bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality in adult-onset and elderly-onset IBD: a nationwide register-based cohort study 1964–2014
Authors: Olén Ola , Askling Johan , Sachs Michael C , Neovius Martin , Smedby Karin E , Ekbom Anders , Ludvigsson Jonas F
Published: May 2019

Objectives

To examine all-cause and cause-specific mortality in adult-onset and elderly-onset IBD and to describe time trends in mortality over the past 50 years.

Design

Swedish nationwide register-based cohort study 1964–2014, comparing mortality in 82 718 incident IBD cases (inpatient and non-primary outpatient care) with 10 times as many matched general population reference individuals (n=801 180) using multivariable Cox regression to estimate HRs. Among patients with IBD, the number of participants with elderly-onset (≥60 years) IBD was 17 873.

Results

During 984 330 person-years of follow-up, 15 698/82 718 (19%) of all patients with IBD died (15.9/1000 person-years) compared with 121 095/801 180 (15.1%) of reference individuals, corresponding to an HR of 1.5 for IBD (95% CI=1.5 to 1.5 (HR=1.5; 95% CI=1.5 to 1.5 in elderly-onset IBD)) or one extra death each year per 263 patients. Mortality was increased specifically for UC (HR=1.4; 95% CI=1.4 to 1.5), Crohn’s disease (HR=1.6; 95% CI=1.6 to 1.7) and IBD-unclasssified (HR=1.6; 95% CI=1.5 to 1.8). IBD was linked to increased rates of multiple causes of death, including cardiovascular disease (HR=1.3; 1.3 to 1.3), malignancy (HR=1.4; 1.4 to 1.5) and digestive disease (HR=5.2; 95% CI=4.9 to 5.5). Relative mortality during the first 5 years of follow-up decreased significantly over time. Incident cases of 2002–2014 had 2.3 years shorter mean estimated life span than matched comparators.

Conclusions

Adult-onset and elderly-onset patients with UC, Crohn’s disease and IBD-unclassified were all at increased risk of death. The increased mortality remained also after the introduction of biological therapies but has decreased over time.
Pressure in dealing with requests for euthanasia or assisted suicide.Experiences of general practitioners
Authors: de Boer Marike E , Depla Marja F I A , den Breejen Marjolein , Slottje Pauline , Onwuteaka-Philipsen Bregje D , Hertogh Cees M P M
Published: May 2019

The majority of Dutch physicians feel pressure when dealing with a request for euthanasia or physician-assisted suicide (EAS). This study aimed to explore the content of this pressure as experienced by general practitioners (GP). We conducted semistructured in-depth interviews with 15 Dutch GPs, focusing on actual cases. The interviews were transcribed and analysed with use of the framework method. Six categories of pressure GPs experienced in dealing with EAS requests were revealed: (1) emotional blackmail, (2) control and direction by others, (3) doubts about fulfilling the criteria, (4) counterpressure by patient’s relatives, (5) time pressure around referred patients and (6) organisational pressure. We conclude that the pressure can be attributable to the patient–physician relationship and/or the relationship between the physician and the patient’s relative(s), the inherent complexity of the decision itself and the circumstances under which the decision has to be made. To prevent physicians to cross their personal boundaries in dealing with EAS request all these different sources of pressure will have to be taken into account.
Defending the two tragedies argument: a response to Simkulet
Authors: Friberg-Fernros Henrik
Published: May 2019

According to the two-tragedies argument proponents of pro-life can justifiably prioritize efforts to prevent abortion rather than miscarriages due to the fact that abortions in contrast to miscarriages involves usually the act of killing. William Simkulet has recently argued against this argument claiming that it fails as it (a) is in conflict with the common sense pro-life view on abortion and (b) leads to an overestimation of the moral value of preventing the ‘second tragedy’, namely the act of killing, compared with the value of preventing the death of an individual. In this article, I argue against to his charges against the two tragedies argument by demonstrating that this argument is not only compatible but also in line with the common sense pro-life view and that the argument does not overestimate moral significance of the act of killing.
Balloon-mounted stents for acute intracranial large vessel occlusion secondary to presumed atherosclerotic disease: evolution in an era of supple intermediate catheters
Authors: Gross Bradley A , Desai Shashvat M , Walker Gregory , Jankowitz Brian Thomas , Jadhav Ashutosh , Jovin Tudor G
Published: May 2019

Introduction

Treatment of acute large vessel occlusion (LVO) stroke secondary to intracranial atherosclerotic disease (ICAD) is more nuanced with disparate and infrequently reported outcomes. The deployment of balloon-mounted stents presents an expedient approach with renewed feasibility in the modern era of supple intermediate catheters.

Methods

A prospectively maintained endovascular stroke database was searched for patients undergoing intracranial stenting with balloon-mounted stents for acute LVO. Demographic, angiographic, and clinical data were extracted to determine procedural technique and success, measured both angiographically and clinically.

Results

Sixty patients underwent stenting for acute LVO secondary to ICAD. Mean presenting National Institutes of Health Stroke Scale (NIHSS) score was 18 and 62% of treated sites were in the posterior circulation. Cases were performed under IV conscious sedation unless the patient was already intubated. Successful recanalization was achieved in 93% of cases (Thrombolysis in Cerebral Infarction (TICI) grade 2b in 48% and TICI grade 3 in 45%). Mean improvement in NIHSS score on post-procedure day 1 was 3.4. Good outcome (modified Rankin Scale score 0–2) at 3 months was 34% and the mortality rate was 34%. The rate of peri-procedural symptomatic hemorrhage was 8% and the rate of acute/subacute stent thrombosis was 7%. In this small cohort, patient age, sex, presenting NIHSS, comorbidities, smoking, tissue plasminogen activator administration, and stent location were not significant predictors of recanalization or good outcome.

Conclusion

Treatment of acute LVO stroke with balloon-mounted stents for ICAD has reperfusion rates and clinical outcomes comparable to thrombectomy, with higher rates of hemorrhage and mortality. Because stent placement was performed after attempted thrombectomy, a trial of primary stenting versus thrombectomy should be considered in patients suspected of underlying ICAD.
Geochemistry, zircon geochronology, and isotopic systematics of the Zhanbuzhale granites in the East Kunlun, Qinghai Province, northwestern China: implications for the tectonic setting
Authors: Li Hao-Ran , Qian Ye , Sun Feng-Yue , Li Liang
Published: May 2019

The Zhanbuzhale region, in the Eastern Kunlun Orogen of northwestern China, is characterized by large volumes of Phanerozoic granitoid rocks and is an ideal region for investigating the tectonic evolution of the Paleo-Tethys system. However, the exact timing of the final closure of the Paleo-Tethys Ocean and initial continental collision remains controversial because of a lack of precise geochronological and detailed geochemical data. In this paper, we report new zircon U–Pb ages and mineralogical, petrographic, and geochemical data for samples of Middle Triassic granodiorite and alkali feldspar granite from the Zhanbuzhale region. The zircon U–Pb ages indicate that the granodiorite and alkali feldspar granite formed at 239 and 236 Ma, respectively. The granodiorites are high-K calc-alkaline, metaluminous, high Sr content, high Sr/Y ratios, low Y content, and show adakite-like affinities. The alkali feldspar granites display high SiO2, extremely low MgO, and low Zr+Nb+Ce+Y contents as well as low Fe2O3t/MgO ratios, showing metaluminous to peraluminous and high-K calc-alkaline features. Geochemical and petrological characteristics of the alkali feldspar granites suggest that they are highly fractionated I-type granites. The granodiorites and alkali feldspar granites have zircon εHf(t) values ranging from –2.26 to –0.18, and from –2.17 to +2.18, respectively. Together with regional geological data, we propose that the Triassic (approximately 239–236 Ma) granitoids were generated during the later stages of northward subduction of the Paleo-Tethys oceanic plate, and that the initial stage of collision between the East Kunlun and the Bayan Har–Songpan Ganzi terrane occurred at approximately 236–227 Ma.
Patterns between crown characteristics and radial increment in trees are similar during recovery and normal growth: a long-term example from old-growth forests
Authors: Podlaski Rafał
Published: May 2019

Crown traits and competition attributes have an important effect on tree radial increment. Relationships among these elements are modeled using the distributions of the crown characteristics in a given calendar year, but these patterns can differ over time. The suitability of the patterns during recovery and normal growth was investigated using silver fir, Abies alba Mill., in old-growth forests. Generalized additive models (GAMs) for silver fir in the older (OG, trees aged 136–300 years) and younger (YG, trees aged 45–135 years) generations were developed. To test the validity of these GAMs, field data sets representing silver fir recovery and normal growth were used. For silver fir in OG, crown transparency had the largest effect on tree growth, explaining more than 25% of the variance. For silver fir in YG, relative crown length had the largest effect on tree growth, explaining more than 15% of the variance. The absolute relative prediction errors, AREmin and AREmax, were less than 0.03 and 1.50 mm, respectively. The developed GAMs are suitable during recovery and normal growth, but the GAMs were fitted to a relatively small area, neglecting climatic gradients and different disturbance types. This type of investigation should be continued on a larger scale.
Information content of the gravitational field of a quantum superposition
Authors: Belenchia Alessio , Wald Robert M. , Giacomini Flaminia , Castro-Ruiz Esteban , Brukner Časlav , Aspelmeyer Markus
Published: May 2019

When a massive quantum body is put into a spatial superposition, it is of interest to consider the quantum aspects of the gravitational field sourced by the body. We argue that in order to understand how the body may become entangled with other massive bodies via gravitational interactions, it must be thought of as being entangled with its own Newtonian-like gravitational field. Thus, a Newtonian-like gravitational field must be capable of carrying quantum information. Our analysis supports the view that table-top experiments testing entanglement of systems interacting via gravity do probe the quantum nature of gravity, even if no “gravitons” are emitted during the experiment.
An Object-Oriented Modeling Approach for Production Scheduling on CNC-Machines in Flexible Manufacturing System to Maximize Cutting Tool Utilization
Authors: Setiawan Ari , Wangsaputra Rachmawati , Martawirya Yatna Yuwana , Halim Abdul Hakim
Published: May 2019

This paper discusses production scheduling problems on CNC-machines having a set of cutting tools in a Flexible Manufacturing System (FMS) to maximize the cutting tools utilization. This objective has been selected because it is frequently found that cutting tools are under-utilized as they are used far below their respective lifetime limits. We will consider the situation where several identical CNC-machines are operated in an FMS; each of which is equipped with the same cutting tool configuration. The jobs to be scheduled are machining parts, and each of the parts requires one to two stages of processes, and each of the stages consists of several sequential operations, where a specific operation requires a certain type of cutting tool. Whenever a certain cutting tool is being used, the time consumption will be accumulated to calculate its remaining lifetime. The assignment of an operation to a particular CNC-machine will be based on the sufficiency of the cutting tool remaining lifetime to complete the operation. We formulate the problem in a mathematical model and then solve it using a solution method based on the object-oriented modeling approach, where the FMS elements are grouped as classes of the objects, i.e. the CNC-machine, the cutting-tool, the product (job) and the storage classes. Numerical examples show that the proposed solution method can effectively solve the scheduling problem.
Solving a Supply Chain Problem Including VMI and Cross-Docking Approaches, with Genetic Algorithm
Authors: Rafie-Majd Zahra , Pasandideh Seyed Hamid Reza
Published: May 2019

In this paper, for the first time the cross-docking concept is considered in a vendor-managed inventory (VMI)-based supply chain. In this supply chain, and based on the economic order quantity (EOQ) model, a vendor prepares and sends several products to retailers. Then, retailers, based upon customers’ order, send products to the cross-dock to be delivered to the customers. Demands of retailers and customers are deterministic and shortage is acceptable as backorder. Presented mathematical model (of integer nonlinear programming type) seeks to minimize the total cost of the supply chain. Thus, a meta-heuristic algorithm (GA) is used to solve the model. In addition, a number of sample problems are analyzed to evaluate the performance of the solving algorithm. Finally, after the conclusion, some suggestions are provided for future researches.
A second-order finite difference scheme for singularly perturbed initial value problem on layer-adapted meshes
Authors: Sahu S. R. , Mohapatra J.
Published: May 2019

In this paper, a second-order singularly perturbed initial value problem is considered. A hybrid scheme which is a combination of a cubic spline and a modified midpoint upwind scheme is proposed on various types of layer-adapted meshes. The error bounds are established for the numerical solution and for the scaled numerical derivative in the discrete maximum norm. It is observed that the numerical solution and the scaled numerical derivative are of second-order convergence on the layer-adapted meshes irrespective of the perturbation parameter. To show the performance of the proposed method, it is applied on few test examples which are in agreement with the theoretical results. Furthermore, existing results are also compared to show the robustness of the proposed scheme.
Quantified fracture (joint) clustering in Archean basement, Wyoming: application of the normalized correlation count method
Authors: Wang Qiqi , Laubach S. E. , Gale J. F. W. , Ramos M. J.
Published: May 2019

We demonstrate statistically significant self-organized clustering over a length scale range from 10
−2
to 10
1
 m for north-striking opening-mode fractures (joints) in Late Archean Mount Owen Quartz Monzonite. Spatial arrangement is a critical fracture network attribute that until recently has only been assessed qualitatively. We use normalized fracture intensity plots and the normalized correlation count (NCC) method of Marrett
et al.
to discriminate clustered from randomly placed or evenly spaced patterns quantitatively over a wide range of length scales and to test the statistical significance of the resulting patterns. We propose a procedure for interpreting cluster patterns on NCC diagrams generated by the freely available spatial analysis software CorrCount. Results illustrate the efficacy of NCC to measure fracture clustering patterns in texturally homogeneous Archean granitic rock in a setting distant (>2 km) from folds or faults. In their current geological setting, these regional fractures are conduits for water flow and their patterns – and the NCC approach to defining clusters – may be useful guides to the spatial arrangement style and clustering magnitude of conductive fractures in other, less accessible fractured basement rocks.

Thematic collection:
This article is part of the Naturally Fractured Reservoirs collection available at:
https://www.lyellcollection.org/cc/naturally-fractured-reservoirs
Biomolecular Data Resources: Bioinformatics Infrastructure for Biomedical Data Science
Authors: Vamathevan Jessica , Apweiler Rolf , Birney Ewan
Published: May 2019

Technological advances have continuously driven the generation of bio-molecular data and the development of bioinformatics infrastructure, which enables data reuse for scientific discovery. Several types of data management resources have arisen, such as data deposition databases, added-value databases or knowledgebases, and biology-driven portals. In this review, we provide a unique overview of the gradual evolution of these resources and discuss the goals and features that must be considered in their development. With the increasing application of genomics in the health care context and with 60 to 500 million whole genomes estimated to be sequenced by 2022, biomedical research infrastructure is transforming, too. Systems for federated access, portable tools, provision of reference data, and interpretation tools will enable researchers to derive maximal benefits from these data. Collaboration, coordination, and sustainability of data resources are key to ensure that biomedical knowledge management can scale with technology shifts and growing data volumes.
How Subtle Bias Infects the Law
Authors: Bilotta Isabel , Corrington Abby , Mendoza Saaid A. , Watson Ivy , King Eden
Published: May 2019

This review describes the ways in which contemporary forms of prejudice and stereotypes, which are often subtle and unconscious, give rise to critical problems throughout the legal system. This summary highlights dominant themes and understudied issues at the intersection of legal and psychological research. Three areas of focus are considered: law enforcement (policing), legal decision making, and the legal profession. Recommendations for future research and practice are offered.
Ecology and Evolution of Plant Microbiomes
Authors: Cordovez Viviane , Dini-Andreote Francisco , Carrión Víctor J. , Raaijmakers Jos M.
Published: May 2019

Microorganisms colonizing plant surfaces and internal tissues provide a number of life-support functions for their host. Despite increasing recognition of the vast functional capabilities of the plant microbiome, our understanding of the ecology and evolution of the taxonomically hyperdiverse microbial communities is limited. Here, we review current knowledge of plant genotypic and phenotypic traits as well as allogenic and autogenic factors that shape microbiome composition and functions. We give specific emphasis to the impact of plant domestication on microbiome assembly and how insights into microbiomes of wild plant relatives and native habitats can contribute to reinstate or enrich for microorganisms with beneficial effects on plant growth, development, and health. Finally, we introduce new concepts and perspectives in plant microbiome research, in particular how community ecology theory can provide a mechanistic framework to unravel the interplay of distinct ecological processes—i.e., selection, dispersal, drift, diversification—that structure the plant microbiome.
Causality and History: Modes of Causal Investigation in Historical Social Sciences
Authors: Ermakoff Ivan
Published: May 2019

Studies at the confluence of history and social science address issues of causation in three ways: morphological, variable-centered, and genetic. These approaches to causal investigation differ with regard to their modi operandi, the types of patterns they look for, their underlying assumptions and the challenges they face. Morphological inquiries elaborate causal arguments by uncovering patterns in the empirical layout of socio-historical phenomena. To this end, these inquiries draw on descriptive techniques of data formalization. Variable-centered studies engage causal issues by investigating patterns of association among empirical categories under the twofold assumption that these categories a priori have explanatory relevance and each category empirically has the same meaning across cases. Genetic analyses ground their causal claims by identifying patterned processes of emergence or production.
Diagnosing differences in what Introductory Biology students in a fully online and an in-person biology degree program know and do regarding medical school admission
Authors: Cooper Katelyn M. , Gin Logan E. , Brownell Sara E.
Published: May 2019

Increasingly, institutions of higher education are adopting fully online degree programs to provide students with cost-effective, accessible postsecondary education. A concern these degrees raise is: Will students be prepared for the next step of their career paths after completing their Bachelor’s degree online? Biology undergraduates often begin their degrees wanting to become medical doctors, but no studies have explored whether students in a fully online biology degree program are being prepared to be admitted to medical school. In this study, we surveyed Introductory Biology students at one institution who were pursuing Bachelor of Science degrees in Biological Sciences, either in an online or an in-person program. The most prevalent career goal for both in-person students (65.2%) and online students (39.7%) was a medical doctor. Online students were more confident in their intentions to become doctors than their in-person peers. However, online students knew fewer criteria that medical schools consider when admitting students than in-person students [in-person: mean = 3.7 (SD 1.6); online: mean  =2.7 (SD 1.7)] and were less likely to plan to become involved in premedical activities, such as undergraduate research. Finally, compared with in-person students, fewer online students were able to name at least one science student (in-person: 76.7%; online: 9.7%), academic advisor (in-person: 21.3%; online: 6.5%), and faculty member (in-person: 33.7%; online: 6.5%) with whom they could talk about pursuing a career in medicine. This work highlights knowledge gaps between students enrolled in a fully online biology degree and an in-person biology degree that are important for developers of online biology degree programs to understand and rectify to better prepare online biology students for admission to medical school.
Exaggerated pressor and sympathetic responses to stimulation of the mesencephalic locomotor region and exercise pressor reflex in type 2 diabetic rats
Authors: Kim Han-Kyul , Hotta Norio , Ishizawa Rie , Iwamoto Gary A. , Vongpatanasin Wanpen , Mitchell Jere H. , Smith Scott A. , Mizuno Masaki
Published: May 2019

The cardiovascular responses to exercise are potentiated in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms causing this abnormality remain unknown. Central command (CC) and the exercise pressor reflex (EPR) are known to contribute significantly to cardiovascular control during exercise. Thus these neural signals are viable candidates for the generation of the abnormal circulatory regulation in this disease. We hypothesized that augmentations in CC as well as EPR function contribute to the heightened cardiovascular responses during exercise in T2DM. To test this hypothesis, changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to electrical stimulation of mesencephalic locomotor region (MLR), a putative component of the central command pathway, and activation of the EPR, evoked by electrically induced hindlimb muscle contraction, were examined in decerebrate animals. Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet (14–16 wk) in combination with two low doses (35 mg/kg week 1, 25 mg/kg week 2) of streptozotocin (T2DM). The changes in MAP and RSNA responses to MLR stimulation were significantly greater in T2DM compared with control (2,739 ± 123 vs. 1,298 ± 371 mmHg/s, 6,326 ± 1,621 vs. 1,390 ± 277%/s, respectively, P < 0.05). Similarly, pressor and sympathetic responses to activation of the EPR in diabetic animals were significantly augmented compared with control animals (436 ± 74 vs. 134 ± 44 mmHg/s, 645 ± 135 vs. 139 ± 65%/s, respectively, P < 0.05). These findings provide the first evidence that CC and the EPR may generate the exaggerated rise in sympathetic activity and blood pressure during exercise in T2DM.
Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model
Authors: Tanimura Satoshi , Tanabe Katsuyuki , Miyake Hiromasa , Masuda Kana , Tsushida Keigo , Morioka Tomoyo , Sugiyama Hitoshi , Sato Yasufumi , Wada Jun
Published: May 2019

Acute kidney injury (AKI) is frequently encountered in clinical practice, particularly secondarily to cardiovascular surgery and administration of nephrotoxic agents, and is increasingly recognized for initiating a transition to chronic kidney disease. Clarifying the pathogenesis of AKI could facilitate the development of novel preventive strategies, because the occurrence of hospital-acquired AKI is often anticipated. Vasohibin-1 (VASH1) was initially identified as an antiangiogenic factor derived from endothelial cells. VASH1 expression in endothelial cells has subsequently been reported to enhance cellular stress tolerance. Considering the importance of maintaining peritubular capillaries in preventing the progression of AKI, the present study aimed to examine whether VASH1 deletion is involved in the pathogenesis of cisplatin-induced AKI. For this, we injected male C57BL/6J wild-type (WT) and VASH1 heterozygous knockout (VASH1+/−) mice intraperitoneally with either 20 mg/kg cisplatin or vehicle solution. Seventy-two hours after cisplatin injection, increased serum creatinine concentrations and renal tubular injury accompanied by apoptosis and oxidative stress were more prominent in VASH1+/− mice than in WT mice. Cisplatin-induced peritubular capillary loss was also accelerated by VASH1 deficiency. Moreover, the increased expression of ICAM-1 in the peritubular capillaries of cisplatin-treated VASH1+/− mice was associated with a more marked infiltration of macrophages into the kidney. Taken together, VASH1 expression could have protective effects on cisplatin-induced AKI probably by maintaining the number and function of peritubular capillaries.
Proteomic Assessment of iTRAQ-Based NaoMaiTong in the Treatment of Ischemic Stroke in Rats
Authors: Li Kening , Xian Minghua , Chen Chi , Liang Shengwang , Chen Lei , Wang Shumei
Published: May 2019

Background. NaoMaiTong (NMT) is widely used in the treatment of cerebral ischemia but the molecular details of its beneficial effects remain poorly characterized. Materials and Methods. In this study, we used iTRAQ using 2D LC-MS/MS technology to investigate the cellular mechanisms governing the protective effects of NMT. The transient middle cerebral artery occlusion (MCAO) rat model was established and evaluated. The degree of cerebral ischemia was assessed through scoring for nerve injury symptoms and through the assessment of the areas of cerebral infarction. Brain tissues were subjected to analysis by iTRAQ. High-pH HPLC and RSLC-MS/MS analysis were performed to detect differentially expressed proteins (DEPs) between the treatment groups (Sham, MCAO, and NMT). Bioinformatics were employed for data analysis and DEPs were validated by western blot. Results. The results showed that NMT offers protection to the neurological damage caused by MCAO and was found to reduce the areas of cerebral infarction. We detected 3216 DEPs via mass spectrometry. Of these proteins, 21 displayed altered expression following NMT intervention. These included DEPs involved in translation, cell cycle regulation, cellular nitrogen metabolism, and stress responses. Pathway analysis revealed seven key DEPs that were enriched in ribosomal synthesis pathways, tight junction formation, and regulation of the actin cytoskeleton. According to protein-protein interaction analysis, RPL17, Tuba, and Rac1 were affected by NMT treatment, which was validated by western blot analysis. Discussion. We therefore identify new pharmacodynamic mechanisms of NMT for the prevention and treatment of ischemic stroke. These DEPs reveal new targets to prevent ischemic stroke induced neuronal damage.
NPY Receptor 2 Mediates NPY Antidepressant Effect in the mPFC of LPS Rat by Suppressing NLRP3 Signaling Pathway
Authors: Wang Wenjiao , Xu Tao , Chen Xinyue , Dong Kemeng , Du Chunkai , Sun Jing , Shi Cuige , Li Xiaoxiao , Yang Yutao , Li Hui , Xu Zhi-Qing David
Published: May 2019

Accumulated evidences show that neuroinflammation play a pivotal role in the pathogenesis of depression. Neuropeptide Y (NPY) and its receptors have been demonstrated to have anti-inflammative as well as antidepressant effects. In the present study, the ability of NPY to modulate depressive-like behaviors induced by lipopolysaccharides (LPS) in rats and the receptors and signaling mechanisms involved were investigated. Continuous injection LPS (i.p) for 4 days led to development of depressive-like behaviors in rats, accompanied with M1-type microglia activation and increased levels of IL-1β as well as decreased levels of NPY and Y2R expression in the mPFC selectively. Local injection of NPY into the medial prefrontal cortex (mPFC) ameliorated the depression-like behaviors and suppressed the NLRP3 inflammasome signaling pathway. Y2R agonist PYY (3-36) mimicked and Y2R antagonist BIIE0246 abolished the NPY effects in the mPFC. All these results suggest that NPY and Y2R in the mPFC are involved in the pathophysiology of depression and NPY plays an antidepressant role in the mPFC mainly via Y2R, which suppresses the NLRP3 signaling pathway, in LPS-induced depression model rats.
Identifying Influential Rumor Spreader in Social Network
Authors: Zhang Ruixia , Li Deyu
Published: May 2019

It is of great significance to identify influential rumor spreaders for preventing and controlling the rumor propagation. In this paper, on four real social networks, based on the classical rumor model and combining one-to-many modes of propagation, we investigate the rumor propagation by Monte Carlo simulations when the spreading rate is small. Firstly, we layer the network nodes according to network characteristics. If the assortative coefficient is positive, we layer the network nodes by the degree centrality and the nodes with large degree are in high layers. If the assortative coefficient is negative, we layer the network nodes by the K-Shell method and the nodes with large Ks value are in high layers. Then the performance of nodes in different layers as origination of rumors and as informed nodes is investigated. We find that the propagation size is larger and the peak prevalence of the rumor is reached in a shorter time when the nodes in higher layers act as origination. Moreover, when the nodes in higher layer are not the origination of the rumor, they are more likely to be informed and they are informed more faster, and they terminate propagation faster. That is, their attendance is more beneficial to propagation size, peak prevalence, and the arrival time of peak prevalence. The conclusion can provide powerful theoretical support for controlling rumor propagation or enhancing information transmission.
Polo-like Kinase 1 Inhibition as a Therapeutic Approach to Selectively Target BRCA1-Deficient Cancer Cells by Synthetic Lethality Induction
Authors: Carbajosa Sofía , Pansa María Florencia , Paviolo Natalia S. , Castellaro Andrés M. , Andino Diego L. , Nigra Ayelén D. , García Iris Alejandra , Racca Ana C. , Rodriguez-Berdini Lucía , Angiolini Virginia , Guantay Laura , Villafañez Florencia , Federico María Belén , Rodríguez-Baili María Celeste , Caputto Beatriz L. , Drewes Gerard , Madauss Kevin P. , Gloger Israel , Fernandez Elmer , Gil Germán A. , Bocco José Luis , Gottifredi Vanesa , Soria Gastón
Published: May 2019

Purpose:

BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds.

Experimental Design:

We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1- and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dual-tumor xenograft model that allowed the confirmation of SL induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on The Cancer Genome Atlas (TCGA) breast cancer database.

Results:

The screening of a kinase inhibitors library revealed that Polo-like kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP inhibitors. Instead, we uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL interaction was validated using several isogenic and nonisogenic cellular models, chimeric spheroids, and mice xenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells.

Conclusions:

We uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patient cohorts.
Mutant-Selective Irreversible EGFR Inhibitor, Naquotinib, Inhibits Tumor Growth in NSCLC Models with EGFR-Activating Mutations, T790M Mutation, and AXL Overexpression
Authors: Tanaka Hiroaki , Sakagami Hideki , Kaneko Naoki , Konagai Satoshi , Yamamoto Hiroko , Matsuya Takahiro , Yuri Masatoshi , Yamanaka Yosuke , Mori Masamichi , Takeuchi Masahiro , Koshio Hiroyuki , Hirano Masaaki , Kuromitsu Sadao
Published: May 2019

First- and second-generation EGFR tyrosine kinase inhibitors (TKI) are effective clinical therapies for patients with non–small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, almost all patients develop resistance to these drugs. The EGFR T790M mutation of EGFR is the most predominant mechanism for resistance. In addition, activation of AXL signaling is one of the suggested alternative bypassing pathways for resistance to EGFR-TKIs. Here, we report that naquotinib, a pyrazine carboxamide–based EGFR-TKI, inhibited EGFR with activating mutations, as well as T790M resistance mutation while sparing wild-type (WT) EGFR. In in vivo murine xenograft models using cell lines and a patient-derived xenograft model, naquotinib induced tumor regression of NSCLC with EGFR-activating mutations with or without T790M resistance mutation, whereas it did not significantly inhibit WT EGFR signaling in skin. Furthermore, naquotinib suppressed tumor recurrence during the treatment period of 90 days. In addition, unlike erlotinib and osimertinib, naquotinib inhibited the phosphorylation of AXL and showed antitumor activity against PC-9 cells overexpressing AXL in vitro and in vivo. Our findings suggest that naquotinib has therapeutic potential in patients with NSCLC with EGFR-activating mutations, T790M resistance mutation, and AXL overexpression.
Current Treatment Patterns of Aplastic Anemia in China: A Prospective Cohort Registry Study
Authors: Zhu Xiao-Fan , He Hai-Long , Wang Shun-Qing , Tang Jing-Yan , Han Bing , Zhang Dong-Hua , Wu Li-Qiang , Wu De-Pei , Li Wei , Xia Ling-Hui , Zhu Huan-Ling , Liu Feng , Shi Hong-Xia , Zhang Xi , Zhou Fang , Hu Jian-Da , Fang Jian-Pei , Chen Xie-Qun , Ye Tie-Zhen , Liang Ying-Min , Jin Jie , Zhang Feng-Kui
Published: May 2019

Aplastic anemia (AA) is a hematologic disease characterized by pancytopenia and hypocellular bone marrow, potentially leading to chronic anemia, hemorrhage, and infection. The China Aplastic Anemia Committee and British Committee for Standards in Haematology guidelines recommend hematopoietic stem-cell transplantation (HSCT) or immunosuppressive therapy (IST) comprising antithymocyte globulin (ATG) with cyclosporine (CsA) as initial treatment for AA patients. With limited epidemiological data on the clinical management of AA in Asia, a prospective cohort registry study involving 22 AA treatment centers in China was conducted to describe the disease characteristics of newly diagnosed AA patients and investigate real-world treatment patterns and patient outcomes. Of 340 AA patients, 72.9, 12.6, and 3.5% were receiving IST, traditional Chinese medicine, and HSCT, respectively, at baseline; only 22.2% of IST-treated patients received guideline-recommended ATG with CsA initially. Almost all patients received supportive care (95.6%) as blood transfusion (97.8%), antibiotics (63.7%), and/or hematopoietic growth factors (58.2%). Overall, 64.8% achieved a partial or complete response, and 0.9% experienced relapse. No new safety concerns were identified; serious adverse events were largely unrelated to the treatment regimen. These results demonstrate the need to identify and minimize treatment barriers to standardize and align AA management in China with treatment guideline recommendations and further improve patient outcomes.
СТРАТЕГІЧНЕ ПЛАНУВАННЯ БІЗНЕС-ДІЯЛЬНОСТІ СТОМАТОЛОГІЧНОГО ЦЕНТРУ, ОСНОВАНОГО НА ЗАСАДАХ ДЕРЖАВНО-ПРИВАТНОГО ПАРТНЕРСТВА
Authors: Chopchik V. D. , Orlova N. M.
Published: May 2019

Мета: науково обґрунтувати методику здійснення стратегічного планування у стоматологічному медичному центрі, основаному на принципах державно-приватного партнерства.

Матеріали і методи. Методику стратегічного планування у стоматологічному центрі обґрунтовано на основі системного підходу і системного аналізу із використанням інформаційно-аналітичного методу. Інформаційною базою для її формування є наукові праці фахівців із організації та управління охороною здоров’я, а також результати власних досліджень.

Результати. У статті представлено методику стратегічного планування бізнес-діяльності стоматологічного центру на принципах державно-приватного партнерства, яка включає послідовність етапів планування, графік і моніторинг їх проведення. Запропонована методика створює організаційно-методичні умови для проведення стратегічного менеджменту та сприяє забезпеченню економічної ефективності діяльності центру. Методика є особливо важливою для центрів, основаних на принципах державно-приватного партнерства, оскільки їх діяльність націлена насамперед на задоволення потреб населення у широкому спектрі послуг, необхідних для збереження і зміцнення стоматологічного здоров’я.

Висновки. Запропоновану методику проведення стратегічного планування бізнес-процесів буде використано при розробці оптимізованої функціонально-організаційної моделі стоматологічного центру, який працює на принципах державно-приватного партнерства.
ГОЛОВНІ АСПЕКТИ ПІДГОТОВКИ СІМЕЙНОГО ЛІКАРЯ В УКРАЇНІ
Authors: Sichkoriz O. Y.
Published: May 2019

Мета: аналіз проблеми та перспективи підготовки сімейних лікарів на післядипломному етапі.

Матеріали і методи. Чинні законодавчі акти проаналізовані за принципом структурно-логічного аналізу.

Результати. Основною метою інтернатури за спеціальністю «Загальна практика – сімейна медицина» є формування професійної компетентності для забезпечення готовності лікарів-інтернів до самостійної роботи як лікаря-спеціаліста. Інтернатура проводиться у формі очно-заочного навчання на кафедрах вищих медичних навчальних закладів і закладів післядипломної освіти та практичного стажування в базових установах охорони здоров’я. Заочне стажування для лікарів-інтернів за спеціальністю «Загальна практика – сімейна медицина» повинно здійснюватись на базі первинної медико-санітарної допомоги та амбулаторій сімейного лікаря.

Навчальний план та програма інтернатури розраховані на 2 роки. Протягом першого року – 6 місяців  навчання на відповідних кафедрах вищих медичних навчальних закладів, 5 місяців – робота на базі первинної медико-санітарної допомоги та амбулаторій сімейного лікаря, один місяць – відпустка. Протягом другого року – 4 місяці – навчання на відповідних кафедрах вищих медичних навчальних закладів, 7 місяців – робота на базі первинної медико-санітарної допомоги та амбулаторій сімейного лікаря, один місяць – відпустка.

Підготовку сімейного лікаря необхідно починати з додипломної освіти з викладанням основ пропедевтики за синдромологічним підходом та специфічного клінічного мислення з орієнтацією на загальну практику – сімейну медицину.

Висновки. Тривалість навчання в інтернатурі з сімейної медицини повинна відповідати рекомендованим термінам міжнародних професійних організацій: WONCA, EURACT, UEMO тощо і тривати не менше 3 років. Заочне навчання має передбачати обов’язкове стажування тривалістю 1–3 місяці в тому закладі, куди скеровані майбутні спеціалісти відповідно до державного розподілу.
ЕФЕКТИВНІСТЬ ГІСТЕРОРЕЗЕКТОСКОПІЇ У ЖІНОК З БЕЗПЛІДДЯМ НА ФОНІ ЛЕЙОМІОМИ МАТКИ В ПРОГРАМАХ ДОПОМІЖНИХ РЕПРОДУКТИВНИХ ТЕХНОЛОГІЙ
Authors: Khmil S. V. , Drozdovska Yu. B. , Khmil M. S. , Chudiyovych N. Ya.
Published: May 2019

Мета: вивчення ефективності гістерорезектоскопії у жінок із безпліддям на фоні лейоміоми матки в програмах допоміжних репродуктивних технологій.

Матеріали і методи. Рандомізоване клінічне дослідження проведено серед 58 жінок, які проходили лікування безпліддя шляхом використання програм допоміжних репродуктивних технологій. Вибірку було поділено на 2 групи. І групу (дослідну) склала 41 жінка з лейоміомою матки з субмукозним та субмукозно-інтрамуральним розташуванням міоматозних вузлів та невдалими спробами екстракорпорального запліднення в анамнезі, цим жінкам запропоновано гістерорезектоскопію як підготовку перед програмами допоміжних репродуктивних технологій. ІІ групу (контрольну)  – 17 жінок із лейоміомою матки з субмукозно-інтрамуральним розташуванням міоматозних вузлів, які відмовились від гістерорезектоскопії. У цьому дослідженні були включені пари виключно з жіночими формами безпліддя.

Результати. Доведено ефективність гістерорезектоскопії на результат циклів екстракорпорального першої спроби екстракорпорального запліднення), ранні мимовільні викидні спостерігали в 2 жінок (11,8 %), у 14 жінок вагітність закінчилась терміновими пологами (82,4 %) та в однієї жінки передчасними (5,9 %). У ІІ групі (контрольній) з 17 пацієнток вагітність настала в 6 жінок (35,3 %), 3 випадки ранніх мимовільних викиднів (50 %), термінові пологи у 3 жінок (50 %).

Висновки. Лейоміома матки в основному є причиною безпліддя за рахунок механічного фактора. Гістерорезектоскопія є оптимальним методом прегравідарної підготовки у жінок із лейоміомою матки, які проходять лікування безпліддя шляхом використання допоміжних репродуктивних технологій. Гістерорезектоскопія є органозберігаючою операцією, що має ряд переваг: легкий післяопераційний період, відсутність спайкового процесу, що, в свою чергу, підвищує частоту настання та виношування вагітності.
Myocardial Fibrosis in Classical Low-Flow, Low-Gradient Aortic Stenosis
Authors: Rosa Vitor E.E. , Ribeiro Henrique B. , Sampaio Roney O. , Morais Thamara C. , Rosa Marcela E.E. , Pires Lucas J.T. , Vieira Marcelo L.C. , Mathias Wilson , Rochitte Carlos E. , de Santis Antonio S.A.L. , Fernandes Joao Ricardo C. , Accorsi Tarso A.D. , Pomerantzeff Pablo M.A. , Rodés-Cabau Josep , Pibarot Philippe , Tarasoutchi Flavio
Published: May 2019

Background

Few data exist on the degree of interstitial myocardial fibrosis in patients with classical low-flow, low-gradient aortic stenosis (LFLG-AS) and its association with left ventricular flow reserve (FR) on dobutamine stress echocardiography. This study sought to evaluate the diffuse interstitial fibrosis measured by T1 mapping cardiac magnetic resonance technique in LFLG-AS patients with and without FR.

Methods

Prospective study including 65 consecutive patients (41 LFLG-AS [mean age, 67.1±8.4 years; 83% men] and 24 high-gradient aortic stenosis used as controls) undergoing dobutamine stress echocardiography to assess FR and cardiac magnetic resonance to determine the extracellular volume (ECV) fraction of the myocardium, indexed ECV (iECV) to body surface area and late gadolinium enhancement.

Results

Interstitial myocardial fibrosis measured by iECV was higher in patients with LFLG-AS with and without FR as compared with high-gradient aortic stenosis (35.25±9.75 versus 32.93±11.00 versus 21.19±6.47 mL/m
2
, respectively;
P
<0.001). However, both ECV and iECV levels were similar between LFLG-AS patients with and without FR (
P
=0.950 and
P
=0.701, respectively). Also, FR did not correlate significantly with ECV (r=−0.16,
P
=0.31) or iECV (r=0.11,
P
=0.51). Late gadolinium enhancement mass was also similar in patients with versus without FR but lower in high-gradient aortic stenosis (13.3±10.2 versus 10.5±7.5 versus 4.8±5.9 g, respectively;
P
=0.018).

Conclusions

Patients with LFLG-AS have higher ECV, iECV, and late gadolinium enhancement mass compared with high-gradient aortic stenosis. Moreover, among patients with LFLG-AS, the degree of myocardial fibrosis was similar in patients with versus those without FR. These findings suggest that diffuse myocardial fibrosis may not be the main factor responsible for the absence of FR in LFLG-AS patients.
Right Ventricular Function Evaluated by Tricuspid Annular Plane Systolic Excursion Predicts Cardiovascular Death in the General Population
Authors: Modin Daniel , Møgelvang Rasmus , Andersen Ditte Madsen , Biering‐Sørensen Tor
Published: May 2019

Background

Cardiovascular disease remains a leading cause of death. Right ventricular (
RV
) function is a strong predictor of outcome in many cardiovascular diseases, but its significance is often neglected. Little is known about the prognostic value of
RV
systolic function in the general population. Therefore, we aimed to determine the prognostic value of
RV
systolic function, evaluated by tricuspid annular plane systolic excursion (
TAPSE
), in predicting cardiovascular death (
CVD
) in the general population.

Methods and Results

A total of 1039 participants from the general population without heart failure or atrial fibrillation had an echocardiogram performed and
TAPSE
measured. The end point was
CVD
. During a median follow‐up of 12.7 years (interquartile range, 12.0–12.9 years), 69 participants (6.6%) experienced
CVD
, whereas 162 participants (15.6%) experienced non‐CVD. Decreasing
RV
systolic function, assessed as
TAPSE
, was a univariable predictor of
CVD
(hazard ratio, 1.13; 95%
CI
, 1.07–1.20;
P
<0.001, per 1‐mm decrease).
TAPSE
remained an independent predictor of
CVD
after adjusting for clinical and echocardiographic parameters (hazard ratio, 1.08; 95%
CI
, 1.01–1.15;
P
=0.017, per 1‐mm decrease). Furthermore, in net reclassification analysis, decreasing
RV
systolic function, assessed as
TAPSE,
significantly improved risk classification with respect to
CVD
when added to established cardiovascular risk factors from the Systematic Coronary Risk Evaluation chart or a modified version of the American Heart Association/American College of Cardiology Pooled Cohort Equation. Decreasing
RV
systolic function, assessed as
TAPSE
, did not predict non‐CVD, indicating specificity for
CVD
.

Conclusions

RV
systolic function, as assessed by
TAPSE
, is associated with
CVD
in the general population. In the general population, assessment of
RV
systolic function may provide novel prognostic information about the risk of
CVD
.