses (HR = −0.56, p < 0.001). Future studies should consider the stove use discontinuance framework.
Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
Authors: Northrop Amy , Byers Holly A. , Radhakrishnan Senthil K.
Published: September 2020

The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.
Skin Absorption of Bisphenol A and Its Alternatives in Thermal Paper
Authors: Reale Elena , Vernez David , Hopf Nancy B
Published: September 2020

Objectives

Bisphenol A (BPA) is the most used colour developer in thermal paper for cashiers receipts, labels, and tickets. BPA can migrate onto the skin and be absorbed when handling these papers. BPA is a known endocrine disruptor and is therefore being replaced in thermal paper by some alternatives such as Bisphenol S (BPS), D-8, and Pergafast 201® (PF201). To our knowledge, no studies have characterized skin permeation of these BPA alternatives.

Methods

We measured/characterized skin absorption for BPA, BPS, D-8, and PF201 through ex vivo human skin using flow-through diffusion cells according to OECD guideline 428. Skin samples were 7–12 per test substance from three different skin donors. Skin metabolism was studied for BPA. Dermal absorption was expressed as the amount of the BPA alternatives in the receptor fluid over applied dose in percent (%).

Results

The absorbed dose after 24 h of exposure was 25% for BPA, 17% for D-8, 0.4% for BPS, and <LLOQ for PF201. The amount of BPA-glucuronide in the receptor fluid after 24 h was under the limit of quantification (LLOQ = 0.2 µg l−1). Despite the 10-fold lower concentration of the aq solution applied on the skin, D-8’s permeation rate JMAX was 5-fold higher than the one for BPS (0.032 versus 0.006 µg cm−2 h−1). Neither D-8 nor BPS permeated readily through the skin (tlag = 3.9 h for D-8, 6.4 h for BPS). None of PF201’s skin permeation kinetic parameters could be determined because this BPA analogue was not quantifiable in the receptor fluid in our test conditions.

Conclusions

Skin absorption was in decreasing order: BPA > D-8 >> BPS > PF201. These results are in agreement with their log Kow and molecular weights. We provided here the necessary data to estimate the extent of skin absorption of BPA analogues, which is a necessary step in risk assessment, and ultimately evaluate public health risks posed by D-8, BPS, and PF201.
Contribution of Components of Metabolic Syndrome to Cognitive Performance in Middle-Aged Adults
Authors: Bahchevanov Karamfil M , Dzhambov Angel M , Chompalov Kostadin A , Massaldjieva Radka I , Atanassova Penka A , Mitkov Mitko D
Published: September 2020

Introduction

Metabolic syndrome (MetS) has been associated with impaired cognition in different cognitive domains. This study investigated the association between MetS and cognitive functioning in middle-aged Bulgarians across different definitions of MetS severity.

Material and Methods

Our cross-sectional sample included 112 participants (67 free of MetS and 45 with MetS) with a mean age of 50.04 ± 3.31 years. The following MetS variables were considered—presence of MetS, continuously measured MetS components, dichotomized MetS components, number of MetS components present, and Metabolic Syndrome Severity Score (MSSS). Participants’ cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB). We employed multivariate regression models to investigate the associations between different measures of MetS severity and CERAD-NB total and subtest scores.

Results

Bivariate analyses showed that the CERAD-NB total score was significantly higher in women, participants with a university degree, those with normal blood pressure, normal waist circumference, and low triglyceride levels, compared with their counterparts. MetS participants had lower CERAD-NB total score (78.87 ± 6.89 vs. 84.97 ± 7.84) and specifically performed poorer on the subtest Word List Recall (7.16 ± 1.52 vs. 7.99 ± 1.52). These findings persisted after controlling for age, gender, and education. Next, generalized linear regression indicated that the CERAD-NB total score was lower in participants with MetS (β = −4.86; 95% confidence interval [CI]: −7.60, −2.11), those with more MetS components (β = −8.31; 95% CI: −14.13, −2.50 for fours vs. 0 components) and with an increase in MSSS (β = −3.19; 95% CI: −4.67, −1.71). Hypertension independently contributed to lower CERAD-NB total score (β = −4.00; 95% CI: −6.81, −1.19).

Conclusions

Across several definitions, MetS was associated with lower cognitive functioning, and MetS severity appeared to be a better predictor than most MetS components. Recognizing and reducing severity of MetS components might be helpful in supporting cognitive functioning. Further longitudinal research is needed to shed more light on the relationship between MetS and cognitive functioning across the life span.
Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19
Authors: Dhall Anjali , Patiyal Sumeet , Sharma Neelam , Usmani Salman Sadullah , Raghava Gajendra P S
Published: September 2020

Interleukin 6 (IL-6) is a pro-inflammatory cytokine that stimulates acute phase responses, hematopoiesis and specific immune reactions. Recently, it was found that the IL-6 plays a vital role in the progression of COVID-19, which is responsible for the high mortality rate. In order to facilitate the scientific community to fight against COVID-19, we have developed a method for predicting IL-6 inducing peptides/epitopes. The models were trained and tested on experimentally validated 365 IL-6 inducing and 2991 non-inducing peptides extracted from the immune epitope database. Initially, 9149 features of each peptide were computed using Pfeature, which were reduced to 186 features using the SVC-L1 technique. These features were ranked based on their classification ability, and the top 10 features were used for developing prediction models. A wide range of machine learning techniques has been deployed to develop models. Random Forest-based model achieves a maximum AUROC of 0.84 and 0.83 on training and independent validation dataset, respectively. We have also identified IL-6 inducing peptides in different proteins of SARS-CoV-2, using our best models to design vaccine against COVID-19. A web server named as IL-6Pred and a standalone package has been developed for predicting, designing and screening of IL-6 inducing peptides (https://webs.iiitd.edu.in/raghava/il6pred/).
Supervised learning on phylogenetically distributed data
Authors: Layne Elliot , Dort Erika N , Hamelin Richard , Li Yue , Blanchette Mathieu
Published: September 2020

Motivation

The ability to develop robust machine-learning (ML) models is considered imperative to the adoption of ML techniques in biology and medicine fields. This challenge is particularly acute when data available for training is not independent and identically distributed (iid), in which case trained models are vulnerable to out-of-distribution generalization problems. Of particular interest are problems where data correspond to observations made on phylogenetically related samples (e.g. antibiotic resistance data).

Results

We introduce DendroNet, a new approach to train neural networks in the context of evolutionary data. DendroNet explicitly accounts for the relatedness of the training/testing data, while allowing the model to evolve along the branches of the phylogenetic tree, hence accommodating potential changes in the rules that relate genotypes to phenotypes. Using simulated data, we demonstrate that DendroNet produces models that can be significantly better than non-phylogenetically aware approaches. DendroNet also outperforms other approaches at two biological tasks of significant practical importance: antiobiotic resistance prediction in bacteria and trophic level prediction in fungi.

Availability and implementation

https://github.com/BlanchetteLab/DendroNet.
Risk of Incident Diabetes Mellitus, Weight Gain, and Their Relationships With Integrase Inhibitor–Based Initial Antiretroviral Therapy Among Persons With Human Immunodeficiency Virus in the United States and Canada
Authors: Rebeiro Peter F , Jenkins Cathy A , Bian Aihua , Lake Jordan E , Bourgi Kassem , Moore Richard D , Horberg Michael A , Matthews W Christopher , Silverberg Michael J , Thorne Jennifer , Mayor Angel M , Lima Viviane D , Palella Frank J , Saag Michael S , Althoff Keri N , Gill M John , Wong Cherise , Klein Marina B , Crane Heidi M , Marconi Vincent C , Shepherd Bryan E , Sterling Timothy R , Koethe John R
Published: September 2020

Background

Integrase strand transfer inhibitor (INSTI)–based combination antiretroviral therapy (cART) is associated with greater weight gain among persons with human immunodeficiency virus (HIV), though metabolic consequences, such as diabetes mellitus (DM), are unclear. We examined the impact of initial cART regimen and weight on incident DM in a large North American HIV cohort (NA-ACCORD).

Methods

cART-naive adults (≥18 years) initiating INSTI-, protease inhibitor (PI)–, or nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens from January 2007 through December 2017 who had weight measured 12 (±6) months after treatment initiation contributed time until clinical DM, virologic failure, cART regimen switch, administrative close, death, or loss to follow-up. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DM by cART class. Mediation analyses, with 12-month weight as mediator, similarly adjusted for all covariates.

Results

Among 22 884 eligible individuals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Overall, 722 (3%) developed DM. Persons starting INSTIs vs NNRTIs had incident DM risk (HR, 1.17 [95% CI, .92–1.48]), similar to PI vs NNRTI initiators (HR, 1.27 [95% CI, 1.07–1.51]). This effect was most pronounced for raltegravir (HR, 1.42 [95% CI, 1.06–1.91]) vs NNRTI initiators. The INSTI–DM association was attenuated (HR, 1.03 [95% CI, .71–1.49] vs NNRTIs) when accounting for 12-month weight.

Conclusions

Initiating first cART regimens with INSTIs or PIs vs NNRTIs may confer greater risk of DM, likely mediated through weight gain.
Public attribution of cyber intrusions
Authors: Egloff Florian J
Published: September 2020

Attribution is central to the debate on how to respond to cyber intrusions. The policy challenge is increasingly moving from identifying who is behind a cyber intrusion to finding the adequate policy response, including whether to publicly attribute. The article examines the use of public attribution as a political strategy for attaining specific political effects beyond the dyadic attacker–victim relationship, including shaping the operational and normative environment of cyber operations, with the potential to exert an independent deterrent effect. My analysis unfolds in three parts. The first part introduces two core concepts—sense-making and meaning-making—to capture different parts of the attribution process. I then introduce a theoretical understanding of public attribution drawing on the literature on revealing covert activity and argue that public attribution can serve the function of defining a particular interaction order, i.e. shape the rules of the ‘game’. In part two and three I discuss two empirical examples of both concepts. I bring to the fore three observations: First, some states have shifted their policy responses from dealing with individual cyber intrusions to responding in a broader political framework of relations with a specific adversary leading to campaign-like responses. Second, the political decision whether to attribute publicly is not only a signal to the adversary, but also aims at shaping the future political and normative operational environment. Third, such norm shaping has the potential to exert an independent—though limited—deterrent effect, particularly on potential adversaries. The analysis demonstrates the importance of the meaning-making process to understanding the politics of attribution and the rewards of theoretically integrating it into the politics of secrecy and exposure of covert activities of states.
408 THE PRESENCE OF LYMPHATIC, VENOUS AND PERINEURAL INFILTRATION FOLLOWING ESOPHAGECTOMY WITHOUT NEOADJUVANT THERAPY TO IDENTIFY PATIENTS AT RISK OF RECURRENCE.
Authors: Hardy K , Chmelo J , Khaw R , Navidi M , Phillips A
Published: September 2020

Staging and prognostication in esophgaeal cancer patients is based on their TNM stage. Previous research has suggested venous invasion (VI), lymph vessel invasion (LI) and perineural invasion (PNI) as adverse prognostic indicators in patients with advanced disease receiving neoadjuvant treatment. The aim of this study was to assess the incidence and prognostic significance of these factors in patients with cancer of the esophagus or gastro-esophageal junction (GEJ) who were treated with unimodality surgery.

Methods

A contemporaneously maintained database was used to identify patients who underwent a primary 2-field transthoracic esophagectomy for adenocarcinoma or squamous cell carcinoma of the esophagus or gastro-esophageal junction. Between January 2000 and January 2018. Patients who died in hospital, underwent palliative resections or where the presence (or absence) of VI, LI or PNI was not reported were excluded. Patients were staged using UICC-TNM 7.

Results

279 patients were included. VI was present in 99 (35%) patients, LI in 120 (43%), and PNI in 120 (43%). Median overall survival was 140 months (95% confidence interval (CI): 79.3–200.7) when PNI, LV and VI were absent, 55 months (95% CI: 42.2–67.8) when one factor was present, 18 months (95% CI: 5.4–30.6) with two factors and 31 months (95% CI: 17.6–44.4) with all three factors present. Univariable analysis revealed that LI, PNI and VI are significant prognostic indicators for length of disease-free survival (p < 0.001) with LI an independent prognostic factor on multivariable analysis (p = 0.05).

Conclusion

These findings suggest the importance of the presence of LI, VI and PNI in patients undergoing unimodality esophagectomy for cancer of the esophagus. It may provide additional information for identifying patients that are high risk who may be candidates for adjuvant therapy.
452 SURVIVAL IMPACT OF CLINICALLY NEGATIVE BUT PATHOLOGICALLY POSITIVE NODES IN CSTAGE I ESOPHAGEAL CANCER PATIENTS
Authors: Momose K , Shiraishi O , Hiraki Y , Kato H , Iwama M , Yasuda A , Shinkai M , Imano M , Yasuda T
Published: September 2020

Clinical diagnosis of lymph node metastasis has a great significance particularly in cT1 or cT2 esophageal cancer patients, since their clinical “N” diagnosis determines the treatment strategy according to the Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society. Then clinically node-negative but pathologically node-positive status could potentially have negative impact on survival outcome. The purpose of this study is to see the impact of clinical node diagnosis.

Methods

Esophageal squamous cell carcinoma patients diagnosed as cT1N0 or cT2N0 who underwent radical esophagectomy from 2003 to 2017 were enrolled retrospectively. Clinically node-positive was defined as any of the followings; 1) 10 mm or more longest diameter, 2) 8 mm or more longest diameter and round or irregular shaped, 3) 5 mm or more longest diameter and FDG uptake on PET-CT scan. Survival curves with Kaplan–Meier method were plotted by the pathological N stage and examined by the log rank test.

Results

Totally 203 patients were enrolled in this study. There were 159(78%)/36(18%)/8(4%)/0(0%) pN0/pN1/pN2/pN3 patients, respectively. There was no significant survival difference between pN0 and pN1 patients (p = 0.9). But pN2 patients had worse survival than pN0 patients (p = 0.0037).

Conclusion

There was no negative survival impact of two or less clinically negative but pathologically positive nodes. This might suggest that clinical node diagnosis should be assessed carefully enough in order to have as less number of clinically negative but pathologically positive nodes as possible. Further investigation is needed for those having three or more clinically negative but pathologically positive nodes.
471 POTENTIAL ROLE OF NEOADJUVANT RADIO-CHEMOTHERAPY ON NEW-ONSET ATRIAL FIBRILLATION AFTER HYBRID IVOR-LEWIS ESOPHAGECTOMY FOR CANCER
Authors: Pansa A , Riva P , Da Roit A , Basato S , Ricchitelli S , Luberto A , Marano S , Castoro C
Published: September 2020

New onset atrial fibrillation (AF) is observed in up to 37% of patients after esophagectomy for esophageal and esophago-gastric junction (EGJ) cancer. Little is known about risk factors for AF in this cohort of patients. Current literature describes an association between postoperative AF and other complications, notably anastomotic leaks and infective or pulmonary complications. The aim of this paper is to determine which factors relate to an increased risk of new-onset AF after esophagectomy.

Methods

We retrospectively analyzed a prospectively collected database in a high-volume, tertiary referral center for esophageal disease. All consecutive patients who underwent hybrid Ivor-Lewis (IL) esophagectomy for esophageal or EGJ cancer at the Upper GI surgery unit in Humanitas Research Hospital from January 2018 to august 2019 were evaluated for inclusion. Patients with a history of paroxysmal or chronic AF were excluded from the analysis. Complications were reported according to the ECCG classification. Association between variables and onset of AF was studied with univariable and multivariable logistic regression analysis.

Results

89 IL cases among 125 esophagectomies were included for analysis. Overall complication rate was 29.2%. AF accounted for 9 cases (10.1%) and was the only complication in these patients. Anastomotic leak occurred in 2 patients (2.25%) both ECCG type 1, 3 developed significant pleural effusion (3.37%), 6 other infective conditions (6.7%). No postoperative deaths occurred. Significantly increased risk of AF was found in patients who underwent chemoradiotherapy(CRT) compared to those who received chemotherapy(CT) or no treatment(OR = 8.4, p = 0.02). If we compare only patients who received neoadjuvant treatment, a higher risk for CRT versus CT alone was found(OR = 5.5), with a trending significance(p = 0.08).

Conclusion

In this study, we did not find any association between AF and other complications. New-onset AF always presented as the only complication and it was significantly associated to neoadjuvant chemoradiotherapy. On the basis of this findings, we are designing a protocol with the aim of studying potential preventive intervention for postoperative FA after esophagectomy.
474 GENOMIC ANALYSIS OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN ESOPHAGEAL ADENOCARCINOMA
Authors: Izadi F , Devonshire G , Walker R , Lloyd M , Gibson J , Secrier M , Fitzgerald R , Rose-Zerilli M , Underwood T
Published: September 2020

In the UK, neoadjuvant chemotherapy (NAC) for locally advanced esophageal adenocarcinoma (EAC) is the standard of care. Unfortunately, response to NAC, following surgery is often low (<30%) and survival benefit at 2 years is only 5.1%. The EAC genome is complex and heterogeneous between patients, where specific mutagenic processes and mutations may result in chemotherapy resistance. Here we report preliminary results from whole-genome sequencing (WGS) of 48 patients who were subsequently treated with NAC.

Methods

We defined response as Mandard Tumor Regression Grade (TRG) 1-2 (n = 15) and non-response as TRG4-5 (n = 33). WGS of 50x coverage and calling of genomic events (Strelka2, SCAT/GISTIC) was performed according to Frankell Nat Genet 2019 with modifications, to differentiate driver from passenger mutations (dNdScv, oncodriveCLUST), determine variant allele frequencies (VAF; copy number-adjusted) and mutation signatures (NMF R-package). Following stringent variant QC (Phred score ≥ 30), filtering (VAF >0.02) and annotation (ANNOVAR, cancer census/helper, the 77 known EAC drivers and false positive genes) and visualisation in maftools, we evaluated the data for associations between genomic events and response to NAC.

Results

COSMIC mutation signatures 2 (TRG1-2; Cosθ = 0.89) and 6 (TRG4-5; Cosθ = 0.82) were enriched, suggesting defective mismatch repair in non-responders. Using 5,193 high-confidence non-silent mutations (TRG1-2,n = 1969; TRG4-5, n = 3224), we identified 39 mutated driver genes (Figure-1) with a median of 2.9(0-5) (TRG1-2) and 2.7(0-9) (TRG4-5) driver events/patient. Shared dysregulated pathways, included DNA-damage (TP53), cell cycle (CDKN2A), TGF-β (SMAD4) and chromatin regulation (ARID1A). There was no difference in the prognostic of SMAD4 and GATA4 genes. Interestingly, NAV3 mutations were only present in non-responders (21%,7/33); and in responders TP53 incidence was higher (93% vs. 58%) with a concomitant reduction in clonal cell fraction (0.25 vs. 0.39;Wilcoxon, p < 0.0001).

Conclusion

The data suggest that specific genomic events, such as NAV3 mutation and the intra-tumoral heterogeneity of mutated DNA-damage response genes may offer additional predictive value. Ongoing work includes analysis of the impact of non-coding variation on response. While our analysis is limited by sample size and requires validation in additional cohorts, it demonstrates the potential of genomic sequencing to identify NAC response biomarkers and may guide alternative or novel treatment modalities for chemo-resistant tumours.
496 THE INFLAMMATORY-METAPLASIA-DYSPLASIA-OESOPHAGEAL ADENOCARCINOMA SEQUENCE: THE ROLE OF THE MICROBIOME
Authors: Barrett M , Elliott J , Hand C , Shanahan F , O'Toole P , Murphy T
Published: September 2020

The human microbiota, the collection of microbes that inhabit the human body, is increasingly recognized as playing a role in human health. A seminal example of this relationship is Helicobacter pylori and gastric cancer oncogenesis. The decline in H.pylori prevalence and non-cardia gastric cancer incidence have coincided with the rise in oesophageal adenocarcinoma (OAC) incidence. We sought to explore the relationship between the gastric and oesophageal microbiome and OAC oncogenesis.

Methods

This study aimed to explore changes in the microbiome associated with oesophageal adenocarcinoma and its precancerous and inflammatory states by performing 16S rRNA gene amplicon sequencing on DNA extracted from oesophago-gastric biopsies from patients with normal oesophageal mucosa, reflux oesophagitis, Barrett’s oesophagus with and without dysplasia, locally advanced but resectable oesophageal adenocarcinoma, and incurable metatstatic oesophageal adenocarcinoma (See Table 1).

We dissected ecological differences between sample site and clinical classification using a variety of approaches including examining differentially abundant taxa and inferred metabolic pathways, alpha diversity and beta-diversity.

Results

There was no statistically significant difference in beta diversity with respect to biopsy location. Alpha diversity was reduced in gastric biopsies compare to oesophageal biopsies. A small but significant shift was noted in beta diversity (Bray–Curtis Dissimilarity) with respect to clinical classification in biopsies derived from the gastroesophageal junction (GEJ) and stomach.

Fusobacterium nucleatum was found to overrepresented in oesophageal biopsies derived from diseased groups relative to the healthy controls. Several taxa assigned to the genus Prevotella were depleted in biopsies of individuals with metastatic OAC compared to all other groups.

Conclusion

Community structure was shifted in samples derived from the GEJ, the epicentre of OAC oncogenesis. Fusobacterium plays a role in cancer development and progression through a number of mechanisms including increasing cell proliferation, immune cell infiltration and chemoresistance. Fusobacterium can cause upregulation of MicroRNA-21, a microRNA upregulated in OAC.
499 SUSTAINED ESOPHAGEAL CONTRACTIONS (SEC) BY FLIP PROVIDES ADDITIONAL CHARACTERISTICS ON ESOPHAGEAL DYSMOTILITY IN PATIENTS WITH ESOPHAGEAL SYMPTOMS
Authors: Nguyen A , Zhang J , Harris S , Podgaetz E , Ward M , Ramesh M , Souza R , Spechler S , Konda V
Published: September 2020

Sustained esophageal contractions (SEC) have previously been described on high frequency esophageal ultrasound, high resolution manometry (HRM), and more recently on real time impedance planimetry with functional lumen imaging probe (FLIP). SEC may demonstrate a discoordination between circular and longitudinal esophageal smooth muscle contractions. The aim of this study was to determine the clinical characterization of SEC as detected on FLIP compared to HRM.

Methods

We performed a retrospective chart review of patients who underwent both FLIP and HRM at our Center for Esophageal Diseases between May 2017 and November 2019. FLIP endoscopic reports were reviewed for the presence of SECs which were defined as vigorous lumen closure ≥5 seconds at the LES or esophageal body as noted by the endoscopist during the real time FLIP examination of a sedated endoscopy. Primary variables recorded included EGJ distensibility index (EGJ-DI), diameter, and the presence of SECs at the 40 mL and 60 mL fill volumes. HRM diagnosis, clinical symptoms and outcomes were also reviewed.

Results

Of 165 patients who underwent HRM and FLIP imaging, 64 patients (mean age 53.7 years, 20 male) with SECs were included in the study. Among these patients, HRM demonstrated a wide variety of motility disorders (Figure 1). 40% of those with EGJOO, Type II or Type III achalasia, and all patients with jackhammer esophagus had SECs on FLIP imaging.

Of 56 patients with normal motility or IEM, 22 had SECs, and 18 patients underwent an endoscopic intervention. Among those who had an intervention, 11 (61%) reported improvement in symptoms with improvement in Eckardt score from 4.9 to 3.9.

Conclusion

SECs are frequently present in hypercontractile esophageal disorders. Interestingly, 39% of patients with normal motility or IEM have SECs noted on FLIP, and 82% of these patients had an intervention performed based on FLIP findings with 61% reporting symptom improvement. Overall, 19% of patients with normal motility or IEM improved due to interventions performed based on SECs found on FLIP. Detection of SEC during FLIP imaging can guide treatment aimed at relaxation of esophageal muscles.
512 OUTCOME OF MULTIMODAL TREATMENT FOR SOLITARY LYMPH NODE RECURRENCE OF ESOPHAGEAL CARCINOMA AFTER CURATIVE RESECTION
Authors: Shoda K
Published: September 2020

Patients with esophageal squamous cell carcinoma (ESCC) often display recurrence in the solitary lymph nodes after surgery. The optimal treatment strategy for these patients has not been established. The aim of the present study was to evaluate the outcome of intensive treatment for recurrent lymph node metastasis retrospectively.

Methods

Of the 19 patients with solitary recurrent lymph node metastasis after curative esophagectomy between 2006 and 2015, 7 had cervical lymph node, 7 had mediastinal lymph node, and 5 had abdominal lymph node recurrence. Multimodal treatment was performed in the patients: 2 patients underwent lymphadenectomy with adjuvant therapy, and 15 received definitive chemoradiotherapy and repeated chemotherapy. The remaining 2 patients received chemotherapy.

Results

Survival of lymphadenectomy group tended to be better than that of other groups (p = 0.1388), and survival of the lymphadenectomy and the chemoradiotherapy groups was significantly better than that of the patients who received chemotherapy (p = 0.0209).

Partial response (PR), stable disease, and progressive disease were obtained in 8 (53%), 1 (7%), and 6 (40%) patients who received chemoradiotherapy, respectively. Among chemoradiotherapy groups, patients with a therapeutic effect (PR) on radiation therapy had significantly better prognosis (p = 0.0175).

Conclusion

Multimodal treatment including lymphadenectomy and chemoradiotherapy could improve survival of the patients with solitary lymph node recurrence of esophageal carcinoma after curative resection.