bluuebunny/crossref_metadata_2025 huggingface dataset:
Community pharmacist patient care services: A systematic review of approaches used for implementation and evaluation
Authors: Bacci Jennifer L. , Bigham Kyle A. , Dillon‐Sumner Laurel , Ferreri Stefanie , Frail Caitlin K. , Hamada Cory Y. , Lantaff Wendy , McGivney Melissa S. , Renner Hannah , Snyder Margie E. , Curran Geoffrey M.
Published: May 2019

Background

Studies have identified the positive impact of community pharmacist patient care services. Identifying the most effective implementation strategies and performing robust research are critical to sustaining evidence‐based patient care in this setting. This systematic review aimed to describe: (1) implementation strategies, and (2) dissemination and implementation (D&I) outcomes used to evaluate the implementation of patient care services in community pharmacies.

Methods

PubMed/MEDLINE, EMBASE, and International Pharmaceutical Abstracts were searched for articles that were: (1) written in English and published in 1985 or later, (2) described a peer‐reviewed empirical study or practice experience implementing a patient care service in a community pharmacy, and (3) described the strategies used to implement and/or evaluate the implementation of the service. Two investigators reviewed the abstract, and full‐text when necessary, of each article to assess eligibility. Data were extracted from each article by two investigators using a standardized form. Implementation strategies were categorized using the Expert Recommendations for Implementation Change (ERIC) study terminology. The D&I outcomes were classified using the Proctor and colleagues terminology. All data were summarized using descriptive statistics.

Results

Two hundred and thirty‐seven articles were included, 223 of which described at least one implementation strategy and 224 described at least one D&I outcome. “Train and educate stakeholders” and “engage consumer” were the most common and “provide interactive assistance” and “adapt and tailor to context” were the least commonly reported implementation strategies. Reach, acceptability, and adoption were the most common and fidelity and sustainability were the least commonly evaluated D&I outcomes. Most studies used quasi‐experimental or observational designs.

Conclusions

This systematic review used published manuscripts to identify the breadth and depth of implementation and evaluation strategies being utilized in various community pharmacies. Findings suggest opportunities for further research and innovation via collaboration between pharmacists and implementation practitioners and researchers.
miRNA‐30‐3p improves myocardial ischemia via the PTEN/PI3K/AKT signaling pathway
Authors: Yin Yugang , Yang Chun
Published: May 2019

The aim of this study was to explain the effect and mechanisms of miRNA‐30‐3p in myocardial ischemia‐induced cell apoptosis in vitro and in vivo studies. In the cell experiment, the H9C2 cells were divided into the normal control (NC), and the model, miRNA, and miRNA + phosphatidylinositol 3‐kinase (PI3K) inhibitor groups. The cell survival rates of the different groups were measured with the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium assay kit; the lactate dehydrogenase (LDH), malondialdehyde (MDA) content, and superoxidedimutase (SOD) activity in the bathing medium were assayed for the evaluation of myocardial cell injury. The cell apoptosis rate of different groups was measured with flow cytometry analysis. The relative protein expressions of different cell groups were evaluated by Western blot analysis. In the vivo study, the Sprague‐Dawley rats were divided into four groups: the NC group, the model group, miRNA group, and the (miRNA + PI3K inhibitor) group. The pathological observations, cell apoptosis, LDH, SOD, MDA, and relative protein expressions were evaluated with hematoxylin and eosin, enzyme‐linked immunosorbent assay, terminal deoxynucleotide transferase dUTP nick‐end labeling or immunohistochemical methods. The results show that miRNA‐30‐3p had the effect of improving cell apoptosis induced by myocardial ischemia in vitro and in vivo studies by the regulation of the PTEN/PI3K/AKT pathway.
Quercetin augments apoptosis of canine osteosarcoma cells by disrupting mitochondria membrane potential and regulating PKB and MAPK signal transduction
Authors: Ryu Soomin , Park Sunwoo , Lim Whasun , Song Gwonhwa
Published: May 2019

Osteosarcoma is a mesenchymal malignant bone tumor accompanied by a high rate of lung metastasis and short survival in dogs. Although various therapies have been reported, the etiological mechanism of osteosarcoma remains undetermined and the development of novel therapeutic agents is warranted. In this study, we have reported the diverse functions of quercetin, one of the well‐known flavonoid, in D‐17 and DSN (canine osteosarcoma) cell lines. Current results indicate that quercetin decreases proliferative properties and increases programmed cell death, in addition to altering the cell cycle, mitochondrial depolarization, level of reactive oxygen species, and concentration of cytoplasmic calcium in both cells. Furthermore, it was observed that quercetin suppresses phosphorylation of AKT, P70S6K, and S6 proteins and upregulates phosphorylation of ERK1 or 2, P38, c‐Jun N‐terminal kinase, and P90RSK proteins in both cell lines. Collectively, we suggest that quercetin can be used as a pharmacological agent for suppressing the proliferation and inducing the apoptosis of canine osteosarcoma cells.
S100 A9 is expressed and secreted by the oviduct epithelium, interacts with gametes and affects parameters of human sperm capacitation in vitro
Authors: Massa Estefanía , Prez Gastón , Zumoffen Carlos , Morente Carlos , Ghersevich Sergio
Published: May 2019

Our previous findings demonstrate that some oviductal secretion proteins bind to gametes and affect sperm physiology and gamete interaction. One of these proteins possesses an estimated molecular weight of 14 kDa. The objective of this study was to isolate and identify this 14 kDa protein, to localize it in the human oviduct, to detect gamete binding sites for the protein, and to evaluate its effects on sperm capacitation parameters and gamete interaction. Explants from the human oviductal tissues of premenopausal women were cultured in the presence of [35S]‐Methionine‐proteins ([35S]‐Met‐proteins). De novo synthesized secreted [35S]‐Met‐proteins were isolated from the culture media by affinity chromatography using their sperm membrane binding ability and analysed by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis. Using liquid chromatography‐tandem mass spectrometry peptide sequencing, human S100 A9 was identified as one of the isolated proteins from the 14 kDa protein band. S100 A9 was detected in oviduct epithelium and oviduct secretion using immunohistochemistry and a Western blot. S100 A9 binding to human oocytes and spermatozoa was assessed by indirect immunofluorescence. The acrosome reaction (AR) affected S100 A9 ability to bind sperm cells. The presence of S100 A9 significantly increased both the induced AR and the sperm protein tyrosine phosphorylation, with respect to controls. However, the protein did not affect sperm‐zona pellucida interaction. Results indicate that S100 A9 is present in the human oviduct and that it modulates parameters of sperm capacitation in vitro. Hence, the protein might contribute to the regulation of the reproductive process in the oviductal microenvironment.
Inhibition of mitochondrial activity ameliorates atherosclerosis in ApoE−/− mice via suppressing vascular smooth cell activation and macrophage foam cell formation
Authors: Xia Weiwei , Li Yuanyuan , Wu Mengying , Yin Jie , Zhang Yue , Chen Hongbing , Huang Songming , Jia Zhanjun , Zhang Aihua
Published: May 2019

Background

Atherosclerosis involves disorders in lipoprotein metabolism and inflammation. Mitochondrial dysfunction plays a critical role in promoting cell apoptosis, inflammation, and oxidative stress involved in the progress of atherosclerosis. Whereas the direct effect of mitochondrial activity modulation on atherogenesis remains unclear. This study evaluated the effect of a mitochondrial complex inhibitor on atherosclerosis in ApoE‐deficient mice as well as the potential mechanisms.

Methods and Results

We treated ApoE‐deficient mice with mitochondrial complex I inhibitor rotenone in the western diet and found that rotenone attenuated early and advanced atherosclerosis with no effect on serum lipoprotein levels. Mechanistic investigation showed that rotenone suppressed primary macrophage foam cell formation possibly by suppressing CD36. In addition, we also found that the inhibitory effect of rotenone on VSMC proliferation and migration possibly by targeting the PI3K/AKT signaling. Consistently, mitochondrial complex III inhibitor azoxystrobin also exhibited similar actions as rotenone in VSMCs but not in macrophages.

Conclusions

Inhibition of mitochondrial activity could significantly attenuate atherosclerosis possibly by modulating CD36‐mediated macrophage foam cell formation and PI3K/AKT signaling pathway‐associated VSMC activation. Targeting mitochondrial activity might be the potential therapeutic strategy for atherosclerosis.
MicroRNA‐181b‐5p modulates tumor necrosis factor‐α‐induced inflammatory responses by targeting interleukin‐6 in cementoblasts
Authors: Wang Xiaoxuan , Sun Hualing , Liu Huan , Ma Li , Jiang Chenxi , Liao Haiqing , Xu Shihan , Xiang Junbo , Cao Zhengguo
Published: May 2019

Tooth cementum is a bone‐like mineralized tissue and serves as a microbial barrier against invasion and destruction. Cementum is also responsible for tooth stability and defending pulp from outside stimuli, which is formed by cementoblasts. Although it is crucial for periodontal and periapical diseases, the mechanisms underlying the pathophysiological changes of cementoblasts and their inflammatory responses remain unclear. MiR‐181b is found to modulate vascular inflammation and endotoxin tolerance. In this study, miR‐181b‐5p was downregulated in tumor necrosis factor‐α (TNF‐α)‐stimulated cementoblasts, whereas proinflammatory molecules increased. The mouse periapical lesions have similar results, which imitate an inflammatory environment for cementoblasts in vivo. The bioinformatics analysis and dual luciferase reporter assay suggested that miR‐181b‐5p targeted interleukin‐6 (IL‐6). Overexpressing miR‐181b‐5p negatively regulated IL‐6 and proinflammatory chemokine. Western blot analysis and luciferase activity reporter assay verified that miR‐181b‐5p weakened the NF‐κB activity. Hence, miR‐181b‐5p moderated proinflammatory chemokine production by targeting IL‐6 in cementoblasts and NF‐κB signaling pathway was involved. Furthermore, miR‐181b‐5p promoted cementoblast apoptosis, which may enhance the resolution of inflammation. Overall, our data revealed that miR‐181b‐5p was a negative regulator of TNF‐α‐induced inflammatory responses in cementoblasts.
Circular RNA circMAN2B2 facilitates glioma progression by regulating the miR‐1205/S100A8 axis
Authors: Xiong Jinsheng , Wang Tianyao , Tang Haitao , Lv Zhonghua , Liang Peng
Published: May 2019

The aim of this study was to research the mechanism of circMAN2B2 in the development of glioma. In our study, we found that circMAN2B2 has a higher expression in glioma tissues and cells, which was negatively related to the overall survival of glioma patients. The cell counting kit‐8 assay, 5‐ethynyl‐2′‐deoxyuridine labeling assay, transwell assay, and the nude mice assay indicated that knockdown of circMAN2B2 inhibited the cell proliferation, invasion, migration and decreased tumor size. In terms of mechanism, knockdown of circMAN2B2 increased the expression of miR‐1205. Moreover, circMAN2B2 regulated S100A8 expression by inhibiting miR‐1205. We also showed that knockdown of S100A8 inhibited cell proliferation, invasion, and migration. Increasing S100A8 expression rescued the effect of si‐circMAN2B2. In conclusion, circMAN2B2 could improve cell proliferation, invasion, and migration of the glioma by inhibiting miR‐1205 and promoting the expression of S100A8.
Dysregulated microRNAs in colorectal carcinogenesis: New insight to cell survival and apoptosis regulation
Authors: Anvarnia Alireza , Mohaddes‐Gharamaleki Farzad , Asadi Milad , Akbari Morteza , Yousefi Bahman , Shanehbandi Dariush
Published: May 2019

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer‐related death worldwide. About 1.8 million new cases were reported in 2018. Accordingly, there is an urgent need for development of effective strategies to lower the mortality and morbidity originated from this malignancy. MicroRNAs (miRNAs) play key roles in several cellular events. They have attracted a great deal of attention in the etiology of a variety of disorders including cancer and might be considered as disease biomarkers or treatment targets. Initiation and development of CRC is a multistep process that is caused by loss of function (LOF) or gain of function (GOF) in genes of different signaling pathways. Particular miRNAs conduct oncogenic impacts by suppressing their target transcripts and simulate the effects of LOF or GOF, whereas there may be no sign of common genetic or epigenetic modifications. On the contrary, some miRNAs serve as tumor suppressor and help to maintain normal functioning and cellular homeostasis. Hence, highlighting the function of each individual miRNA in CRC tumorigenesis could assign it as a therapeutic target or molecular marker for further investigations. In the present review, we have tried to compile the latest information regarding the dysregulated miRNAs in CRC and their function in different disease stages and signaling pathways involved.
Long noncoding RNA LINC‐PINT regulates laryngeal carcinoma cell stemness and chemoresistance through miR‐425‐5p/PTCH1/SHH axis
Authors: Yuan Zhennan , Xiu Cheng , Liu Daming , Zhou Guangkai , Yang Hao , Pei Rong , Ding Chao , Cui Xiaowei , Sun Ji , Song Kaibin
Published: May 2019

Functional, noncoding RNA of about 200 nucleotides in length are known as long noncoding RNA (lncRNA). Advances in ‐omics have revolutionized the information with respect to the coding and noncoding regions of the genome. Several studies have illustrated the role of lncRNA in cell growth and cancer. Profiling and bioinformatic studies of laryngeal cancer has identified LINC‐PINT as one of the lncRNA. However, the functional aspects of the deregulation have not been studied in laryngeal tumors. In this study, LINC‐PINT expression in normal and tumor tissues were studied. Using a bioinformatic approach, microRNA (miRNA) targets of LINC‐PINT and gene targets of the miRNA were determined. The impact of LINC‐PINT on cell proliferation and chemoresistance was determined. Further through a set of silencing and re‐expression studies phenotype rescue was studied. LINC‐PINT expression was downregulated in laryngeal tumors. LINC‐PINT targeted miR‐425‐5p by three sites. miR‐425‐5p also targeted PTCH1 a protein of the Hedgehog pathway. Downregulation of LINC‐PINT was associated with increased cancer stemness and chemoresistance to cisplatin. Our results indicate a probable role of LINC‐PINT in the pathology of laryngeal tumors. LINC‐PINT re‐expression in laryngeal tumors may be explored for reversion of cancer cell stemness and also for rescue of drug resistance phenotype.
Effects of Sitagliptin on Lipid Profile in Patients With Type 2 Diabetes Mellitus After 7 Years of Therapy
Authors: Derosa Giuseppe , Tritto Isabella , Romano Davide , D'Angelo Angela , Catena Gabriele , Maffioli Pamela
Published: May 2019

The aim of this study was to investigate whether the effects of sitagliptin on lipid profile were maintained even after 7 years of treatment. We treated 591 patients who had not been well controlled by current therapy with the addition of sitagliptin 100 mg/d. Data were compared with those of 612 patients treated with sulfonylureas plus metformin, pioglitazone plus metformin, and pioglitazone plus sulfonylureas. We observed that, compared with patients treated with sulfonylureas plus metformin, patients receiving sitagliptin in addition to metformin experienced a greater decrease of total cholesterol and low‐density lipoprotein cholesterol (LDL‐C) compared with baseline and with sulfonylureas plus metformin. Compared with patients treated with metformin plus pioglitazone, sitagliptin resulted in a greater reduction of total cholesterol and LDL‐C relative to baseline and to metformin plus pioglitazone. We also observed a higher increase of high‐density lipoprotein cholesterol (HDL‐C) after sitagliptin had been added to pioglitazone, both compared with baseline and to the competitor. Compared with patients treated with pioglitazone plus sulfonylureas, the combination of sitagliptin and sulfonylureas was more effective in reducing LDL‐C and in increasing HDL‐C. High‐sensitivity C‐reactive protein was decreased by all pharmacological combinations. We can conclude that the addition of sitagliptin led to a better and more durable improvement of lipid profile compared with sulfonylureas or thiazolidinediones.
Food wastes and sewage sludge as feedstock for an urban biorefinery producing biofuels and added‐value bioproducts
Authors: Battista Federico , Frison Nicola , Pavan Paolo , Cavinato Cristina , Gottardo Marco , Fatone Francesco , Eusebi Anna L , Majone Mauro , Zeppilli Marco , Valentino Francesco , Fino Debora , Tommasi Tonia , Bolzonella David
Published: May 2019

The updated Bioeconomy Strategy document “A sustainable bioeconomy for Europe: strengthening the connection between economy, society and the environment”, which was issued by the European Commission in October 2018, encourages the exploitation of organic wastes according to a pyramidal hierarchy in which the extraction of valuable biomolecules, which will be used as they are or as precursors of high‐added‐value compounds, is a priority in biofuel production. This review considers a biorefinery platform in which food waste and sewage sludge are adopted to produce volatile fatty acids (VFAs) through a dark fermentation process. VFA fermentation is optimized by slightly acid pH (6–7), short hydraulic retention time (1–7 days) and high organic load rate (more than 10 gTS L−1 d−1). Attention has been focused on VFA exploitation for polyhydroxyalkanoate (PHA) production via a ‘feast and famine’ strategy performed in sequencing batch reactors. The obtained PHA yields are around 0.4–0.5 gPHA gCOD−1. Moreover, VFAs allow for the production of biofuels, such as hydrogen and methane, through single‐ or double‐staged anaerobic digestion. Innovative bioelectrochemical upgrade strategies for biogas helps producers to obtain biomethane for the automotive sector. Moreover, biogas has recently been tested for the production of polyhydroxybutyrate, a biodegradable and biocompatible thermoplastic made by microorganisms from C1 carbon sources (CO2 and CH4). Digestates from anaerobic bioreactors are still rich in nitrogen and phosphorus compounds. These latter compounds have been identified as critical raw materials due to their low availability in the European Union and to increasing demand from the growing global population. Thus, nutrient recovery from digestate allows users to close the loop of the ‘circular economy’ approach. © 2019 Society of Chemical Industry
Gonadal macrophage aggregates in fish: A preliminary quantitative study in red mullet
Authors: Micale Valeria , Perdichizzi Anna , Muglia Ugo , Rinelli Paola , Cosenza Alessandro , Mita Damiano Gustavo
Published: May 2019

A histological study was conducted in red mullet, Mullus barbatus, collected from two sites characterized by different anthropogenic impacts. The aim of the study was to assess sex‐, size‐, season‐ and site‐related variation in gonadal macrophage aggregate (MA) size, number, and relative area. Gonadal MAs were most abundant in males than in females. The number of MA was significantly higher in males from the most impacted site in October, with larger individuals showing more MA than smaller ones. MAs were always found in ripe testes, whereas they occurred only in regressing ovaries. These preliminary findings suggest that the presence of ovarian MA in red mullet is most likely related to ovary regression after spawning, whereas the presence of testicular MA is not necessarily associated to gonad regression, and may vary with season, size, and water quality.
Improvement of display performance of electrowetting displays by optimized waveforms and error diffusion
Authors: Lin Shanling , Zeng Suyun , Qian Mingyong , Lin Zhixian , Guo Tailiang , Tang Biao
Published: May 2019

The electrowetting display (EWD) has a low gray level, and there are some phenomena that affect the display quality, such as oil backflow and charge trapping. In this paper, an error diffusion algorithm based on pixel neighborhood gray information and direct current (DC)‐balanced driving waveform are proposed for display quality of EWD. The proposed algorithm and driving waveform are implemented in the proposed driving system based on Digital Visual Interface (DVI) video codec system and field‐programmable gate array (FPGA) control system. The experiment results show that the driving waveform suppresses the oil backflow, charge trapping and keeps DC balance, and the proposed error diffusion preserves the edges and richness of image. The whole driving system successfully plays video in real time with computer and improves the display quality of EWD.
Supporting fibula free flap harvest with augmented reality: A proof‐of‐concept study
Authors: Pietruski Piotr , Majak Marcin , Świątek‐Najwer Ewelina , Żuk Magdalena , Popek Michał , Jaworowski Janusz , Mazurek Maciej
Published: May 2019

Objective

To analyze a novel navigation system utilizing augmented reality (AR) as a supporting method for fibula free flap (FFF) harvest and fabrication.

Methods

A total of 126 simulated osteotomies supported with a cutting guide or one of two AR‐based intraoperative navigation modules—simple AR (sAR) or navigated AR (nAR)—were carried out on 18 identical models of the fibula (42 osteotomies per method). After fusing postoperative computed tomography scans of the operated fibulas with the virtual surgical plan based on preoperative images, the objective outcomes—angular deviations from the planned osteotomy trajectory (o) and deviations of control points marked on the trajectory (mm)—were determined.

Results

All analyzed methods provided similar accuracy of assisted osteotomies. The only significant difference referred to angular deviation in the sagittal plane, which was smaller after the cutting guide‐assisted procedures than after the application of sAR and nAR (4.1 ± 2.29 vs. 5.08 ± 3.64 degrees, P = 0.031 and 4.1 ± 2.29 vs. 4.97 ± 2.91, P = 0.002, respectively). Mean deviation of control points after the cutting guide‐assisted procedures was 2.76 ± 1.06 mm, as compared with 2.67 ± 1.09 mm for sAR and 2.95 ± 1.11 mm for nAR.

Conclusion

Our study demonstrated that both novel AR‐based methods provided similar accuracy of assisted harvesting and contouring of the FFF as the cutting guides. This fact, as well as the acceptability of the concept by clinicians, justify their further development and evaluation in preclinical settings.

Level of Evidence

NA

Laryngoscope, 130:1173–1179, 2020
Synthesis and evaluation of hexamethylenetetramine quaternary ammonium salt as corrosion inhibitor
Authors: Liu Dexin , Qiu Xiaolong , Shao Minglu , Gao Jianchong , Xu Jiaju , Liu Qixin , Zhou Hua , Wang Zizhao
Published: May 2019

A novel corrosion inhibitor, hexamethylenetetramine quaternary ammonium salt, is synthesized using hexamethylenetetramine (HMTA) and bromohexane as main reactants. The inhibitive action of HQAS on QT800‐2 steel in hydrochloric acid medium is evaluated by weight‐loss method, electrochemical method, and quantum chemical calculation. The obtained results show that the efficiency of 0.5 wt% HQAS inhibitor in 30 wt.% HCl solution at 363 K is 92.95% and HQAS can form an excellent synergistic effect with some additives. Polarization curves reveal that HQAS behaves as a mixed‐type inhibitor with dominant anodic inhibition. Furthermore, the theoretical calculation verifies the relationship between the HQAS molecular structure and corrosion inhibition properties.
The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration
Authors: Hinkle Jared T. , Dawson Valina L. , Dawson Ted M.
Published: May 2019

We recently demonstrated that NLY01, a novel glucagon‐like peptide‐1 receptor agonist, exerts neuroprotective effects in two mouse models of PD in a glia‐dependent manner. NLY01 prevented microglia from releasing inflammatory mediators known to convert astrocytes into a neurotoxic A1 reactive subtype. Importantly, we provided evidence that this neuroprotection was not mediated by a direct action of NLY01 on neurons or astrocytes (e.g., by activating neurotrophic pathways or modulating astrocyte reactivity per se). In the present article, we provide a generalist review of microglia and astrocytes in neurodegeneration and discuss the emerging paradigm of A1 astrocyte neurotoxicity in more detail. We comment on specific inferences that are naturally suggested by our work in this area and the differential level of support it offers to each. Finally, we discuss implications for the overall goal of creating disease‐modifying therapies for PD, survey emerging methodologies for accelerating translational research on glia in neurodegeneration, and describe expected challenges for developing glia‐directed therapies that do not impede essential physiological functions carried out by glia in the CNS. © 2019 International Parkinson and Movement Disorder Society
IL‐7R gene polymorphisms among patients with rheumatoid arthritis: A case–control study
Authors: Bai Mei , He Xue , He Yongjun , Yuan Dongya , Jin Tianbo , Wang Li
Published: May 2019

Background

Rheumatoid arthritis (RA) is the most common inflammatory disease which refers to bony erosions and joint destruction largely caused by genetic factors. Our study aimed to explore whether interleukin‐7 receptor (IL‐7R) gene polymorphisms influenced RA risk in the Han Chinese population.

Methods

Five single nucleotide polymorphisms (SNPs) in IL‐7R gene were successfully genotyped using Agena MassARRAY platform. The associations between IL‐7R polymorphisms and RA were evaluated by the Chi‐squared test, T test, genetic model analysis, and haplotype analysis. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression analysis.

Results

Rs969129 and rs6451231 in the IL‐7R gene were associated with an increased risk of RA in the allele model (OR = 1.25, 95% CI = 1.05–1.49, p = 0.013; OR = 1.23, 95% CI = 1.03–1.48, p = 0.023), respectively. In the genetic models, rs969129 and rs6451231 were associated with an increased risk of RA. After stratification analysis by age, rs969129 and rs6451231 were associated with an increased risk of RA in patients (age <54). After stratification analysis by gender, rs6451231 was associated with an increased risk of RA in males, while rs969129 was found to be associated with an elevated risk of RA in females. And there was a strong linkage disequilibrium among the four SNPs (rs969129, rs118137916, rs10053847, and rs6451231).

Conclusion

These results suggested rs969129 and rs6451231 in the IL‐7R gene were associated with an increased risk of RA in the Han Chinese population.
Molecular Modelling of Potential Candidates for the Treatment of Depression
Authors: Silva Daniela Rodrigues , Barigye Stephen J. , Santos‐Garcia Letícia , Fontes Ferreira da Cunha Elaine
Published: May 2019

A lot of research initiatives in the last decades have been focused on the search of new strategies to treat depression. However, despite the availability of various antidepressants, current treatment is still far from ideal. Unwanted side effects, modest response rates and the slow onset of action are the main shortcomings. As a strategy to improve symptomatic relief and response rates, the dual modulation of the serotonin transporter and the histamine H3 receptor by a single chemical entity has been proposed in the literature. Accordingly, this work aims to elucidate key structural features responsible for the dual inhibitory activity of the hexahydro‐pyrrolo‐isoquinoline derivatives. For this purpose, two approaches were employed, four‐dimensional quantitative structure‐activity relationship (4D‐QSAR) and molecular docking. The 4D‐QSAR models for both receptors allowed the identification of the pharmacophore groups critical for the modelled biological activity, whereas the binding mode of this class of compounds to the human serotonin transporter was assessed by molecular docking. The findings can be applicable to design new antidepressants.
Computationally efficient deep neural network for computed tomography image reconstruction
Authors: Wu Dufan , Kim Kyungsang , Li Quanzheng
Published: May 2019

Purpose

Deep neural network‐based image reconstruction has demonstrated promising performance in medical imaging for undersampled and low‐dose scenarios. However, it requires large amount of memory and extensive time for the training. It is especially challenging to train the reconstruction networks for three‐dimensional computed tomography (CT) because of the high resolution of CT images. The purpose of this work is to reduce the memory and time consumption of the training of the reconstruction networks for CT to make it practical for current hardware, while maintaining the quality of the reconstructed images.

Methods

We unrolled the proximal gradient descent algorithm for iterative image reconstruction to finite iterations and replaced the terms related to the penalty function with trainable convolutional neural networks (CNN). The network was trained greedily iteration by iteration in the image domain on patches, which requires reasonable amount of memory and time on mainstream graphics processing unit (GPU). To overcome the local‐minimum problem caused by greedy learning, we used deep UNet as the CNN and incorporated separable quadratic surrogate with ordered subsets for data fidelity, so that the solution could escape from easy local minimums and achieve better image quality.

Results

The proposed method achieved comparable image quality with state‐of‐the‐art neural network for CT image reconstruction on two‐dimensional (2D) sparse‐view and limited‐angle problems on the low‐dose CT challenge dataset. The difference in root‐mean‐square‐error (RMSE) and structural similarity index (SSIM) was within [−0.23,0.47] HU and [0,0.001], respectively, with 95% confidence level. For three‐dimensional (3D) image reconstruction with ordinary‐size CT volume, the proposed method only needed 2 GB graphics processing unit (GPU) memory and 0.45 s per training iteration as minimum requirement, whereas existing methods may require 417 GB and 31 min. The proposed method achieved improved performance compared to total variation– and dictionary learning–based iterative reconstruction for both 2D and 3D problems.

Conclusions

We proposed a training‐time computationally efficient neural network for CT image reconstruction. The proposed method achieved comparable image quality with state‐of‐the‐art neural network for CT reconstruction, with significantly reduced memory and time requirement during training. The proposed method is applicable to 3D image reconstruction problems such as cone‐beam CT and tomosynthesis on mainstream GPUs.
In vivo 1H MRS detection of cystathionine in human brain tumors
Authors: Branzoli Francesca , Deelchand Dinesh K. , Sanson Marc , Lehéricy Stéphane , Marjańska Małgorzata
Published: May 2019

Purpose

To report the technical aspects of noninvasive detection of cystathionine in human brain glioma with edited MRS, and to investigate possible further acquisition improvements for robust quantification of this metabolite.

Methods

In vivo 1H MR spectra were acquired at 3 T in 15 participants with an isocitrate dehydrogenase‐mutated glioma using a MEGA‐PRESS (MEscher GArwood point resolved spectroscopy) sequence previously employed for 2‐hydroxyglutarate detection (TR = 2 s, TE = 68 ms). The editing pulse was applied at 1.9 ppm for the edit‐on condition and at 7.5 ppm for the edit‐off condition. To evaluate the editing efficiency, spectra were acquired in 1 participant by placing the editing pulse for the edit‐on condition at 1.9, 2.03, and 2.16 ppm. Cystathionine concentration was quantified using LCModel and a simulated basis set. To confirm chemical shifts and J‐coupling values of cystathionine, the 1H NMR cystathionine spectrum was measured using a high‐resolution 500 MHz spectrometer.

Results

In 12 gliomas, cystathionine was observed in the in vivo edited MR spectra at 2.72 and 3.85 ppm and quantified. The signal intensity of the cystathionine resonance at 2.72 ppm increased 1.7 and 2.13 times when the editing pulse was moved to 2.03 and 2.16 ppm, respectively. Cystathionine was not detectable in normal brain tissue.

Conclusion

Cystathionine can be detected in vivo by edited MRS using the same protocol as for 2‐hydroxyglutarate detection. This finding may enable a more accurate, noninvasive investigation of cellular metabolism in glioma.
Ultrashort echo time magnetic resonance fingerprinting (UTE‐MRF) for simultaneous quantification of long and ultrashort T2 tissues
Authors: Li Qing , Cao Xiaozhi , Ye Huihui , Liao Congyu , He Hongjian , Zhong Jianhui
Published: May 2019

Purpose

To demonstrate an ultrashort echo time magnetic resonance fingerprinting (UTE‐MRF) method that allows quantifying relaxation times for muscle and bone in the musculoskeletal system and generating bone enhanced images that mimic CT scans.

Methods

A fast imaging steady‐state free precession MRF sequence with half pulse excitation and half projection readout was designed to sample fast T2 decay signals. Varying echo time (TE) of a sinusoidal pattern was applied to enhance sensitivity for tissues with short and ultrashort T2 values. The performance of UTE‐MRF was evaluated via simulations, phantom, and in vivo experiments.

Results

A minimal TE of 0.05 ms was achieved. Simulations indicated the sinusoidal TE sampling increased T2 quantification accuracy in the cortical bone and tendon but had little impact on long T2 muscle quantifications. For the rubber phantom, the averaged relaxometries from UTE‐MRF (T1 = 162 ms and T2 = 1.07 ms) compared well with the gold standard (T1 = 190 ms and = 1.03 ms). For the long T2 agarose phantom, the linear regression slope between UTE‐MRF and gold standard was 1.07 (R2 = 0.991) for T1 and 1.04 (R2 = 0.994) for T2. In vivo experiments showed the detection of the cortical bone (averaged T2 = 1.0 ms) and Achilles tendon (averaged T2 = 15 ms). Scalp structures from the bone enhanced image show high similarity with CT.

Conclusion

The UTE‐MRF with sinusoidal TEs can simultaneously quantify T1, T2, proton density, and B0 in long, short, even ultrashort T2 musculoskeletal structures. Bone enhanced images can be achieved in the brain with UTE‐MRF.
Assessment of intravoxel incoherent motion MRI with an artificial capillary network: analysis of biexponential and phase‐distribution models
Authors: Schneider Moritz Jörg , Gaass Thomas , Ricke Jens , Dinkel Julien , Dietrich Olaf
Published: May 2019

Purpose

To systematically analyze intravoxel incoherent motion (IVIM) MRI in a perfusable capillary phantom closely matching the geometry of capillary beds in vivo and to compare the validity of the biexponential pseudo‐diffusion and the recently introduced phase‐distribution IVIM model.

Methods

IVIM‐MRI was performed at 12 different flow rates () in a capillary phantom using 4 different DW‐MRI sequences (2 with monopolar and 2 with flow‐compensated diffusion‐gradient schemes, with up to values between and ). Resulting parameters from the assessed IVIM models were compared to results from optical microscopy.

Results

The acquired data were best described by a static and a flowing compartment modeled by the phase‐distribution approach. The estimated signal fraction of the flowing compartment stayed approximately constant over the applied flow rates, with an average of in excellent agreement with optical microscopy (). The estimated average particle flow speeds showed a highly significant linear correlation to the applied flow. The estimated capillary segment length of approximately agreed well with optical microscopy measurements. Using the biexponential model, the signal fraction was substantially underestimated and displayed a strong dependence on the applied flow rate.

Conclusion

The constructed phantom facilitated the detailed investigation of IVIM‐MRI methods. The results demonstrate that the phase‐distribution method is capable of accurately characterizing fluid flow inside a capillary network. Parameters estimated using the biexponential model, specifically the perfusion fraction , showed a substantial bias because the model assumptions were not met by the underlying flow pattern.
Prognosis of cervical myelopathy based on diffusion tensor imaging with artificial intelligence methods
Authors: Jin Richu , Luk Keith Dk , Cheung Jason Pui Yin , Hu Yong
Published: May 2019

Diffusion tensor imaging (DTI) has been proposed for the prognosis of cervical myelopathy (CM), but the manual analysis of DTI features is complicated and time consuming. This study evaluated the potential of artificial intelligence (AI) methods in the analysis of DTI for the prognosis of CM. Seventy‐five patients who underwent surgical treatment for CM were recruited for DTI imaging and were divided into two groups based on their one‐year follow‐up recovery. The DTI features of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were extracted from DTI maps of all cervical levels. Conventional AI models using logistic regression (LR), k‐nearest neighbors (KNN), and a radial basis function kernel support vector machine (RBF‐SVM) were built using these DTI features. In addition, a deep learning model was applied to the DTI maps. Their performances were compared using 50 repeated 10‐fold cross‐validations. The accuracy of the classifications reached 74.2% ± 1.6% for LR, 85.6% ± 1.4% for KNN, 89.7% ± 1.6% for RBF‐SVM, and 59.2% ± 3.8% for the deep leaning model. The RBF‐SVM algorithm achieved the best accuracy, with sensitivity and specificity of 85.0% ± 3.4% and 92.4% ± 1.9% respectively. This finding indicates that AI methods are feasible and effective for DTI analysis for the prognosis of CM.
Deconstructing Weight Management Interventions for Young Adults: Looking Inside the Black Box of the EARLY Consortium Trials
Authors: Tate Deborah F. , Lytle Leslie , Polzien Kristen , Diamond Molly , Leonard Kelsey R. , Jakicic John M. , Johnson Karen C. , Olson Christine M. , Patrick Kevin , Svetkey Laura P. , Wing Rena R. , Lin Pao‐Hwa , Coday Mathilda , Laska Melissa N. , Merchant Gina , Czaja Sara J. , Schulz Richard , Belle Steven H.
Published: May 2019

Objective

The goal of the present study was to deconstruct the 17 treatment arms used in the Early Adult Reduction of weight through LifestYle (EARLY) weight management trials.

Methods

Intervention materials were coded to reflect behavioral domains and behavior change techniques (BCTs) within those domains planned for each treatment arm. The analytical hierarchy process was employed to determine an emphasis profile of domains in each intervention.

Results

The intervention arms used BCTs from all of the 16 domains, with an average of 29.3 BCTs per intervention arm. All 12 of the interventions included BCTs from the six domains of Goals and Planning, Feedback and Monitoring, Social Support, Shaping Knowledge, Natural Consequences, and Comparison of Outcomes; 11 of the 12 interventions shared 15 BCTs in common across those six domains.

Conclusions

Weight management interventions are complex. The shared set of BCTs used in the EARLY trials may represent a core intervention that could be studied to determine the required emphases of BCTs and whether additional BCTs add to or detract from efficacy. Deconstructing interventions will aid in reproducibility and understanding of active ingredients.
Adaptive functioning in pediatric brain tumor survivors: An examination of ethnicity and socioeconomic status
Authors: Raghubar Kimberly P. , Orobio Jessica , Ris M. Douglas , Heitzer Andrew M. , Roth Alexandra , Brown Austin L. , Okcu M. Fatih , Chintagumpala Murali , Grosshans David R. , Paulino Arnold C. , Mahajan Anita , Kahalley Lisa S.
Published: May 2019

Background

Survivors of pediatric brain tumor are at risk for adaptive difficulties. The present study examined adaptive functioning in a multiethnic sample of survivors accounting for socioeconomic status, and whether demographic, diagnostic, and/or treatment‐related variables predict adaptive outcomes.

Method

Participants included a multiethnic sample of survivors (58 Caucasian, 34 Hispanic, and 22 other non‐Caucasian; M age = 14.05 years, SD = 4.33) who were approximately seven years post‐treatment. Parents rated adaptive functioning and provided demographic information. Diagnostic and treatment‐related information was abstracted from the electronic medical record.

Results

Parent ratings of adaptive functioning were similar across Caucasian, Hispanic, and other non‐Caucasian survivors covarying for family income and primary caregiver education, both of which served as proxies for socioeconomic status. All ethnic groups were rated lower than the normative mean in overall adaptive functioning as well as the specific domains of conceptual, social, and practical skills. Demographic, diagnostic, and treatment‐related variables were differentially associated with adaptive functioning in survivors of pediatric brain tumor, though socioeconomic status emerged as a strong significant predictor of adaptive functioning domains.

Conclusions

Adaptive outcomes do not differ as a function of ethnicity after accounting for primary caregiver education and family income. Racial and ethnic minorities may be at increased risk for poorer outcomes given their overrepresentation at lower income levels. Assessing demographic and treatment‐related variables early on may be helpful in identifying children likely to develop adaptive difficulties.
Neurocognitive and psychological effects of persistent pain in pediatric sickle cell disease
Authors: Connolly Megan E. , Bills Sarah E. , Hardy Steven J.
Published: May 2019

Background

Pain is a major complication of sickle cell disease (SCD), spanning vaso‐occlusive crises and persistent pain. Although it is known that persistent pain is associated with considerable impairment in youth without SCD, little is known about the functional effects of persistent pain in SCD. The current study aimed to (a) characterize persistent pain in youth with SCD and (b) determine the extent to which youth with SCD and persistent pain differ in disease morbidity, functional impairment, and neurocognitive and psychological functioning.

Procedure

Eighty‐nine participants (ages 7‐16) and caregivers completed questionnaires (BRIEF [Behavior Rating Inventory of Executive Function], Conners‐3 [Conners—third edition], and PedsQL™‐SCD Module, where PedsQL is Pediatric Quality of Life Inventory). Participants completed neurocognitive tests WISC‐V [Wechsler Intelligence Scale for Children‐fifth edition], WJ‐III [Woodcock Johnson Tests of Achievement—third edition], and WIAT‐III [Wechsler Individual Achievement Test—third edition]). Youth were classified as having persistent pain if they reported daily pain for 7 days. Chi‐square and independent sample t‐test analyses were used to assess group differences (those with vs without persistent pain).

Results

Patients with persistent pain (n = 18) reported lower health‐related quality of life (P = .000). Caregivers were more likely to rate youth with persistent pain as having lower planning/organization abilities (P = .011) and clinically elevated symptoms of defiance/aggression and oppositional defiance (Ps = .00; .01). Patients with persistent pain demonstrated poorer working memory (P = .023) and processing speed (P = .027), and fewer demonstrating reading fluency abilities in the average or above range (P = .026).

Conclusions

Youth with SCD and persistent pain are at risk for psychosocial and neurocognitive impairments, suggesting that persistent pain may be an important indicator of disease burden. Furthermore, disease management may be enhanced by assessing cognitive and psychosocial functioning and incorporating interdisciplinary treatments addressing impairment associated with persistent pain.
Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma
Authors: Morrell Miriam B. G. , Alvarez‐Florez Claudia , Zhang Aiqian , Kleinerman Eugenie S. , Savage Hannah , Marmonti Enrica , Park Minjeong , Shaw Angela , Schadler Keri L.
Published: May 2019

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.