bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on Scheduling Model and Algorithm of Drop-and-hook Transport Vehicles Based on Land-Sea Combined Transport
Authors: Xinyu Dou , Yang Li , Luhua Zhao , Baoyuan Wang
Published: October 2020

Background China’s squatting transportation mode has been continuously developed. A single road hoisting transportation can no longer meet the market demand, and a variety of ways to coexist in the transportation mode is constantly emerging. Objective To study how the stern transport vehicles can complete the dispatching task more efficiently under the conditions of land and sea transportation. Methods analyzes the advantages of the sling transport operation under the condition of land and sea transportation, and establishes the scheduling model of the stern transport vehicle based on land and sea transportation. This paper designs a heuristic algorithm to solve the initial solution of the model. Based on this, combined with the application of simulated annealing The algorithm performs the objective function minimization solution. Results The vehicle scheduling model was verified by practical examples, which proved the practicability of the model and algorithm.
RETRACTED: Analysis and applicability of road temperature stress behavior in cold area under large temperature difference
Authors: Zhang Yiluo , Deng Zhan Wei , Guo Chuang
Published: October 2020

In order to understand variation of temperature stress in pavement interior in exterme or great cooling climate, the temperature stress behavior and structural applicability of three different base types in cold region were studied. With the help of Abaqus software, the temperature stress of the pavement under the environment of large temperature difference of 20°C, 30°C and 40°C daily is obtained, and the mechanical response of different base courses under the coupling effect of temperature and dynamic load is analyzed. The results show that composite base pavement has the best applicability in the cold region with large temperature difference. When the daily temperature difference increases by 10°C in winter, the variation range of road surface, asphalt base and cement stabilized macadamite top is about 30%∼35%, 15%∼28% and 41%∼50%, respectively. When the daily temperature difference increases by 10°C in summer, the stre-ss increases by 102%∼121%, 77%∼80% and 18%∼21%, respect-vely. The stress increase of composite base pavement is the least. Moreover, it still has advantages under the coupling effect of temperature and dynamic load. To be specific, all the mechanical indexes are small under the coupling effect of low temperature a-nd dynamic load. The shear stress of asphalt layer is better und-er the action of high temperature and dynamic load.
Optimal Terminal Iterative Learning Control for the Parking Control System of Maglev Train
Authors: Zhang Pengju
Published: October 2020

This paper analyzes the parking process of maglev trains, establishes the corresponding mathematical model, based on the method of terminal iterative learning control(TILC), uses the stopping position error in the previous braking process to update the current control curve. In this paper, we select the initial braking position, initial speed or braking force or a combination thereof as the control input, and formulate the corresponding learning law. Finally, a line is simulated, and the traditional TILC method and the optimal TILC method are compared through simulation experiments, which verify that the latter has a faster convergence speed.
Driving Strategy of Heavy Haul Train Based on Support Vector Regression
Authors: Yang Shuo , Lin Zhengnan , Yang Xiaofeng
Published: October 2020

In order to reduce the labor intensity of heavy-haul train drivers in the downgrade section and near the split phase area, the paper analyzes the factors that affect the driving strategy of heavy-haul train in accordance with the manual driving strategy. In this paper, a control model of heavy-haul train electric braking force based on support vector regression (SVR) is proposed to control the electric braking force. With the manual driving records used as training data, Electric braking force and other information are extracted as output results and features to train the control model. By trial and error, parameters of the control model are adjusted to optimize the model. The results show that the control model in this paper is close to the manual driving in the same situation, which is positive for reducing the labor intensity of drivers in heavy-haul railway.
A Conflict-free Trajectory Generation Method for Pre-tactical Phase in Trajectory Based Operation
Authors: Yang Zhang , Pei Chu , Yungang Tian , Longbiao Ma
Published: October 2020

Trajectory Based Operation (TBO) is the future vision of air traffic management, and provides efficiency, capacity and safety benefits by managing aircraft trajectories cooperatively. According to air traffic operational characteristic of responsibility airspace division, this paper presents a conflict-free trajectory generation for pre-tactical phase in TBO environment. Considering the traffic flow distribution and flight conflict, a detailed conflict-free trajectory planning algorithm based on waypoint trajectory constraint is developed. Some simulation results based on typical operational data are carried out to show the feasibility of proposed method. This work is of great significance to the development of trajectory management and decision tools to support TBO.
Modeling of Energy Consumption Influencing Factors of Urban Rail Transit Station based on System Dynamics
Authors: Zhang Chenchen , Wang Yanhui , Xiao Xuemei , Luo Zhiwei
Published: October 2020

The energy consumption of urban rail transit station is an important part of the total energy consumption. In this paper, we focus on the energy consumption of urban rail transit stations. After analyzing the influencing factors and their relationship of station energy consumption from the aspects of electromechanical equipment and operation level, we establish the causal loop diagram of the influencing factors of station energy consumption based on system dynamics, and construct the system dynamics model of station energy consumption. Through simulation calculation, the effects of various influencing factors on the total energy consumption of the station are obtained. Moreover the key factors affecting station energy consumption are found. At last, the concrete measures to improve the energy consumption and energy saving efficiency of the station are presented, which provides theoretical support for the optimization of energy saving of the urban rail transit system.
Analysis of the Causes and Countermeasures of Low Passenger Flow Effect of Tram Lines in China
Authors: Xu Zhengliang , He Liying
Published: October 2020

The development of modern tram in China is very rapid while the passenger flow effects of many existing tram lines are not as good as expected. In order to find out the main causes and countermeasures, this paper compares the passenger flow effects of 49 tram lines at home and abroad by indicator named passenger flow intensity. Then the impacts of land exploitative intensity of nearby regions, average distance between stations and traffic conditions of the same corridor on passenger flow effect are analyzed based on specific cases. Suggestions of strengthening land exploitative intensity of regions along the tram line, shortening the average distance between stations, avoiding setting tram line on the corridor where road traffic is not heavy or there are multiple parallel rail transit lines are finally made to improve pass enger flow effect of tram line.
Safety Audit of Construction Drawing Design of the NR3 Highway Reconstruction & Expansion Project and Traffic Safety Developing Suggestion in Cambodia
Authors: Gong Baiyan , Di Shengde , Hao Siyuan , Chen Lei , Zhou Zhiwei
Published: October 2020

The highway safety audit is a means to improve the safety level and service ability of highway. Based on the safety audit of Cambodian highway in the construction drawing design and the investigation on the local road network conditions, the countermeasures for improving the road traffic safety and the suggestions for the future development of road traffic safety are put forward.
In situ functionalization of graphene
Authors: Greben Kyrylo , Kovalchuk Sviatoslav , Valencia Ana M , Kirchhof Jan N , Heeg Sebastian , Rietsch Philipp , Reich Stephanie , Cocchi Caterina , Eigler Siegfried , Bolotin Kirill I
Published: October 2020

While the basal plane of graphene is inert, defects in it are centers of chemical activity. An attractive application of such defects is towards controlled functionalization of graphene with foreign molecules. However, the interaction of the defects with reactive environment, such as ambient, decreases the efficiency of functionalization and makes it poorly controlled.

Here, we report a novel approach to generate, monitor with time resolution, and functionalize the defects in situ without ever exposing them to the ambient. The defects are generated by an energetic argon plasma and their properties are monitored using in situ Raman spectroscopy. We find that these defects are functional, very reactive, and strongly change their density from ≈1 × 1013 cm−2 to ≈5 × 1011 cm−2 upon exposure to air. We perform the proof of principle in situ functionalization by generating defects using the argon plasma and functionalizing them in situ using ammonia functional. The functionalization induces the n-doping with a carrier density up to 5 × 1012 cm−2 in graphene and remains stable in ambient conditions.
Maximum likelihood reconstruction of ancestral networks by integer linear programming
Authors: Rajan Vaibhav , Zhang Ziqi , Kingsford Carl , Zhang Xiuwei
Published: October 2020

Motivation

The study of the evolutionary history of biological networks enables deep functional understanding of various bio-molecular processes. Network growth models, such as the Duplication–Mutation with Complementarity (DMC) model, provide a principled approach to characterizing the evolution of protein–protein interactions (PPIs) based on duplication and divergence. Current methods for model-based ancestral network reconstruction primarily use greedy heuristics and yield sub-optimal solutions.

Results

We present a new Integer Linear Programming (ILP) solution for maximum likelihood reconstruction of ancestral PPI networks using the DMC model. We prove the correctness of our solution that is designed to find the optimal solution. It can also use efficient heuristics from general-purpose ILP solvers to obtain multiple optimal and near-optimal solutions that may be useful in many applications. Experiments on synthetic data show that our ILP obtains solutions with higher likelihood than those from previous methods, and is robust to noise and model mismatch. We evaluate our algorithm on two real PPI networks, with proteins from the families of bZIP transcription factors and the Commander complex. On both the networks, solutions from our ILP have higher likelihood and are in better agreement with independent biological evidence from other studies.

Availability and implementation

A Python implementation is available at https://bitbucket.org/cdal/network-reconstruction.

Supplementary information

Supplementary data are available at Bioinformatics online.
Hypoxia-inducible factor (HIF1alpha) inhibition modulates cumulus cell function and affects bovine oocyte maturation in vitro†
Authors: Turhan Aslihan , Pereira Miguel Tavares , Schuler Gerhard , Bleul Ulrich , Kowalewski Mariusz P
Published: October 2020

Various metabolic and hormonal factors expressed in cumulus cells are positively correlated with the in vitro maturation (IVM) of oocytes. However, the role of hypoxia sensing both during maturation of cumulus–oocyte complexes (COCs) as well as during the resumption of meiosis remains uncertain. HIF1alpha plays major roles in cellular responses to hypoxia, and here we investigated its role during bovine COC maturation by assessing the expression of related genes in cumulus cells. COCs were divided into the following groups: immature (control), in vitro matured (IVM/control), or matured in the presence of a blocker of HIF1alpha activity (echinomycin, IVM/E). We found an inhibition of cumulus cell expansion in IVM/E, compared with the IVM/control. Transcript levels of several factors (n = 13) were assessed in cumulus cells. Decreased expression of HAS2, TNFAIP6, TMSB4, TMSB10, GATM, GLUT1, CX43, COX2, PTGES, and STAR was found in IVM/E (P < 0.05). Additionally, decreased protein levels were detected for STAR, HAS2, and PCNA (P < 0.05), while activated-Caspase 3 remained unaffected in IVM/E. Progesterone output decreased in IVM/E. The application of PX-478, another blocker of HIF1alpha expression, yielded identical results. Negative effects of HIF1alpha suppression were further observed in the significantly decreased oocyte maturation and blastocyst rates from COCs matured with echinomycin (P < 0.05) or PX-478 (P < 0.05). These results support the importance of HIF1alpha for COC maturation and subsequent embryo development. HIF1alpha is a multidirectional factor controlling intercellular communication within COCs, steroidogenic activity, and oocyte development rates, and exerting effects on blastocyst rates.
Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease
Authors: Pereira Joana B , Janelidze Shorena , Ossenkoppele Rik , Kvartsberg Hlin , Brinkmalm Ann , Mattsson-Carlgren Niklas , Stomrud Erik , Smith Ruben , Zetterberg Henrik , Blennow Kaj , Hansson Oskar
Published: October 2020

It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer’s disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer’s disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
Rostro-Caudal Specificity of Corticospinal Tract Projections in Mice
Authors: Steward Oswald , Yee Kelly M , Metcalfe Mariajose , Willenberg Rafer , Luo Juan , Azevedo Ricardo , Martin-Thompson Jacob H , Gandhi Sunil P
Published: October 2020

Rostro-caudal specificity of corticospinal tract (CST) projections from different areas of the cortex was assessed by retrograde labeling with fluorogold and retrograde transfection following retro-AAV/Cre injection into the spinal cord of tdT reporter mice. Injections at C5 led to retrograde labeling of neurons throughout forelimb area of the sensorimotor cortex and a region in the dorsolateral cortex near the barrel field (S2). Injections at L2 led to retrograde labeling of neurons in the posterior sensorimotor cortex (hindlimb area) but not the dorsolateral cortex. With injections of biotinylated dextran amine (BDA) into the main sensorimotor cortex (forelimb region), labeled axons terminated selectively at cervical levels. With BDA injections into caudal sensorimotor cortex (hindlimb region), labeled axons passed through cervical levels without sending collaterals into the gray matter and then elaborated terminal arbors at thoracic sacral levels. With BDA injections into the dorsolateral cortex near the barrel field, labeled axons terminated at high cervical levels. Axons from medial sensorimotor cortex terminated primarily in intermediate laminae and axons from lateral sensorimotor cortex terminated primarily in laminae III–V of the dorsal horn. One of the descending pathways seen in rats (the ventral CST) was not observed in most mice.
Diagnosis and Management of Intraabdominal Infection: Guidelines by the Chinese Society of Surgical Infection and Intensive Care and the Chinese College of Gastrointestinal Fistula Surgeons
Authors: Wu Xiuwen , Wu Jie , Wang Peige , Fang Xueling , Yu Yunsong , Tang Jianguo , Xiao Yonghong , Wang Minggui , Li Shikuan , Zhang Yun , Hu Bijie , Ma Tao , Li Qiang , Wang Zhiming , Wu Anhua , Liu Chang , Dai Menghua , Ma Xiaochun , Yi Huimin , Kang Yan , Wang Daorong , Han Gang , Zhang Ping , Wang Jianzhong , Yuan Yufeng , Wang Dong , Wang Jian , Zhou Zheng , Ren Zeqiang , Liu Yuxiu , Guan Xiangdong , Ren Jianan
Published: October 2020

The Chinese guidelines for IAI presented here were developed by a panel that included experts from the fields of surgery, critical care, microbiology, infection control, pharmacology, and evidence-based medicine. All questions were structured in population, intervention, comparison, and outcomes format, and evidence profiles were generated. Recommendations were generated following the principles of the Grading of Recommendations Assessment, Development, and Evaluation system or Best Practice Statement (BPS), when applicable. The final guidelines include 45 graded recommendations and 17 BPSs, including the classification of disease severity, diagnosis, source control, antimicrobial therapy, microbiologic evaluation, nutritional therapy, other supportive therapies, diagnosis and management of specific IAIs, and recognition and management of source control failure. Recommendations on fluid resuscitation and organ support therapy could not be formulated and thus were not included. Accordingly, additional high-quality clinical studies should be performed in the future to address the clinicians’ concerns.
A New Specimen for Syphilis Diagnosis: Evidence by High Loads ofTreponema pallidumDNA in Saliva
Authors: Wang Cuini , Hu Zhixiang , Zheng Xin , Ye Meiping , Liao Chunjie , Shang Mengya , Gong Weiming , Guan Zhifang , Lu Haikong , Gu Xin , Shi Mei , Zhou Pingyu
Published: October 2020

Background

DNA from many pathogens can be detected in saliva. However, the presence and quantity of Treponema pallidum DNA in patients with syphilis in saliva is unknown.

Methods

234 patients with syphilis with different stages and 30 volunteers were enrolled. Paired saliva and plasma samples were collected from all participants. Consecutive saliva samples from 9 patients were collected every 4 hours following treatment. Treponema pallidum DNA in samples was determined by nested polymerase chain reaction (PCR) and droplet digital PCR targeting polA and Tpp47.

Results

Treponema pallidum DNA detection rates in saliva and plasma were 31.0% (9/29) and 51.7% (15/29) in primary syphilis (P = .11), 87.5% (63/72) and 61.1% (44/72) in secondary syphilis (P < .001), 25.6% (21/82) and 8.5% (7/82) in latent syphilis (P = .004), and 21.6% (11/51) and 5.9% (3/51) in symptomatic neurosyphilis (P = .021), respectively. Median (range) loads of Tpp47 and polA in saliva were 627 (0–101 200) and 726 (0–117 260) copies/mL, respectively, for patients with syphilis. In plasma, however, loads of Tpp47 and polA were low: medians (range) of 0 (0–149.6) and 0 (0–176) copies/mL, respectively. Loads of T. pallidum DNA in saliva during treatment fluctuated downward; the clearance time was positively correlated with the loads of T. pallidum DNA before treatment.

Conclusions

Collection of saliva is noninvasive and convenient. The high loads of T. pallidum DNA in saliva and reduction after treatment indicated that saliva can be not only a diagnostic fluid for syphilis but also an indicator of therapeutic effectiveness.
International Progress, International Order, and the Liberal International Order
Authors: Barnett Michael
Published: October 2020

Most explanations for the crisis of the liberal order revolve around geopolitics, globalization, economic resentment fueling new forms of populism and nationalism, and Western states following their interests away from liberal values and institutions of their creation. But international orders are produced and legitimated by both material and spiritual forces. The spirit in liberalism is moral progress defined by practices of humanity. If the Liberal International Order (LIO) is in decline, then perhaps we should consider its moral foundations. Section “Introduction” briefly introduces the question of international order, categorizes international relations theories according to the mixture of consent and coercion, and how legitimacy often refers not only to the existing order but a vision of progress. This is particularly true of the liberal international order. Section “International Order, Legitimacy, and Progress” turns to the liberal international order, progress, and the possible spiritual decline of the liberal international order. After briefly considering the liberal in international liberalism and the late 20th-century emergence of the liberal international order, I argue that one reason for its declining moral foundations is because of the pronounced individualism that resides at the heart of the contemporary international order. In other words, the sources of decline are not exogenous but rather part of liberalism. The Conclusion asks: what is next? The conjunction of the decline of the LIO and COVID-19 has complicated the debate about the future international order, and much of the conversation hinges on whether and how the United States can recover from its self-destructive tendencies and China’s intentions. But where is the spirit of moral progress and humanity in this discussion?
B-Type Natriuretic Peptide Is Associated with Indices of Left Ventricular Dysfunction in Healthy Subjects from the General Population: The Akershus Cardiac Examination 1950 Study
Authors: Lyngbakken Magnus Nakrem , Kvisvik Brede , Aagaard Erika Nerdrum , Berge Trygve , Pervez Mohammad Osman , Brynildsen Jon , Tveit Arnljot , Steine Kjetil , Røsjø Helge , Omland Torbjørn
Published: October 2020

Background

Concentrations of B-type natriuretic peptide (BNP) reflect myocardial distension and stress, and are associated with poor prognosis in patients with cardiovascular disease. Accordingly, we hypothesized that concentrations of BNP would be associated with indices of adverse left ventricular (LV) remodeling and early stages of LV systolic and diastolic dysfunction in healthy participants from the general population.

Methods

We measured BNP in 1757 women and 1677 men free from known coronary heart disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive cardiovascular phenotyping at baseline, including detailed echocardiography with assessment of indexed LV mass (LVMI), diastolic [tissue Doppler e’, E/e’ ratio, indexed left atrial volume (LAVI), maximal tricuspid regurgitation velocity (TRVmax), and E/A ratio], and systolic [global longitudinal strain (GLS) and LV ejection fraction (LVEF)] function.

Results

Study participants with the highest BNP concentrations had higher GLS, LVMI, e’, E/e’ ratio, LAVI, TRVmax, and E/A ratio. In adjusted analyses, both GLS and LVEF exhibited significant nonlinear associations with BNP, with reduced LV systolic function observed in both the low and high concentration range of BNP.

Conclusions

In healthy participants recruited from the general population, concentrations of BNP exhibit nonlinear associations with LV systolic function, and both low and high concentrations are associated with reduced LV systolic function. This supports the notion that natriuretic peptides are beneficial and elicit cardioprotective effects, and may have important implications for the interpretation of BNP measurements in the general population.
Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart
Authors: Chung Yu Jin , Park Kyung Chan , Tokar Sergiy , Eykyn Thomas R , Fuller William , Pavlovic Davor , Swietach Pawel , Shattock Michael J
Published: October 2020

Aims 

Emipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i). However, at resting intracellular pH (pHi), NHE1 activity is very low and its pharmacological inhibition is not expected to meaningfully alter steady-state [Na+]i. We re-evaluate this putative EMPA target by measuring cardiac NHE1 activity.

Methods and results 

The effect of EMPA on NHE1 activity was tested in isolated rat ventricular cardiomyocytes from measurements of pHi recovery following an ammonium pre-pulse manoeuvre, using cSNARF1 fluorescence imaging. Whereas 10 µM cariporide produced near-complete inhibition, there was no evidence for NHE1 inhibition with EMPA treatment (1, 3, 10, or 30 µM). Intracellular acidification by acetate-superfusion evoked NHE1 activity and raised [Na+]i, reported by sodium binding benzofuran isophthalate (SBFI) fluorescence, but EMPA did not ablate this rise. EMPA (10 µM) also had no significant effect on the rate of cytoplasmic [Na+]i rise upon superfusion of Na+-depleted cells with Na+-containing buffers. In Langendorff-perfused mouse, rat and guinea pig hearts, EMPA did not affect [Na+]i at baseline nor pHi recovery following acute acidosis, as measured by 23Na triple quantum filtered NMR and 31P NMR, respectively.

Conclusions 

Our findings indicate that cardiac NHE1 activity is not inhibited by EMPA (or other SGLT2i’s) and EMPA has no effect on [Na+]i over a wide range of concentrations, including the therapeutic dose. Thus, the beneficial effects of SGLT2i’s in failing hearts should not be interpreted in terms of actions on myocardial NHE1 or intracellular [Na+].
TopoDB: a novel multifunctional management system for laboratory animal colonies
Authors: Renschen Adam , Matsunaga Atsuko , Oksenberg Jorge R , Santaniello Adam , Didonna Alessandro
Published: October 2020

Animal models are widely employed in basic research to test mechanistic hypotheses in a complex biological environment as well as to evaluate the therapeutic potential of candidate compounds in preclinical settings. Rodents, and in particular mice, represent the most common in vivo models for their small size, short lifespan and possibility to manipulate their genome. Over time, a typical laboratory will develop a substantial number of inbred strains and transgenic mouse lines, requiring a substantial effort, in both logistic and economic terms, to maintain an animal colony for research purposes and to safeguard the integrity of results. To meet this need, here we present TopoDB, a robust and extensible web-based platform for the rational management of laboratory animals. TopoDB allows an easy tracking of individual animals within the colony and breeding protocols as well as the convenient storage of both genetic and phenotypic data generated in the different experiments. Altogether, these features facilitate and enhance the design of in vivo research, thus reducing the number of necessary animals and the housing costs. In summary, TopoDB represents a novel valuable tool in modern biomedical research.

Database URL: https://github.com/UCSF-MS-DCC/TopoDB
Continuation of Anti-TNF in Patients With Ulcerative Colitis in Remission Is Not Cost-effective Compared With Treatment Withdrawal: A Markov Model
Authors: Mahmoud Remi , van Lieshout Chris , Frederix Geert W J , Jharap Bindia , Oldenburg Bas
Published: October 2020

Background and Aims

Anti-tumour necrosis factor alpha [anti-TNF] treatment accounts for 31% of health care expenditures associated with ulcerative colitis [UC]. Withdrawal of anti-TNF in patients with UC in remission may decrease side effects and infections, while promoting cost containment. Approximately 36% of patients relapse within 12–24 months of anti-TNF withdrawal, but reintroduction of treatment is successful in 80% of patients. We aimed to evaluate the cost-effectiveness of continuation versus withdrawal of anti-TNF in patients with UC in remission.

Methods

We developed a Markov model comparing cost-effectiveness of anti-TNF continuation versus withdrawal, from a health care provider perspective. Transition probabilities were calculated from literature, or estimated by an expert panel of 11 gastroenterologists. Deterministic and probabilistic sensitivity analyses were performed to account for assumptions and uncertainty. The cost-effectiveness threshold was set at an incremental cost-effectiveness ratio of €80,000 per quality-adjusted life-year [QALY].

Results

At 5 years, anti-TNF withdrawal was less costly [-€10,781 per patient], but also slightly less effective [-0.04 QALY per patient] than continued treatment. Continuation of anti-TNF compared with withdrawal costs €300,390/QALY, exceeding the cost-effectiveness threshold. Continued therapy would become cost-effective if the relapse rate following anti-TNF withdrawal was ≥43% higher, or if adalimumab or infliximab [biosimilar] prices fell below €87/40 mg and €66/100 mg, respectively.

Conclusions

Continuation of anti-TNF in UC patients in remission is not cost-effective compared with withdrawal. A stop-and-reintroduction strategy is cost-saving but is slightly less effective than continued therapy. This strategy could be improved by identifying patients at increased risk of relapse.
Screening for texturing Leuconostoc and genomics behind polysaccharide production
Authors: Poulsen Vera Kuzina , Koza Anna , Al-Nakeeb Kosai , Oeregaard Gunnar
Published: October 2020

Synthesis of polysaccharides by Leuconostoc can result in improved texture of fermented products. A total of 249 Leuconostoc strains were screened for homo-polysaccharide production and for texturing capabilities in milk. A total of six Ln. mesenteroides strains with superior texturing properties had the genetic blueprint for both homo- (HoPS) and hetero-polysaccharide (HePS) synthesis. Only one strain produced texture in milk without added sucrose, suggesting HePS synthesis via the Wzy dependent pathway. In milk acidification experiments with added sucrose, all six strains depleted the sucrose and released fructose. Thus, they can be used for both texture and possibly also for sweetness enhancement.
Development of a common scale for measuring healthy ageing across the world: results from the ATHLOS consortium
Authors: Sanchez-Niubo Albert , Forero Carlos G , Wu Yu-Tzu , Giné-Vázquez Iago , Prina Matthew , De La Fuente Javier , Daskalopoulou Christina , Critselis Elena , De La Torre-Luque Alejandro , Panagiotakos Demosthenes , Arndt Holger , Ayuso-Mateos José Luis , Bayes-Marin Ivet , Bickenbach Jerome , Bobak Martin , Caballero Francisco Félix , Chatterji Somnath , Egea-Cortés Laia , García-Esquinas Esther , Leonardi Matilde , Koskinen Seppo , Koupil Ilona , Mellor-Marsá Blanca , Olaya Beatriz , Pająk Andrzej , Prince Martin , Raggi Alberto , Rodríguez-Artalejo Fernando , Sanderson Warren , Scherbov Sergei , Tamosiunas Abdonas , Tobias-Adamczyk Beata , Tyrovolas Stefanos , Haro Josep Maria ,   the ATHLOS Consortium
Published: October 2020

Background

Research efforts to measure the concept of healthy ageing have been diverse and limited to specific populations. This diversity limits the potential to compare healthy ageing across countries and/or populations. In this study, we developed a novel measurement scale of healthy ageing using worldwide cohorts.

Methods

In the Ageing Trajectories of Health-Longitudinal Opportunities and Synergies (ATHLOS) project, data from 16 international cohorts were harmonized. Using ATHLOS data, an item response theory (IRT) model was used to develop a scale with 41 items related to health and functioning. Measurement heterogeneity due to intra-dataset specificities was detected, applying differential item functioning via a logistic regression framework. The model accounted for specificities in model parameters by introducing cohort-specific parameters that rescaled scores to the main scale, using an equating procedure. Final scores were estimated for all individuals and converted to T-scores with a mean of 50 and a standard deviation of 10.

Results

A common scale was created for 343 915 individuals above 18 years of age from 16 studies. The scale showed solid evidence of concurrent validity regarding various sociodemographic, life and health factors, and convergent validity with healthy life expectancy (r = 0.81) and gross domestic product (r = 0.58). Survival curves showed that the scale could also be predictive of mortality.

Conclusions

The ATHLOS scale, due to its reliability and global representativeness, has the potential to contribute to worldwide research on healthy ageing.
The Block-and-Lock Strategy for Human Immunodeficiency Virus Cure: Lessons Learned from Didehydro–Cortistatin A
Authors: Li Chuan , Mori Luisa , Valente Susana T
Published: October 2020

Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) infection. However, a reservoir of latently infected cells persists under suppressive therapy, constituting a major barrier to an HIV cure. The block-and-lock approach to a functional cure aims at the transcriptional and epigenetic silencing of proviruses, blocking viral reactivation in the absence of therapy, preventing disease progression and transmission, despite the presence of detectable integrated proviruses. This approach has been put forward for exploration based on the activity of didehydro–cortistatin A, an inhibitor of the HIV transcriptional activator Tat. Here we review the mechanisms by which didehydro–cortistatin A inhibition of Tat’s feedback loop transcriptional amplification results in epigenetic silencing of the HIV promoter, and we discuss the benefits and limitations of the block-and-lock approach for an HIV cure.
Implementation of a learning healthcare system for sickle cell disease
Authors: Miller Robin , Coyne Erin , Crowgey Erin L , Eckrich Dan , Myers Jeffrey C , Villanueva Raymond , Wadman Jean , Jacobs-Allen Sidnie , Gresh Renee , Volchenboum Samuel L , Kolb E Anders
Published: October 2020

ABSTRCT

Objective

Using sickle cell disease (SCD) as a model, the objective of this study was to create a comprehensive learning healthcare system to support disease management and research. A multidisciplinary team developed a SCD clinical data dictionary to standardize bedside data entry and inform a scalable environment capable of converting complex electronic healthcare records (EHRs) into knowledge accessible in real time.

Materials and Methods

Clinicians expert in SCD care developed a data dictionary to describe important SCD-associated health maintenance and adverse events. The SCD data dictionary was deployed in the EHR using EPIC SmartForms, an efficient bedside data entry tool. Additional data elements were extracted from the EHR database (Clarity) using Pentaho Data Integration and stored in a data analytics database (SQL). A custom application, the Sickle Cell Knowledgebase, was developed to improve data analysis and visualization. Utilization, accuracy, and completeness of data entry were assessed.

Results

The SCD Knowledgebase facilitates generation of patient-level and aggregate data visualization, driving the translation of data into knowledge that can impact care. A single patient can be selected to monitor health maintenance, comorbidities, adverse event frequency and severity, and medication dosing/adherence.

Conclusions

Disease-specific data dictionaries used at the bedside will ultimately increase the meaningful use of EHR datasets to drive consistent clinical data entry, improve data accuracy, and support analytics that will facilitate quality improvement and research.
Effects on nitrogen balance and metabolism of branched-chain amino acids by growing pigs of supplementing isoleucine and valine to diets with adequate or excess concentrations of dietary leucine
Authors: Kwon Woong B , Soto Jose A , Stein Hans H
Published: October 2020

Diets based on high levels of corn protein have elevated concentrations of Leu, which may negatively affect N retention in pigs. An experiment was, therefore, conducted to test the hypothesis that Ile and Val supplementation may overcome the detrimental effects of excess dietary Leu on N balance and metabolism of branched-chain amino acids (BCAA) in growing pigs. A total of 144 barrows (initial body weight: 28.5 kg) were housed in metabolism crates and randomly assigned to 1 of 18 dietary treatments. The basal diet contained 0.98% standardized ileal digestible (SID) Lys and had SID Leu, Val, and Ile ratios to SID Lys of 100%, 60%, and 43%, respectively. Crystalline l-Leu (0% or 2.0%), l-Ile (0%, 0.1%, or 0.2%), and l-Val (0%, 0.1%, or 0.2%) were added to the basal diet resulting in a total of 18 dietary treatments that were arranged in a 2 × 3 × 3 factorial. Urine and fecal samples were collected for 5 d after 7 d of adaptation. Blood, skeletal muscle, and liver samples were collected at the conclusion of the experiment. There were no three-way interactions among the main effects. Excess Leu in diets reduced (P < 0.05) N retention and biological value of protein and increased (P < 0.001) plasma urea N (PUN), but PUN was reduced (P < 0.05) as dietary Val increased. Concentrations of Leu in the liver were greater (P < 0.001) in pigs fed excess Leu diets than in pigs fed adequate Leu diets, but concentrations of BCAA in muscle were greater (P < 0.05) in pigs fed low-Leu diets. Increasing dietary Ile increased (P < 0.001) plasma-free Ile and plasma concentration of the Ile metabolite, α-keto-β-methylvalerate, but the increase was greater in diets without excess Leu than in diets with excess Leu (interaction, P < 0.001). Plasma concentrations of Val and the Val metabolite α-keto isovalerate increased (P < 0.001) with increasing dietary Val in diets with adequate Leu, but not in diets with excess Leu (interaction, P < 0.001). Increasing dietary Leu increased (P < 0.001) plasma-free Leu and plasma concentration of the Leu metabolite, α-keto isocaproate (KIC). In contrast, increased dietary Val reduced (P < 0.05) the plasma concentration of KIC. In conclusion, excess dietary Leu reduced N retention and increased PUN in growing pigs, but Val supplementation to excess Leu diets may increase the efficiency of amino acid utilization for protein synthesis as indicated by reduced PUN.
Toward precise CRISPR DNA fragment editing and predictable 3D genome engineering
Authors: Wu Qiang , Shou Jia
Published: October 2020

Ever since gene targeting or specific modification of genome sequences in mice was achieved in the early 1980s, the reverse genetic approach of precise editing of any genomic locus has greatly accelerated biomedical research and biotechnology development. In particular, the recent development of the CRISPR/Cas9 system has greatly expedited genetic dissection of 3D genomes. CRISPR gene-editing outcomes result from targeted genome cleavage by ectopic bacterial Cas9 nuclease followed by presumed random ligations via the host double-strand break repair machineries. Recent studies revealed, however, that the CRISPR genome-editing system is precise and predictable because of cohesive Cas9 cleavage of targeting DNA. Here, we synthesize the current understanding of CRISPR DNA fragment-editing mechanisms and recent progress in predictable outcomes from precise genetic engineering of 3D genomes. Specifically, we first briefly describe historical genetic studies leading to CRISPR and 3D genome engineering. We then summarize different types of chromosomal rearrangements by DNA fragment editing. Finally, we review significant progress from precise 1D gene editing toward predictable 3D genome engineering and synthetic biology. The exciting and rapid advances in this emerging field provide new opportunities and challenges to understand or digest 3D genomes.
Temporal Detection Limits of Remnant Larval Bloodmeals in Nymphal Ixodes scapularis (Say, Ixodida: Ixodidae) Using Two Next-Generation Sequencing DNA Barcoding Assays
Authors: Lumsden Genevieve A M , Zakharov Evgeny V , Dolynskyj Sarah , Weese J Scott , Lindsay L Robbin , Jardine Claire
Published: October 2020

Using next-generation sequencing DNA barcoding, we aimed to determine: 1) if the larval bloodmeal can be detected in Ixodes scapularis nymphs and 2) the post-moult temporal window for detection of the larval bloodmeal. Subsets of 30 nymphs fed on a domestic rabbit (Oryctolagus cuniculus Linnaeus, Lagomorphia: Leporidae) as larvae were reared and frozen at 11 time points post-moult, up to 150 d. Vertebrate DNA was amplified using novel universal (UP) and species-specific primers (SSP) and sequenced for comparison against cytochrome c oxidase subunit I barcodes to infer host identification. Detectable bloodmeals decreased as time since moult increased for both assays. For the SSP assay, detection of bloodmeals decreased from 96.7% (n = 29/30) in day 0 nymphs to 3.3% (n = 1/30) and 6.7% (n = 2/30) at 4- and 5-mo post-moult, respectively. A shorter temporal detection period was achieved with the UP assay, declining from 16.7% (n = 5/30) in day 0 nymphs to 0/30 in 3-d-old nymphs. Bloodmeal detection was nonexistent for the remaining cohorts, with the exception of 1/30 nymphs at 2-mo post-moult. Host detection was significantly more likely using the SSP assay compared to the UP assay in the first three time cohorts (day 0: χ 2 = 39.1, P < 0.005; day 2: χ 2 = 19.2, P < 0.005; day 3: χ 2 = 23.3, P < 0.005). Regardless of the primer set used, the next-generation sequencing DNA barcoding assay was able to detect host DNA from a larval bloodmeal in the nymphal life stage; however, a short window with a high proportion of detection post-moult was achieved.
Personal Data Portability In The Platform Economy: Economic Implications And Policy Recommendations
Authors: Krämer Jan
Published: October 2020

Article 20 of the General Data Protection Regulation (GDPR) gave consumers in the European Union the right to port their personal data between digital service providers. We critically assess the economic implications of this new right in the light of the extant economic literature and with a focus on competition and innovation in the digital platform economy. In particular, we conclude that observed user behaviour data should clearly fall under the scope of data portability and that, above and beyond the regulations set out under GDPR, a right to port personal data continuously and in real-time would be necessary to truly empower consumers in the context of the digital platform economy. We also discuss the economics of Personal Information Management Systems (PIMSs), which many policymakers see as an essential tool for consumers in an economy where data portability becomes more widespread. However, we are sceptical that PIMS will be self-sustainable and instead advocate to facilitate the development of open-source projects, which have made little progress so far due to a lack of interfaces (which would come about with a right to continuous data portability) and due to a lack of common standards.
Configuration of the Martian dust rings: shapes, densities, and size distributions from direct integrations of particle trajectories
Authors: Liu Xiaodong , Schmidt Jürgen
Published: October 2020

It is expected since the early 1970s that tenuous dust rings are formed by grains ejected from the Martian moons Phobos and Deimos by impacts of hypervelocity interplanetary projectiles. In this paper, we perform direct numerical integrations of a large number of dust particles originating from Phobos and Deimos. In the numerical simulations, the most relevant forces acting on the dust are included: Martian gravity with spherical harmonics up to fifth degree and fifth order, gravitational perturbations from the Sun, Phobos, and Deimos, solar radiation pressure, as well as the Poynting–Robertson drag. In order to obtain the ring configuration, simulation results of various grain sizes ranging from submicrometres to 100 μm are averaged over a specified initial mass distribution of ejecta. We find that for the Phobos ring grains smaller than about 2 μm are dominant; while the Deimos ring is dominated by dust in the size range of about 5–20 μm. The asymmetries, number densities, and geometric optical depths of the rings are quantified from simulations. The results are compared with the upper limits of the optical depth inferred from Hubble observations. We compare to previous work and discuss the uncertainties of the models.
On the delay times of merging double neutron stars
Authors: Greggio Laura , Simonetti Paolo , Matteucci Francesca
Published: October 2020

The merging rate of double neutron stars (DNS) has a great impact on many astrophysical issues, including the interpretation of gravitational waves signals, of the short gamma-ray bursts (GRBs), and of the chemical properties of stars in galaxies. Such rate depends on the distribution of the delay times (DDT) of the merging events. In this paper, we derive a theoretical DDT of merging DNS following from the characteristics of the clock controlling their evolution. We show that the shape of the DDT is governed by a few key parameters, primarily the lower limit and the slope of the distribution of the separation of the DNS systems at birth. With a parametric approach, we investigate on the observational constraints on the DDT from the cosmic rate of short GRBs and the europium-to-iron ratio in Milky Way stars, taken as tracer of the products of the explosion. We find that the local rate of DNS merging requires that $\sim \! 1 {{\ \rm per\ cent}}$ of neutron stars progenitors live in binary systems which end their evolution as merging DNS within a Hubble time. The redshift distribution of short GRBs does not yet provide a strong constraint on the shape of the DDT, although the best-fitting models have a shallow DDT. The chemical pattern in Milky Way stars requires an additional source of europium besides the products from merging DNS, which weakens the related requirement on the DDT. At present both constraints can be matched with the same DDT for merging DNS.