bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of human norovirus binding to gut-associated bacterial ligands
Authors: Almand Erin A. , Moore Matthew D. , Jaykus Lee-Ann
Published: September 2019

Objective

Research suggests human norovirus binding to histo-blood group antigen (HBGA)-like molecules on enteric bacteria may enhance viral pathogenesis; however, the properties of these bacterial ligands are not well known. Previous work identified, but did not characterize, seven norovirus-binding bacteria. To further examine this bacteria–virus binding interaction, enteric bacteria were analyzed via Western blot with anti-HBGA antibodies and lectins targeting HBGA-associated sugar components. Virus overlay assays using capsids from six different human norovirus strains further identified responsible ligands and strain dependent binding properties.

Results

Each bacterial species possessed varying degrees of HBGA-like activity, and lectin binding further elucidated potential sugar residues involved (N-acetyl-galactosamine, α-d-galactose or α-l-fucose). Both GI and GII norovirus capsids bound specific bacterial ligand sizes, and generally corresponded to anti-HBGA Western blot patterns. A 35-kDa band reacted with all HBGA antibodies, bound all six of the noroviruses tested, and had a high affinity for the lectins. Collectively, this work characterizes the varying carbohydrate residues potentially responsible for norovirus–bacteria interactions and provides a basis for future ligand identification.
A battery of self-screening instruments and self-reported body frame could not detect eating disorders among college students
Authors: Hayakawa Norika , Tanaka Satoshi , Hirata Naoko , Ogino Sachiko , Ozaki Norio
Published: September 2019

Objective

Although studies have shown inconsistent results in terms of prevalence of eating disorders, the Eating Attitudes Test (EAT-26) was used to screen students for abnormal eating behaviors. The results of the self-reported EAT-26 and body frame, as well as the efficacy of using self-administered questionnaires (SAQs) were examined to detect eating disorders in new college students.

Results

An anonymous questionnaire (EAT-26) was provided to 7738 new students; 4552 (58.8%) responders were included in the final analysis. Semi-structured interviews were conducted for 131 (1.7%) students. Among them, 6 students showed a high EAT-26 score, but were not diagnosed with an eating disorder based on the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Three students were diagnosed with an eating disorder using SCID-I, but their EAT-26 scores were below the threshold. From these results, in a non-clinical population, findings on EAT-26 do not agree with those on SCID-I in terms of the diagnosis of eating disorders, and this battery is not appropriate for detecting eating disorders.
Reconstruction techniques for cardiac cine MRI
Authors: Menchón-Lara Rosa-María , Simmross-Wattenberg Federico , Casaseca-de-la-Higuera Pablo , Martín-Fernández Marcos , Alberola-López Carlos
Published: September 2019

The present survey describes the state-of-the-art techniques for dynamic cardiac magnetic resonance image reconstruction. Additionally, clinical relevance, main challenges, and future trends of this image modality are outlined. Thus, this paper aims to provide a general vision about cine MRI as the standard procedure in functional evaluation of the heart, focusing on technical methodologies.
Development and validation of image quality scoring criteria (IQSC) for pediatric CT: a preliminary study
Authors: Padole Atul M. , Sagar Pallavi , Westra Sjirk J. , Lim Ruth , Nimkin Katherine , Kalra Mannudeep K. , Gee Michael S. , Rehani Madan M.
Published: September 2019

Objective

To develop and assess the value and limitations of an image quality scoring criteria (IQSC) for pediatric CT exams.

Methods

IQSC was developed for subjective assessment of image quality using the scoring scale from 0 to 4, with 0 indicating desired anatomy or features not seen, 3 for adequate image quality, and 4 depicting higher than needed image quality. Pediatric CT examinations from 30 separate patients were selected, five each for routine chest, routine abdomen, kidney stone, appendicitis, craniosynostosis, and ventriculoperitoneal (VP) shunt. Five board-certified pediatric radiologists independently performed image quality evaluation using the proposed IQSC. The kappa statistics were used to assess the interobserver variability.

Results

All five radiologists gave a score of 3 to two-third (67%) of all CT exams, followed by a score of 4 for 29% of CT exams, and 2 for 4% exams. The median image quality scores for all exams were 3 and the interobserver agreement among five readers (acceptable image quality [scores 3 or 4] vs sub-optimal image quality ([scores 1 and 2]) was moderate to very good (kappa 0.4–1). For all five radiologists, the lesion detection was adequate for all CT exams.

Conclusions

The image quality scoring criteria covering routine and some clinical indication-based imaging scenarios for pediatric CT examinations has potential to offer a simple and practical tool for assessing image quality with a reasonable degree of interobserver agreement. A more extensive and multi-centric study is recommended to establish wider usefulness of these criteria.
Techniques and future perspectives for the prevention and treatment of endoleaks after endovascular repair of abdominal aortic aneurysms
Authors: Orgera Gianluigi , Tipaldi Marcello Andrea , Laurino Florindo , Lucatelli Pierleone , Rebonato Alberto , Paraskevopoulos Ioannis , Rossi Michele , Krokidis Miltiadis
Published: September 2019

The presence of endoleaks remains one of the main drawbacks of endovascular repair of abdominal aortic aneurysms leading to the increase of the size of the aneurysmal sac and in most of the cases to repeated interventions. A variety of devices and percutaneous techniques have been developed so far to prevent and treat this phenomenon, including sealing of the aneurysmal sac, endovascular embolisation, and direct sac puncture. The aim of this review is to analyse the indications, the effectiveness, and the future perspectives for the prevention and treatment of endoleaks after endovascular repair of abdominal aortic aneurysms.
Structured report data can be used to develop deep learning algorithms: a proof of concept in ankle radiographs
Authors: Pinto dos Santos Daniel , Brodehl Sebastian , Baeßler Bettina , Arnhold Gordon , Dratsch Thomas , Chon Seung-Hun , Mildenberger Peter , Jungmann Florian
Published: September 2019

Background

Data used for training of deep learning networks usually needs large amounts of accurate labels. These labels are usually extracted from reports using natural language processing or by time-consuming manual review. The aim of this study was therefore to develop and evaluate a workflow for using data from structured reports as labels to be used in a deep learning application.

Materials and methods

We included all plain anteriorposterior radiographs of the ankle for which structured reports were available. A workflow was designed and implemented where a script was used to automatically retrieve, convert, and anonymize the respective radiographs of cases where fractures were either present or absent from the institution’s picture archiving and communication system (PACS). These images were then used to retrain a pretrained deep convolutional neural network. Finally, performance was evaluated on a set of previously unseen radiographs.

Results

Once implemented and configured, completion of the whole workflow took under 1 h. A total of 157 structured reports were retrieved from the reporting platform. For all structured reports, corresponding radiographs were successfully retrieved from the PACS and fed into the training process. On an unseen validation subset, the model showed a satisfactory performance with an area under the curve of 0.850 (95% CI 0.634–1.000) for detection of fractures.

Conclusion

We demonstrate that data obtained from structured reports written in clinical routine can be used to successfully train deep learning algorithms. This highlights the potential role of structured reporting for the future of radiology, especially in the context of deep learning.
Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A
Authors: Choi Yoon Jeong , Koo Jun Bon , Kim Hee Yeon , Seo Jin Won , Lee Eun Jeong , Kim Woo Ram , Cho Joo Young , Hahm Ki Baik , Hong Sung Pyo , Kim Duk Hwan , Yoo Jun-Hwan
Published: September 2019

Background

The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs).

Methods

The HIMFs were treated with TGF-β1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-β1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs.

Results

UC/PL-MSCs reduced TGF-β1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-β1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-β1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression.

Conclusions

UC/PL-MSCs suppress TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis.
miR-205-5p inhibits human endometriosis progression by targeting ANGPT2 in endometrial stromal cells
Authors: Zhou Chen-Fei , Liu Min-Juan , Wang Wei , Wu Sha , Huang Yu-Xin , Chen Guo-Bin , Liu Li-Min , Peng Dong-Xian , Wang Xue-Feng , Cai Xu-Zi , Li Xiao-Xuan , Feng Wan-Qin , Ma Ying
Published: September 2019

Background

miRNA expression profiles in ectopic endometrium (EC) serving as pathophysiologic genetic fingerprints contribute to determining endometriosis progression; however, the underlying molecular mechanisms remain unknown.

Methods

miRNA microarray analysis was used to determine the expression profiling of EC fresh tissues. qRT-PCR was performed to screen miR-205-5p expression in EC tissues. The roles of miR-205-5p and its candidate target gene, angiopoietin-2 (ANGPT2), in endometriosis progression were confirmed on the basis of both in vitro and in vivo systems. miR-205-5p and ANGPT2 expression were measured by in situ hybridization and immunochemistry, and their clinical significance was statistically analysed.

Results

miR-205-5p was screened as a novel suppressor of endometriosis through primary ectopic endometrial stromal cell migration, invasion, and apoptosis assay in vitro, along with endometrial-like xenograft growth and apoptosis in vivo. In addition, ANGPT2 was identified as a direct target of miR-205-5p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of ANGPT2 could respectively rescue and simulate the effects induced by miR-205-5p. Importantly, the miR-205-5p-ANGPT2 axis was found to activate the ERK/AKT pathway in endometriosis. Finally, miR-205-5p and ANGPT2 expression were closely correlated with the endometriosis severity.

Conclusion

The newly identified miR-205-5p-ANGPT2-AKT/ERK axis illustrates the molecular mechanism of endometriosis progression and may represent a novel diagnostic biomarker and therapeutic target for disease treatment.
The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction
Authors: Chen Yueqiu , Zuo Jianfeng , Chen Weiqian , Yang Ziying , Zhang Yanxia , Hua Fei , Shao Lianbo , Li Jingjing , Chen Yihuan , Yu Yunsheng , Shen Zhenya
Published: September 2019

Background

Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats.

Methods and results

First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats.

Conclusion

These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections.

Graphical Abstract

IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.
Nanofibrillar cellulose wound dressing supports the growth and characteristics of human mesenchymal stem/stromal cells without cell adhesion coatings
Authors: Kiiskinen Jasmi , Merivaara Arto , Hakkarainen Tiina , Kääriäinen Minna , Miettinen Susanna , Yliperttula Marjo , Koivuniemi Raili
Published: September 2019

Background

In the field of regenerative medicine, delivery of human adipose-derived mesenchymal stem/stromal cells (hASCs) has shown great promise to promote wound healing. However, a hostile environment of the injured tissue has shown considerably to limit the survival rate of the transplanted cells, and thus, to improve the cell survival and retention towards successful cell transplantation, an optimal cell scaffold is required. The objective of this study was to evaluate the potential use of wood-derived nanofibrillar cellulose (NFC) wound dressing as a cell scaffold material for hASCs in order to develop a cell transplantation method free from animal-derived components for wound treatment.

Methods

Patient-derived hASCs were cultured on NFC wound dressing without cell adhesion coatings. Cell characteristics, including cell viability, morphology, cytoskeletal structure, proliferation potency, and mesenchymal cell and differentiation marker expression, were analyzed using cell viability assays, electron microscopy, immunocytochemistry, and quantitative or reverse transcriptase PCR. Student’s t test and one-way ANOVA followed by a Tukey honestly significant difference post hoc test were used to determine statistical significance.

Results

hASCs were able to adhere to NFC dressing and maintained high cell survival without cell adhesion coatings with a cell density-dependent manner for the studied period of 2 weeks. In addition, NFC dressing did not induce any remarkable cytotoxicity towards hASCs or alter the morphology, proliferation potency, filamentous actin structure, the expression of mesenchymal vimentin and extracellular matrix (ECM) proteins collagen I and fibronectin, or the undifferentiated state of hASCs.

Conclusions

As a result, NFC wound dressing offers a functional cell culture platform for hASCs to be used further for in vivo wound healing studies in the future.
A novel construct with biomechanical flexibility for articular cartilage regeneration
Authors: Cheng Baixiang , Tu Teng , Shi Xiao , Liu Yanzheng , Zhao Ying , Zhao Yinhua , Li Yijie , Chen Hui , Chen Yongjin , Zhang Min
Published: September 2019

Background

Although tissue-engineered cartilage has been broadly studied, complete integration of regenerated cartilage with residual cartilage is still difficult for the inferior mechanical and biochemical feature of neocartilage. Chondrogenesis of mesenchymal stem cells can be induced by biophysical and biochemical factors.

Methods

In this study, autologous platelet-rich fibrin (PRF) membrane was used as a growth factor-rich scaffold that may facilitate differentiation of the transplanted bone marrow mesenchymal stem cells (BMSCs). At the same time, hydrostatic pressure was adopted for pre-adjustment of the seed cells before transplantation that may promote the mechanical flexibility of neocartilage.

Results

An in vitro study showed that the feasible hydrostatic pressure stimulation substantially promoted the chondrogenic potential of in vitro-cultured BMSC/PRF construct. In vivo results revealed that at every time point, the newborn tissues were the most favorable in the pressure-pretreated BMSC/PRF transplant group. Besides, the transplantation of feasible hydrostatic pressure-pretreated construct by BMSC sheet fragments and PRF granules could obviously improve the integration between the regenerated cartilage and host cartilage milieu, and thereby achieve boundaryless repair between the neocartilage and residual host cartilage tissue in rabbit temporomandibular joints. It could be concluded that feasible hydrostatic pressure may effectively promote the proliferation and chondrogenic differentiation of BMSCs in a BMSC/PRF construct.

Conclusion

This newly formed construct with biomechanical flexibility showed a superior capacity for cartilage regeneration by promoting the mechanical properties and integration of neocartilage.
S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation
Authors: Wu Yan , Liu Xin , Guo Ling-Yun , Zhang Lei , Zheng Fei , Li Shan , Li Xing-Yuan , Yuan Ye , Liu Yu , Yan Yu-wen , Chen Shi-You , Wang Jia-Ning , Zhang Jin-xuan , Tang Jun-Ming
Published: September 2019

Introduction

Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown.

Methods and results

The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells’ differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA.

Conclusions

S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.
Approximate coincidence point and common fixed point results for a hybrid pair of mappings with constraints in partially ordered Menger PM-spaces
Authors: Wu Zhaoqi , Liu Mengdi , Zhu Chuanxi , Chen Chunfang
Published: September 2019

We study an approximate coincidence point and a common fixed point problem for a hybrid pair of mappings with constraints in Menger PM-spaces, and obtain some new results. We derive interesting consequences of the main results by using the properties of a Menger–Hausdorff metric, and analogous results based on graphs instead of partial orders can be similarly formulated. Moreover, we construct two examples to reveal that the main results are valid, and show that the main results can be used to explore the existence of solutions to a system of nonlinear integral equations.
Determination of differential pencils with impulse from interior spectral data
Authors: Guo Yongxia , Wei Guangsheng , Yao Ruoxia
Published: September 2019

In this paper, we are concerned with the inverse spectral problems for differential pencils defined on$[0,\pi ]$[0,π]with an interior discontinuity. We prove that two potential functions are determined uniquely by one spectrum and a set of values of eigenfunctions at some interior point$b\in (0,\pi )$b∈(0,π)in the situation of$b=\pi /2$b=π/2and$b\neq \pi /2$b≠π/2. For the latter, we need the knowledge of a part of the second spectrum.
Study of nonlinear Pachpatte’s inequalities on time scales
Authors: Sarfaraz Sarah , Ahmad Naveed , ur Rahman Ghaus
Published: September 2019

In this paper, we develop a fundamental dynamic inequality, a generalization of comparison theorem and reproduce the proofs of some nonlinear integral Pachpatte’s inequalities by using their continuous analogue. We also unify and extend these improved integral Pachpatte’s inequalities and their corresponding discrete analogues on arbitrary time scales. The results are used to make qualitative analysis of higher order dynamic equations.
Stability of discrete-time HIV dynamics models with three categories of infected CD4+ T-cells
Authors: Elaiw A. M. , Alshaikh M. A.
Published: September 2019

This paper studies the global stability of two discrete-time HIV infection models. The models integrate (i) latently infected cells, (ii) long-lived chronically infected cells and (iii) short-lived infected cells. The second model generalizes the first one by assuming that the incidence rate of infection as well as the production and removal rates of the HIV particles and cells are modeled by general nonlinear functions. We discretize the continuous-time models by using a nonstandard finite difference scheme. The positivity and boundedness of solutions are established. The basic reproduction number is derived. By using the Lyapunov method, we prove the global stability of the models. Numerical simulations are presented to illustrate our theoretical results.
Generalized continued fractions: a unified definition and a Pringsheim-type convergence criterion
Authors: Baumann Hendrik
Published: September 2019

In the literature, many generalizations of continued fractions have been introduced, and for each of them, convergence results have been proved. In this paper, we suggest a definition of generalized continued fractions which covers a great variety of former generalizations as special cases. As a starting point for a convergence theory, we prove a Pringsheim-type convergence criterion which includes criteria for the aforementioned special cases. Furthermore, we address several fields in which our definition may be applied.
Oscillation and nonoscillation theorems of neutral dynamic equations on time scales
Authors: Zhou Yong , Alsaedi Ahmed , Ahmad Bashir
Published: September 2019

We present the oscillation criteria for the following neutral dynamic equation on time scales:
$$ \bigl(y(t)-C(t)y(t-\zeta )\bigr)^{\Delta }+P(t)y(t-\eta )-Q(t)y(t-\delta )=0, \quad t\in {\mathbb{T}}, $$

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where $C, P, Q\in C_{\mathit{rd}}([t_{0},\infty ),{\mathbb{R}}^{+})$
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. New conditions for the existence of nonoscillatory solutions of the given equation are also obtained.
Correction to: Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma: a propensity score matched analysis
Authors: Liao Jun‐Fang , Zhang Qun , Du Xiao‐Jing , Lan Mei , Liu Shan , Xia Yun‐Fei , Cai Xiu‐Yu , Luo Wei
Published: September 2019

In the original publication of this article [1], the first affiliation name in the Author details section should be updated to ‘Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China’ because the affiliation has been renamed from Jun. 15th, 2019.
Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia
Authors: Soff Gerald A. , Miao Yimei , Bendheim Gemma , Batista Jeanette , Mones Jodi V. , Parameswaran Rekha , Wilkins Cy R. , Devlin Sean M. , Abou-Alfa Ghassan K. , Cercek Andrea , Kemeny Nancy E. , Sarasohn Debra M. , Mantha Simon
Published: September 2019

PURPOSE

Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment.

METHODS

We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point.

RESULTS

The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT.

CONCLUSION

This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.
Sex Hormone Replacement Therapy in Turner Syndrome: Impact on Morbidity and Mortality
Authors: Viuff Mette H , Berglund Agnethe , Juul Svend , Andersen Niels H , Stochholm Kirstine , Gravholt Claus H
Published: September 2019

Context

The long-term effects of female hormone replacement therapy (HRT) in Turner syndrome (TS) are unknown.

Objective

To examine morbidity, mortality and medicinal use in TS and the impact of HRT in 45,X women.

Design and Setting

National cohort study, following all TS individuals ever diagnosed in Denmark from 1977 to 2014.

Patients and Methods

In the Danish Cytogenetic Central Registry, we identified 1156 females diagnosed with TS from 1960 to 2014, and, subsequently, Statistics Denmark randomly identified 115 577 age-matched female controls. TS women and their matched controls were linked with person-level data from the National Patient Registry and the Medication Statistics Registry, and they were compared concerning mortality, hospitalizations, and medical prescriptions. Among 329 45,X women, 44 had never been HRT treated, and 285 had been treated at some point. HRT treated women were compared with untreated concerning mortality, hospitalizations, and medical prescriptions.

Results

Endocrine and cardiovascular mortality and morbidity were significantly increased in TS compared with the matched controls. Comparing HRT treated with nontreated 45,X women, we found a similar mortality (hazard ratio 0.83, 95% confidence interval 0.38–1.79). Among the HRT-treated 45,X women, we found a significantly lower use of antihypertensives, antidiabetics, and thyroid hormones and significantly reduced hospitalization rates for stroke and osteoporotic fractures.

Conclusion

Women with TS have an increased overall mortality and morbidity. HRT seems to have a beneficial effect on endocrine conditions, hypertension, and stroke in women with 45,X karyotype, with no clear impact on mortality.
SCF/SCFR signaling plays an important role in the early morphogenesis and neurogenesis of human embryonic neural retina
Authors: Gong Yu , He Xiangyu , Li Qiyou , He Juncai , Bian Baishijiao , Li Yijian , Ge Linlin , Zeng Yuxiao , Xu Haiwei , Yin Zheng Qin
Published: September 2019

The stem cell factor receptor (SCFR) has been demonstrated to be expressed in the neural retina of mice, rat, and human for decades. Previous reports indicate that SCFR correlates with glia differentiation of late retinal progenitor cells (RPCs), retinal vasculogenesis, and homeostasis of the blood-retinal barrier. However, the role of SCF/SCFR signaling in the growth and development of the neural retina (NR), especially in the early embryonic stage, remains poorly understood. Here we show that the SCF/SCFR signaling orchestrates invagination of the human embryonic stem cell (hESC)-derived NR via regulation of cell cycle progression, cytoskeleton dynamic, and apical constriction of RPCs in the ciliary marginal zone (CMZ). Furthermore, activation of SCF/SCFR signaling promotes neurogenesis in the central-most NR via accelerating the migration of immature ganglion cells and repressing apoptosis. Our study reveals an unreported role of SCF/SCFR signaling in controlling ciliary marginal cellular behaviors during early morphogenesis and neurogenesis of the human embryonic NR, providing a new potential therapeutic target for human congenital eye diseases such as anophthalmia, microphthalmia, and congenital high myopia.
Deep learning enables automated volumetric assessments of cardiac function in zebrafish
Authors: Akerberg Alexander A. , Burns Caroline E. , Burns C. Geoffrey , Nguyen Christopher
Published: September 2019

Although the zebrafish embryo is a powerful animal model of human heart failure, the methods routinely employed to monitor cardiac function produce rough approximations that are susceptible to bias and inaccuracies. We developed and validated a deep learning-based image-analysis platform for automated extraction of volumetric parameters of cardiac function from dynamic light-sheet fluorescence microscopy (LSFM) images of embryonic zebrafish hearts. This platform, the Cardiac Functional Imaging Network (CFIN), automatically delivers rapid and accurate assessments of cardiac performance with greater sensitivity than current approaches.

This article has an associated First Person interview with the first author of the paper.
An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth
Authors: Sceniak Michael P. , Fedder Karlie N. , Wang Qian , Droubi Sammy , Babcock Katie , Patwardhan Sagar , Wright-Zornes Jazmin , Pham Lucynda , Sabo Shasta L.
Published: September 2019

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with multiple genetic associations. Analysis of de novo mutations identified GRIN2B, which encodes the GluN2B subunit of NMDA receptors, as a gene linked to ASDs with high probability. However, the mechanisms by which GRIN2B mutations contribute to ASD pathophysiology are not understood. Here, we investigated the cellular phenotypes induced by a human mutation that is predicted to truncate GluN2B within the extracellular loop. This mutation abolished NMDA-dependent Ca2+ influx. Mutant GluN2B co-assembled with GluN1 but was not trafficked to the cell surface or dendrites. When mutant GluN2B was expressed in developing cortical neurons, dendrites appeared underdeveloped, with shorter and fewer branches, while spine density was unaffected. Mutant dendritic arbors were often dysmorphic, displaying abnormal filopodial-like structures. Interestingly, dendrite maldevelopment appeared when mutant GluN2B was expressed on a wild-type background, reflecting the disease given that individuals are heterozygous for GRIN2B mutations. Restoring the fourth transmembrane domain and cytoplasmic tail did not rescue the phenotypes. Finally, abnormal development was not accompanied by reduced mTOR signaling. These data suggest that mutations in GluN2B contribute to ASD pathogenesis by disrupting dendrite development.
Maternal food supplementation and perceived predation risk modify egg composition and eggshell traits but not offspring condition
Authors: Morosinotto Chiara , Thomson Robert L. , Korpimäki Erkki , Mateo Rafael , Ruuskanen Suvi
Published: September 2019

Mothers may vary resource allocation to eggs and embryos, which may affect offspring fitness and prepare them to future environmental conditions. The effects of food availability and predation risk on reproduction have been extensively studied, yet their simultaneous impacts on reproductive investment and offspring early life conditions are still unclear. We experimentally manipulated these key environmental elements using a 2 × 2 full factorial design in wild, free-living pied flycatchers (Ficedula hypoleuca), and measured egg composition, eggshell traits and offspring condition. Eggs laid in food-supplemented nests had larger yolks and thicker shells independently of predation risk, while eggs laid in nests exposed to predator cues had lower levels of immunoglobulins, independently of food-supplementation. In nests without predator cues, shell biliverdin content was higher in eggs laid in food-supplemented nests. Incubation was one day shorter in food-supplemented nests and shorter incubation periods were associated with higher hatching success, but there were no direct effects of maternal treatments on hatching success. To investigate the impact of maternal treatment (via egg composition) on the offspring, we performed full brood cross-fostering after hatching to unmanipulated nests. Maternal treatments did not significantly affect body mass and immunoglobulin levels of offspring. Our results suggest that although prenatal maternal cues affected egg composition, these egg-mediated effects may not have detectable consequences for offspring growth or immune capacity. Unpredictable environmental stressors may thus affect parental investment in the eggs, but parental care may level off costs and benefits of differential maternal egg allocation.
Specialized landing maneuvers in Spix's disk-winged bats (Thyroptera tricolor) reveal linkage between roosting ecology and landing biomechanics
Authors: Boerma David B. , Barrantes José P. , Chung Charles , Chaverri Gloriana , Swartz Sharon M.
Published: September 2019

Disk-winged bats (Thyroptera spp.) are the only mammals that use suction to cling to smooth surfaces, having evolved suction cups at the bases of the thumbs and feet that facilitate attachment to specialized roosts: the protective funnels of ephemeral furled leaves. We predicted that this combination of specialized morphology and roosting ecology is coupled with concomitantly specialized landing maneuvers. We tested this prediction by investigating landings in Thyroptera tricolor using high-speed videography and a force-measuring landing pad disguised within a furled leaf analogue. We found that their landing maneuvers are distinct among all bats observed to date. Landings comprised three phases: 1) approach, 2) ballistic descent, and 3) adhesion. During approach, bats adjusted trajectory until centered in front of and above the landing site, typically the leaf's protruding apex. Bats initiated ballistic descent by arresting the wingbeat cycle and tucking their wings to descend toward the leaf, simultaneously extending the thumb-disks cranially. Adhesion commenced when the thumb-disks contacted the landing site. Significant body reorientation occurred only during adhesion, and only after contact, when the thumb-disks acted as fulcra about which the bats pitched 75.02±26.17° (mean±s.d.) to swing the foot-disks into contact. Landings imposed 6.98±1.89 bodyweights of peak impact force. These landing mechanics are likely influenced by the orientation, spatial constraints, and compliance of furled leaf roosts. Roosting ecology influences critical aspects of bat biology, and taken as a case-study, this work suggests that roosting habits and landing mechanics could be functionally linked across bats.
Oxidative status and telomere length are related to somatic and physiological maturation in chicks of European starlings (Sturnus vulgaris)
Authors: Criscuolo F. , Cornell A. , Zahn S. , Williams T. D.
Published: September 2019

Telomere length can be considered as an indicator of an organism's somatic state, long telomeres reflecting higher energy investment in self-maintenance. Early-life is a period of intense investment in somatic growth and in physiological maturation but how this is reflected in telomere length remains unclear. Using European starling chicks we tested: (i) how telomere length measured at asymptotic mass is related to proxies of somatic growth and physiological maturity in 17 days-old nestlings; (ii) how telomere length measured at 17 days then predicts the changes in somatic and physiological maturity occurring in fledglings (between 17-21 days); (iii) how growth and telomere length co-vary when chicks are under experimentally good (fed) growth conditions. Depending on environmental conditions, our data suggest links between somatic growth, physiological maturation, and body maintenance parameters (positive with oxidative stress and negative with telomere length) in nestlings. Telomere length measured at day 17 predicted subsequent change in physiological maturation variables observed in fledglings, but only in second-brood chicks: chicks with shorter telomeres had a higher pre-fledging rate of increase in hematocrit, haemoglobin content and a greater decrease in reticulocytes count. Finally, food-supplementation of chicks did not change telomere length compared to control siblings. Our results suggest that physiological maturation prior to fledging may occur at the expense of telomere length but only when environmental conditions are sub-optimal.
Sonar strobe groups and buzzes are produced before powered flight is achieved in the juvenile big brown bat, Eptesicus fuscus
Authors: Mayberry Heather W. , Faure Paul A. , Ratcliffe John M.
Published: September 2019

Laryngeally echolocating bats produce a rapid succession of echolocation calls just before landing. These landing buzzes exhibit an increase in call rate and decreases in call peak frequency and duration relative to pre-buzz calls and resemble the terminal buzz phase calls of an aerial hawking bat's echolocation attack sequence. Sonar strobe groups (SSGs) are clustered sequences of non-buzz calls whose pulse intervals (PIs) are fairly regular and shorter than the PIs both before and after the cluster, but longer than the PIs of buzz calls. Like buzzes, SSGs are thought to indicate increased auditory attention. We recorded the echolocation calls emitted by juvenile big brown bats (Eptesicus fuscus) over postnatal development from birth to 32 days old, when full flight has normally been achieved, and tested the following hypotheses: (i) buzz production precedes the onset of controlled, powered flight; (ii) the emission of SSGs precedes buzzes and coincides with the onset of fluttering behaviour and, (iii) the onset of flight is attained first by young bats with adult-like wing loadings. We found that E. fuscus pups emitted landing buzzes before they achieved powered flight and produced SSGs several days before emitting landing buzzes Both observations indicate the onset of adult-like echolocation behaviour occurs prior to adult-like flight behaviour. Pups that achieved flight first were typically those that also first achieved low, adult-like wing loadings. Our results demonstrate that echolocation and flight develop in parallel but maybe temporally offset, such that the sensory system precedes the locomotory system during post-natal ontogeny.
Deep inspiration breath hold in locally advanced lung cancer radiotherapy: validation of intrafractional geometric uncertainties in the INHALE trial
Authors: Josipovic Mirjana , Aznar Marianne C , Thomsen Jakob B , Scherman Jonas , Damkjaer Sidsel MS , Nygård Lotte , Specht Lena , Pøhl Mette , Persson Gitte F
Published: September 2019

Objectives:

Patients with locally advanced non-small cell lung cancer (NSCLC) were included in a prospective trial for radiotherapy in deep inspiration breath hold (DIBH). We evaluated DIBH compliance and target position reproducibility.

Methods:

Voluntary, visually guided DIBHs were performed with optical tracking. Patients underwent three consecutive DIBH CT scans for radiotherapy planning. We evaluated the intrafractional uncertainties in the position of the peripheral tumour, lymph nodes and differential motion between them, enabling PTV margins calculation. Patients who underwent all DIBH imaging and had tumour position reproducibility <8 mm were up-front DIBH compliant. Patients who performed DIBHs throughout the treatment course were overall DIBH compliant. Clinical parameters and DIBH-related uncertainties were validated against our earlier pilot study.

Results:

69 of 88 included patients received definitive radiotherapy. 60/69 patients (87%) were up-front DIBH compliant. DIBH plan was not superior in seven patients and three lost DIBH ability during the treatment, leaving 50/69 patients (72%) overall DIBH compliant.

The systematic and random errors between consecutive DIBHs were small but differed from the pilot study findings. This led to slightly different PTV margins between the two studies.

Conclusions:

DIBH compliance and reproducibility was high. Still, this validation study highlighted the necessity of designing PTV margins in larger, representative patient cohorts.

Advances in knowledge:

We demonstrated high DIBH compliance in locally advanced NSCLC patients. DIBH does not eliminate but mitigates the target position uncertainty, which needs to be accounted for in treatment margins. Margin design should be based on data from larger representative patient groups.
Autoactivation of small GTPases by the GEF–effector positive feedback modules
Authors: Goryachev Andrew B. , Leda Marcin
Published: September 2019

Small GTPases are organizers of a plethora of cellular processes. The time and place of their activation are tightly controlled by the localization and activation of their regulators, guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Remarkably, in some systems, the upstream regulators of GTPases are also found downstream of their activity. Resulting feedback loops can generate complex spatiotemporal dynamics of GTPases with important functional consequences. Here we discuss the concept of positive autoregulation of small GTPases by the GEF–effector feedback modules and survey recent developments in this exciting area of cell biology.
Labor Activities in the Field of Internal Financial Audit in the State Sector
Authors: Парушина Наталья , Parushina Natalya , Лытнева Наталья , Lytnyeva Natalya , Билиходзе Александр , Bilikhodze Alexander
Published: September 2019

Th e article considers the prerequisites, patterns and trends in the development of activities for conducting internal financial audits in the public sector. A review of the regulatory documents governing the work of internal auditors is given, the principles of auditing in the public sector are summarized, prospects for the development of internal audits are considered, taking into account the adoption of federal standards.
Consumer Search and Automobile Dealer Colocation
Authors: Murry Charles , Zhou Yiyi
Published: September 2019

Retailers colocate with rivals to take advantage of economies of agglomeration even though colocation implies greater competition. Using data on all new car transactions registered in Ohio from 2007 to 2014, we estimate a structural model of consumer search for spatially differentiated products that explicitly captures the agglomeration and competition effects of retail colocation. Search frictions generate an average of $333 per car in dealer markups. Agglomeration implies that dealer closures could harm incumbent colocated dealers, even though the incumbent dealers would face less competition. Our results inform the recent policy debate surrounding the massive downsizing of car retail networks and highlight the role of contagion in brick-and-mortar retailing.

This paper was accepted by Matthew Shum, marketing.