bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular detection of porcine reproductive and respiratory syndrome virus, porcine circovirus 2 and hepatitis E virus in oral fluid compared to their detection in faeces and serum
Authors: Plut Jan , Jamnikar-Ciglenecki Urska , Stukelj Marina
Published: May 2020

Background

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), Porcine Circovirus Type 2 (PCV2) and Hepatitis E virus (HEV) are common and economically important viral disease causative agents detected in pig oral fluid (OF), faeces and serum at some infection stages. The purpose of this study was to detect PRRSV, PCV2 and HEV on six pig farms to determine which of the three sample types, OF, faeces or serum is appropriate for the diagnosis of these viruses in different pig categories.

The following pig categories were included: 5 weeks-old (w/o), 7 w/o, 9 w/o, 11 w/o weaners, fatteners and breeding sows. Pursuant to the preliminary detection of each pathogen at the selected farms, OF samples, faeces, serum pools and 10 individual sera were examined, using PCR, for each age category. If any of the viruses were found in pools of faeces and OF, then faeces and OF from positive farms were tested separately for each pig category. The viral nucleic acids were detected using RT-PCR, PCR and real-time RT-PCR, for PRRSV, PCV2 and HEV respectively.

Results

PRRSV and HEV were detected on one farm and PCV2 on three others, positive results being more often obtained from the OF than from the faeces of the same animals. Ten individual serum samples from pigs from the same group of animals were also tested. The viruses were detected in almost all individual sera and OF in the same pig category with some exceptions: PRRSV was detected in the OF of fatteners but was absent in their sera; on Farm 2, PCV2 was detected in sera of 11 w/o pigs and fatteners but absent in group samples of their OF and, vice versa, in case of 9 w/o animals; HEV was detected in the OF of the youngest, 5 w/o weaners and absent in sera of the same age group.

Conclusions

The primary finding of the study is that OF is a welfare-friendly, non-invasive and highly efficient matrix for pathogen detection, thus evidencing the usefulness of pig OF as a matrix in which each of the three viruses considered can be detected with the highest probability.
Measuring the impact of sea surface temperature on the human incidence of Vibrio sp. infection in British Columbia, Canada, 1992–2017
Authors: Galanis Eleni , Otterstatter Michael , Taylor Marsha
Published: May 2020

Background

Vibrio growth in the environment is related to sea surface temperature (SST). The incidence of human Vibrio illness increased sharply in British Columbia (BC) between 2008 and 2015 for unknown reasons, culminating in the largest outbreak of shellfish-associated Vibrio parahaemolyticus (Vp) in Canadian history in 2015. Our objective was to assess the relationship between SST and Vibrio illness in BC, Canada during 1992–2017 and assess the role of SST and other environmental factors in the 2015 Vp outbreak.

Methods

Cases of Vibrio infection reported to the BC Centre for Disease Control during 1992–2017 were used. SST data were obtained from NOAA and NASA. We assessed changes in incidence trend of annual Vibrio cases during 1992–2017 using a Poisson regression. We assessed the correlation between annual Vibrio cases and the average annual maximum SST using a Spearman rank-order correlation. We modeled the association between weekly Vp case counts, SST and other environmental factors during 2007–2017 using a Poisson regression.

Results

There was a significant increase in Vibrio cases between 2008 and 2015 (annual slope = 0.163, P < 0.001). Increased Vibrio incidence was observed in most El Niño years. There was a significant correlation between annual Vibrio cases and maximum SST from 1992 to 2017 (r = 0.46, P = 0.018). Our model captured observed seasonal variation in shellfish-associated Vp in most years, but underestimated the 2015 Vp outbreak.

Conclusions

Vibrio incidence has been increasing concurrently with increasing SST in BC during 2008–2015. The 2015 Vp outbreak was not fully explained by climatic factors and may in part have been associated with other factors. Vp subtyping would be useful in the future to understand the combined effects of SST changes and strain emergence.
Long non-coding RNAs towards precision medicine in gastric cancer: early diagnosis, treatment, and drug resistance
Authors: Yuan Li , Xu Zhi-Yuan , Ruan Shan-Ming , Mo Shaowei , Qin Jiang-Jiang , Cheng Xiang-Dong
Published: May 2020

Gastric cancer is a deadly disease and remains the third leading cause of cancer-related death worldwide. The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%, whereas that of patients with distant metastasis is less than 5%. Surgical resection is the best option for early-stage gastric cancer, while chemotherapy is mainly used in the middle and advanced stages of this disease, despite the frequently reported treatment failure due to chemotherapy resistance. Therefore, there is an unmet medical need for identifying new biomarkers for the early diagnosis and proper management of patients, to achieve the best response to treatment. Long non-coding RNAs (lncRNAs) in body fluids have attracted widespread attention as biomarkers for early screening, diagnosis, treatment, prognosis, and responses to drugs due to the high specificity and sensitivity. In the present review, we focus on the clinical potential of lncRNAs as biomarkers in liquid biopsies in the diagnosis and prognosis of gastric cancer. We also comprehensively discuss the roles of lncRNAs and their molecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastric cancer precision medicine.
Cigarette smoking is associated with high level of ferroptosis in seminal plasma and affects semen quality
Authors: Ou Zhanhui , Wen Qirong , Deng Yu , Yu Yang , Chen Zhiheng , Sun Ling
Published: May 2020

Purpose

The effects of cigarette smoking on male semen quality are controversial, and the molecular mechanisms underlying how cigarette smoking affects semen quality are not clear yet.

Methods

In this study, semen samples from 70 heavy smokers and 75 non-smokers receiving infertility treatment were included. Basic semen parameters in non-smokers and heavy smokers were evaluated. Levels of glutathione (GSH), lipid reactive oxygen species (ROS), iron and GSH-dependent peroxidase 4 (GPX4) protein level were observed in human seminal plasma and in GC-2Spd cells exposed to cigarette smoke condensate (CSC).

Results

Heavy smokers had significantly higher abnormalities (sperm viability and sperm progressive motility) than non-smoking counterparts. Comparing non-smokers group, GSH level was reduced in the group of heavy smokers (P < 0.05). However, the level of lipid ROS and iron were significantly increased (P < 0.05). Besides, GSH level was reduced following treatment with CSC for 24 h, while lipid ROS and iron levels were increased (P < 0.05). However, the levels were reduced after being co-cultured with Ferrostatin-1 (Fer-1) (P < 0.05). The level of GPX4 protein was reduced after being treated with CSC in 24 h, and increased after being co-cultured with Fer-1(P < 0.05).

Conclusion

Cigarette smoking is associated with high level of ferroptosis in seminal plasma and affect semen quality.
Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study
Authors: Mané Camille , Delmas Clément , Porterie Jean , Jourdan Géraldine , Verwaerde Patrick , Marcheix Bertrand , Concordet Didier , Georges Bernard , Ruiz Stéphanie , Gandia Peggy
Published: May 2020

Background

Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of ceftolozane-tazobactam.

Methods

An ex vivo model (closed-loop ECMO circuits primed with human whole blood) was used to study adsorption during 8-h inter-dose intervals over a 24-h period (for all three ceftolozane/tazobactam injections) with eight samples per inter-dose interval. Two different dosages of ceftolozane/tazobactam injection were studied and a control (whole blood spiked with ceftolozane/tazobactam in a glass tube) was performed. An in vivo porcine model was developed with a 1-h infusion of ceftolozane–tazobactam and concentration monitoring for 11 h. Pigs undergoing ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (non-compartmental analysis and non-linear mixed effects modelling) was performed to determine the influence of ECMO.

Results

With the ex vivo model, variations in concentration ranged from − 5.73 to 1.26% and from − 12.95 to − 2.89% respectively for ceftolozane (concentrations ranging from 20 to 180 mg/l) and tazobactam (concentrations ranging from 10 to 75 mg/l) after 8 h. In vivo pharmacokinetic exploration showed that ECMO induces a significant decrease of 37% for tazobactam clearance without significant modification in the pharmacokinetics of ceftolozane, probably due to a small cohort size.

Conclusions

Considering that the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam is not clinically significant, normal ceftolozane and tazobactam dosing in critically ill patients should be effective for patients undergoing ECMO.
Three-dimensional morphological analysis of the femoral neck torsion angle—an anatomical study
Authors: Zhang Ru-Yi , Su Xiu-Yun , Zhao Jing-Xin , Li Jian-Tao , Zhang Li-Cheng , Tang Pei-Fu
Published: May 2020

Background

The femoral neck torsion angle (FNTA) is an important but often neglected parameter in assessments of the anatomical morphology of the femoral neck, which is often confused with the femoral neck anteversion angle (FNAA) in the current literature. Currently, the measurement methods reported in the literature all adopt the naked eye or two-dimensional (2D) visualization method, and the measurement parameters and details are not clearly defined. The objection of this research was to provide a reliable 3D method for determining the femoral neck axis, to improve the measurement method of the FNTA, and to analyze the anatomical and clinical significance of the results.

Methods

Computed tomography (CT) data of 200 patients who received a lower extremity CT angiography examination were selected, and the bilateral femurs were reconstructed with three dimensional CT (3D CT). First, the 3D axis of the femoral neck was built. Second, the long axis of the cross section the femoral neck isthmus (FNI) and femoral neck basilar part (FNB) were confirmed by the “inertia axes” method, and the plane consisting of the long axis of the cross-section and the center of the femoral head was defined as the long axial plane. Third, the coronal plane of the proximal femur was determined through the long axis of the proximal femur and the femoral coronal. Finally, the FNTAs (the angles between the long axial planes and the coronal plane of the proximal femur) of FNI and FNB were measured. The size of FNTA was compared between the sexes and sides and different locations, the correlation between the parameters and age, height, and weight were evaluated.

Results

The difference in FNTA was statistically significant between the isthmus and the basilar part (isthmus 30.58 ± 8.90° vs. basilar part 23.79 ± 3.98°; p < 0.01). Significant difference in the FNTA was observed between the sexes (males 31.99 ± 9.25° vs. females 27.49 ± 7.19°; p < 0.01). The increase in FNTA from the basilar part to the isthmus was 6.79 ± 8.06°, and the male (7.87 ± 8.57°) was greater than the female (4.44 ± 6.23°, p < 0.01). However, no significant difference in the values was observed between sides. Height exerted the greatest effect on the FNTA according to the correlation analysis (r = 0.255, p< 0.001).

Conclusions

This study found a reliable 3D method for the determination of the femoral neck axis improved the measurement method of the FTNTA and made it more accurate and repeatable. The results provided a methodological basis and theoretical support for the research and development of internal fixation device for femoral neck fracture and the spatial configuration of implants in treatment. And the optimal opening point of the femoral medullary cavity was recommended to locate at the posterior position of the top of the femoral neck cross-section during hip replacement.
Learning curve associated with thoraco-laparoscopic esophagectomy for esophageal cancer patients in the prone position
Authors: Wang Tao , Ma Mu-yuan , Wu Bo , Zhao Yang , Ye Xiao-feng , Li Tao
Published: May 2020

Objective

To observe the surgical index at the different learning stages of thoraco-laparoscopic esophagectomy in the prone position for esophageal cancer and to investigate the learning curve of this surgical procedure.

Methods

Sixty thoraco-laparoscopic esophagectomies in the prone position for esophageal cancer conducted by the same group of surgeons between January 2014 and December 2015 were retrospectively analyzed. The surgeries were divided into 5 groups, A, B, C, D, and E, in chronological order. The duration of surgery, intraoperative blood loss, total number of lymph nodes removed, rate of the intraoperative conversion to open surgery, complication rate, and length of postoperative hospitalization were recorded and analyzed.

Results

The general information of the patients did not significantly differ among the 5 groups (P > 0.05). The duration of surgery, intraoperative blood loss, number of lymph node removed, rate of intraoperative conversion to open surgery, and number of injuries to the recurrent laryngeal nerve all significantly differed (P < 0.05). The rates of postoperative pulmonary infection, anastomotic fistula, pneumothorax, and hospitalization did not significantly differ (P > 0.05).

Conclusion

Thoracic physicians with some endoscopic experience can meet the requirements of the thoraco-laparoscopic esophagectomy in the prone position for esophageal cancer after completing 24–30 surgeries.
Molecular delineation of small supernumerary marker chromosomes using a single nucleotide polymorphism array
Authors: Zhou Lili , Zheng Zhaoke , Wu Lianpeng , Xu Chenyang , Wu Hao , Xu Xueqin , Tang Shaohua
Published: May 2020

Background

Defining the phenotype-genotype correlation of small supernumerary marker chromosomes (sSMCs) remains a challenge in prenatal diagnosis. We karyotyped 20,481 amniotic fluid samples from pregnant women and explored the molecular characteristics of sSMCs using a single nucleotide polymorphism (SNP) array.

Results

Out of the 20,481 samples, 15 abnormal karyotypes with sSMC were detected (frequency: 0.073%) and the chromosomal origin was successfully identified by SNP array in 14 of them. The origin of sSMCs were mainly acrocentric-derived chromosomes and the Y chromosome. Two cases of sSMC combined with uniparental disomy (UPD) were detected, UPD(1) and UPD(22). More than half of the cases of sSMC involved mosaicism (8/15) and pathogenicity (9/15) in prenatal diagnosis. A higher prevalence of mosaicism for non-acrocentric chromosomes than acrocentric chromosomes was also revealed. One sSMC derived from chromosome 3 with a neocentromere revealed a 24.99-Mb pathogenic gain of the 3q26.31q29 region on the SNP array, which presented as an abnormal ultrasound indicating nasal bone hypoplasia.

Conclusion

The clinical phenotypes of sSMCs are variable and so further genetic testing and parental karyotype analysis are needed to confirm the characteristics of sSMCs. The SNP array used here allows a detailed characterisation of the sSMC and establishes a stronger genotype-phenotype correlation, thus allowing detailed genetic counselling for prenatal diagnosis.
Microbiota-driven interleukin-17 production provides immune protection against invasive candidiasis
Authors: Li Mengmeng , Li Congya , Wu Xianan , Chen Tangtian , Ren Lei , Xu Banglao , Cao Ju
Published: May 2020

Background

The intestinal microbiota plays a crucial role in human health, which could affect host immunity and the susceptibility to infectious diseases. However, the role of intestinal microbiota in the immunopathology of invasive candidiasis remains unknown.

Methods

In this work, an antibiotic cocktail was used to eliminate the intestinal microbiota of conventional-housed (CNV) C57/BL6 mice, and then both antibiotic-treated (ABX) mice and CNV mice were intravenously infected with Candida albicans to investigate their differential responses to infection. Furthermore, fecal microbiota transplantation (FMT) was applied to ABX mice in order to assess its effects on host immunity against invasive candidiasis after restoring the intestinal microbiota, and 16S ribosomal RNA gene sequencing was conducted on fecal samples from both uninfected ABX and CNV group of mice to analyze their microbiomes.

Results

We found that ABX mice displayed significantly increased weight loss, mortality, and organ damage during invasive candidiasis when compared with CNV mice, which could be alleviated by FMT. In addition, the level of IL-17A in ABX mice was significantly lower than that in the CNV group during invasive candidiasis. Treatment with recombinant IL-17A could improve the survival of ABX mice during invasive candidiasis. Besides, the microbial diversity of ABX mice was significantly reduced, and the intestinal microbiota structure of ABX mice was significantly deviated from the CNV mice.

Conclusions

Our data revealed that intestinal microbiota plays a protective role in invasive candidiasis by enhancing IL-17A production in our model system.
Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer
Authors: Kim Hee Jeong , Noh Woo Chul , Lee Eun Sook , Jung Yong Sik , Kim Lee Su , Han Wonshik , Nam Seok Jin , Gong Gyung -Yub , Kim Hwa Jung , Ahn Sei Hyun
Published: May 2020

Introduction

Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer.

Patients and methods

In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints.

Results

A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6–44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4–24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group.

Conclusions

Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET.

Trial registration

Clinicaltrials.gov, NCT01622361. Registration June 19, 2012.
Managing clustering effects and learning effects in the design and analysis of multicentre randomised trials: a survey to establish current practice
Authors: Conroy Elizabeth J. , Blazeby Jane M. , Burnside Girvan , Cook Jonathan A. , Gamble Carrol
Published: May 2020

Background

Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional’s skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials.

Methods

A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate.

Results

Forty-four Units participated (N = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis (n = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided.

Conclusions

Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered.
Glioma patients in outpatient care—optimization of psychosocial care in neuro-oncological patients (GLIOPT): Protocol for a cluster randomized controlled trial
Authors: Renovanz Mirjam , Hippler Melina , Voss Martin , Wehinger Jens , Keßler Almuth F. , Gempt Jens , Nadji-Ohl Minou , Weiß Lucas Carolin , Rapp Marion , Misch Martin , Coburger Jan , Mehlitz Marcus , Meixensberger Jürgen , Keric Naureen , Tabatabai Ghazaleh , Blettner Maria , Schranz Melanie , Singer Susanne
Published: May 2020

Background

Patients with high-grade gliomas (HGG) often suffer from high distress and require psychosocial support. However, due to neurological and neurocognitive deficits, adequate assessment of distress and support needs remains challenging in clinical practice. The objective of the present study is to investigate whether a systematic implementation of signaling questions into the routine outpatient consultation will be helpful to bridge this gap.

Methods/design

This is a multicenter cluster randomized study with two arms. Randomization is done on a cluster level with 13 hospitals providing regular neuro-oncological outpatient services conducted by neurologists and/or neurosurgeons. The intervention will include an assessment of psychosocial distress of patients in doctor–patient conversation compared to assessment of psychosocial distress via questionnaire (control, standard of care).

In total, 616 HGG patients will be enrolled. The outcome will be the number of HGG patients with increased psychosocial distress who receive professional support from psychosocial services.

Secondary endpoints are inter alia number of patients reporting psychosocial distress and unmet needs detected correctly by the respective method; quality of life; psychological well-being and burden of the patients before and after doctor–patient consultation; as well as the length of the doctor–patient consultation.

Discussion

Patients with HGG are confronted with an oncological diagnosis and at the same time with high symptom burden. This often leads to distress, which is not always adequately recognized and treated. So far, only a limited number of adequate instruments are available to assess HGG patient’s distress. Yet, an adequate care and support network might facilitate the course of the disease and tumor therapies for patients. Our hypothesis is that an assessment conducted directly by attending doctors and in which the doctors talk to patients with HGG will be more effective than an assessment via a questionnaire, leading to better identifying patients in need of support. This may lead to an improvement of health care in these patients. Further, this method might be implemented also in other brain tumor patients (e.g., patients with brain metastases).

Trial registration

German Clinical Trials Register, DRKS00018079. Registered on 3rd September 2019.
Urinary activated leukocyte cell adhesion molecule as a novel biomarker of lupus nephritis histology
Authors: Ding Huihua , Lin Cheng , Cai Jingyi , Guo Qiang , Dai Min , Mohan Chandra , Shen Nan
Published: May 2020

Background

Lupus nephritis (LN) is one of the most severe complications of SLE patients. We aim to validate urinary ALCAM as a biomarker in predicting renal disease histpathology in a Chinese lupus cohort.

Methods

In this cross-sectional study, a total of 256 patients and controls were recruited. Urinary levels of ALCAM were determined by ELISA. Renal histopathology was reviewed by an experienced renal pathologist.

Results

Urinary ALCAM levels were significantly increased in active LN patients when compared to active SLE patients without renal involvement (p < 0.001), inactive LN patients (p = 0.023), inactive SLE patients without renal involvement (p < 0.001), and healthy controls (p < 0.001). Correlation analysis revealed a positive correlation between urinary ALCAM and general disease activity—SLEDAI score (r = 0.487, p < 0.001), as well as renal disease activity—rSLEDAI (r = 0.552, p < 0.001) and SLICC RAS (r = 0.584, p < 0.001). Urinary ALCAM also correlated with lab parameters including 24-h urine protein, hemoglobin, and complement 3. Moreover, urinary ALCAM levels were significantly increased in class III and IV (proliferative) LN as compared to those in class V (membranous) LN. It outperformed conventional biomarkers (anti-dsDNA antibody, C3, C4, proteinuria) in discriminating the two groups of LN. On renal histopathology, urinary ALCAM levels correlated positively with activity index (r = 0.405, p < 0.001) but not chronicity index (r = 0.079, p = 0.448).

Conclusion

Urinary ALCAM is a potential biomarker for predicting renal pathology activity in LN and may serve as a valuable surrogate marker of renal histopathology.
Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors
Authors: Varderidou-Minasian Suzy , Hinz Lisa , Hagemans Dominique , Posthuma Danielle , Altelaar Maarten , Heine Vivi M.
Published: May 2020

Background

Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages.

Methods

To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development.

Results

We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed.

Limitations

The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms.

Conclusions

During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3–4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome.
Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury
Authors: Cao Jingyuan , Wang Bin , Tang Taotao , Lv Linli , Ding Zhaoying , Li Zuolin , Hu Ruoyu , Wei Qing , Shen Anran , Fu Yuqi , Liu Bicheng
Published: May 2020

Background

Exosomes derived from mesenchymal stem cells (MSC-exos) have been demonstrated with great potential in the treatment of multiple human diseases including acute kidney injury (AKI) by virtue of their intrinsic cargoes. However, there are major challenges of low yield and the lack of an established biomanufacturing platform to efficiently produce MSC-exos, thereby limiting their therapeutic application. Here, we aimed to establish a novel strategy to produce MSC-exos with a hollow fiber bioreactor-based three-dimensional (3D) culture system and evaluate the therapeutic efficacy of 3D-exosomes (3D-exos) on AKI.

Methods

Mesenchymal stem cells (MSCs) were isolated from fresh human umbilical cord and cultured in two-dimensional (2D) flasks. 2 × 108MSCs were inoculated into the hollow fiber bioreactor for 3D culture. The culture supernatants were collected every 1 or 2 days for isolating exosomes. Exosomes from 2D (2D-exos) and 3D cultures were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting analysis of exosome markers. The yield of exosomes from 2 × 108MSCs seeded in 2D and 3D culture system was compared, based on protein quantification. The therapeutic efficacy of 2D-exos and 3D-exos was investigated in a murine model of cisplatin-induced AKI in vivo and in vitro.

Results

3D culture did not significantly change the surface markers of MSCs, as well as the morphology, size, and exosomal markers of 3D-exos when compared to those of 2D-exos. Compared with conventional 2D culture, the 3D culture system increased total exosome production up to 19.4-fold. 3D-exos were more concentrated in the harvested supernatants (15.5-fold) than 2D-exos, which led to a higher exosome collection efficiency of 3D culture system. In vivo,both 2D-exos and 3D-exos significantly alleviated cisplatin-induced murine AKI evidenced by improved renal function, attenuated pathological changes of renal tubules, reduced inflammatory factors, and repressed T cell and macrophage infiltration. Impressively, 3D-exos were more effective than 2D-exos. Moreover, 3D-exos were taken up by tubular epithelial cells (TECs) with improved efficiency, thereby exhibiting superior anti-inflammatory effect and improved viability of TECs in vitro.

Conclusions

In summary, our findings demonstrate that the hollow fiber 3D culture system provides an efficient strategy for the continuous production of MSC-exos which has enhanced therapeutic potential for cisplatin-induced AKI.
The influence of fear effect to the Lotka–Volterra predator–prey system with predator has other food resource
Authors: Zhu Zhenliang , Wu Runxin , Lai Liyun , Yu Xiangqin
Published: May 2020

A Lotka–Volterra predator–prey system incorporating fear effect of the prey and the predator has other food resource is proposed and studied in this paper. It is shown that the trivial equilibrium and the predator free equilibrium are both unstable, and depending on some inequalities, the system may have a globally asymptotically stable prey free equilibrium or positive equilibrium. Our study shows the fear effect is one of the most important factors that lead to the extinction of the prey species. Such a finding is quite different from the known result. Numeric simulations are carried out to show the feasibility of the main results.
A preconditioned fast collocation method for a linear bond-based peridynamic model
Authors: Zhang Xuhao , Li Xiao , Cheng Aijie , Wang Hong
Published: May 2020

We develop a fast collocation method for a static bond-based peridynamic model. Based on the analysis of the structure of the stiffness matrix, a fast matrix-vector multiplication technique was found, which can be used in the Krylov subspace iteration method. In this paper, we also present an effective preconditioner to accelerate the convergence of the Krylov subspace iteration method. Using the block-Toeplitz–Toeplitz-block (BTTB)-type structure of the stiffness matrix, we give a block-circulant-circulant-block (BCCB)-type preconditioner. The numerical experiments show the utility of the preconditioned fast collocation method.
Fractional operators for the Wright hypergeometric matrix functions
Authors: Abdalla M.
Published: May 2020

In this paper, we contribute to the results of Bakhet et al. (Integral Transforms Spec. Funct. 30:138–156, 2019) by applying fractional operators to the Wright hypergeometric matrix functions. We give matrix recurrence relations and integral formulas for the Wright hypergeometric matrix functions. We also clarify particular cases of the main results.
Interactions between abiotic factors and the bioactivity of biodynamic horn manure on the growth of garden cress (Lepidium sativum L.) in a bioassay
Authors: Morau Alain , Piepho Hans-Peter
Published: May 2020

Background

The use of biostimulants like humic substances is a promising innovative approach in agriculture to activate and sustain physiological plant processes. The development of specific bioassays is required to study their bioactivity in laboratory conditions. In previous investigations, a soil-less bioassay with cress seedlings (Lepidium sativumL.) was developed for a biostimulant used in the biodynamic agriculture, the horn-manure preparation (HMP), a fermented cow manure sprayed at low concentrations onto fields. Objectives of the present study were to refine the bioassay by investigating the interactions between the HMP bioactivity and the test factors (i) water volume, (ii) gravistimulation, and (iii) exposure to fluorescent light.

Results

The interactions between the test factors and the HMP treatment were significant in all series (p < 0.05, WaldF-test). Water overdose and gravitropic stress reduced root growth (down to − 24.2% and − 19.9%, respectively,p < 0.0001, Tukey–Kramer test). The HMP treatment partly compensated these effects by enhancing root growth by (i) water overdose (up to + 4.3%,p = 0.048,n = 4), and (ii) gravitropic stress (up to + 9.5%,p = 0.0004,n = 8). (iii) Furthermore, under the combined stress factors, fluorescent light exposure enhanced the HMP enhancing effect (up to + 12.3%,p = 0.007,n = 6).

Conclusions

The HMP bioactivity appeared to consist of a compensatory mode of action regarding the stress factors water overdose and gravistimulation, and a synergetic interaction with fluorescent light exposure. The HMP seems to interact with the plant sensory systems, likely stimulating the plant’s adaptability to its environment by increasing self-regulating processes. The bioassay sensitivity was successfully increased by integrating these interactions in the experimental set-up and adjusting the growth environment. This approach can be used to adjust the bioassay to other biostimulants.
A cultural comparison of Persian and English short stories regarding the use of emotive words: implications for teaching English to Iranian young learners
Authors: Namaziandost Ehsan , Nasri Mehdi , Rahimi Esfahani Fariba , Neisi Leila , Ahmadpour KarimAbadi Farahnaz
Published: May 2020

Using a contrastive analysis approach, this study aimed to study emotive words (EWs) in Persian and English short stories for children. It actually tries to find the similarities and differences between the two languages in terms of using emotive words based on different types and tokens of emotions introduced by Wierzbicka (Emotions across cultures: Diversity and universality, 1999) and Devon (The origin of emotions, 2006). Additionally, it sought to investigate the impact of teaching emotive narratives on the learners’ practical knowledge of controlling emotions. To fulfill this objective, 20 short stories with similar length and level of difficulty were randomly selected, 10 in English and l0 in Persian, and 35 lines of each story were investigated to identify and classify their EWs based on the two models employed for classification. To examine the extent of similarities and differences between the frequency of EWs used in English and Persian short stories, a Chi-square test was run. The results revealed that there was not a significant difference between the two groups of stories in terms of emotion tokens; however, a significant difference was found between the frequency of EWs used in English and Persian short stories concerning different types of emotion. In the second phase of the study, emotive short stories were explicitly taught to a sample of 25 EFL learners; a DCT was utilized as the pre-test and post-test to find if learners’ practical knowledge would improve in the wake of this intervention. The findings revealed a significant improvement in the practical understanding of the participants after being exposed to the instruction of emotive narratives. The results also demonstrated that literature-based activities containing emotional cues could improve young learners’ practical knowledge required for controlling their emotions.
Simulcast: a case study in the establishment of a virtual community of simulation practice
Authors: Symon Benjamin , Spurr Jesse , Brazil Victoria
Published: May 2020

Virtual Communities of Practice (vCoP) is a nascent approach to professional development for simulation educators (Thoma et al., Simul Healthc. 2018;13(2):124-30). vCoPs overcome geographic barriers to accessing expertise and professional networks and may promote ‘democratisation’ of voices in the simulation community. However, the optimal process for creating, nurturing and joining vCoPs in healthcare simulation is not well understood.

We report on the establishment of our healthcare simulation hybrid podcast/blog—Simulcast (www.simulationpodcast.com)—utilising the conceptual framework of Wenger’s three dimensions of Communities of Practice. In exploring these dimensions—joint enterprise, mutual engagement and shared repertoire—we hope to contextualise vCoP within professional development approaches for simulation faculty and invite readers to engage with our existing community.
The effect of nocturnal epileptic seizures on cognitive functions in children with idiopathic epilepsy
Authors: Al-Malt Ayman M. , Abo Hammar Shereen A. , Rashed Khaled H. , Ragab Osama A.
Published: May 2020

Background

Cognitive impairment is a common finding epileptic children. Studies have linked nocturnal epileptic discharges to delayed cognitive abilities in children.

Objective

The study aims to evaluate the effect of nocturnal epileptic seizures on cognitive functions in children with idiopathic epilepsy.

Patients and methods

The study was conducted on 70 children with idiopathic generalized or benign focal epilepsy. Based on seizures semiology, they were classified into cases either with nocturnal epileptic seizures (NES) (n = 40) or with diurnal epileptic seizures (DES) (n = 30). Patients receiving antiepileptic drugs (AEDs) that affect cognitive function, patients with intelligence quotient (IQ) below 70, and those having other neurological or psychiatric disorders' were excluded. All patients were subjected to neurological examination, brain magnetic resonance imaging (MRI), and electroencephalography. Cognition was assessed using Wechsler Intelligence scale for children (WISC) to measure IQ, Wisconsin card sorting test (WCST) (computerized version), Trail Making Test, and Digit spans test.

Results

There was no significant difference between both groups regarding age, sex, age of epilepsy onset, or seizure frequency. There was a significant difference in almost all cognitive variables including digit forward, digit backward, processing speed, verbal IQ, WCST perseverative responses, WCST failure to maintain set, Trail Making Test A (error), Trail Making Test B (Time), and Trail Making Test B (error). There was no significant difference regarding the associated sleep disturbances between the studied groups.

Conclusion

Children with idiopathic epilepsy suffering from predominant nocturnal seizure have overt and subtle cognitive functions impairments compared to children with predominant diurnal seizure.
Pharmacist-Driven Oral Oncolytic Medication Education and Consent
Authors: Bowles Harmony , Tawfik Bernard , Abernathy Janet , Lauer Richard , Hashemi Neda , Dayao Zoneddy
Published: May 2020

PURPOSE:

The numbers and types of oral oncolytics in oncology are expanding rapidly. Oral oncolytics have serious adverse effects, and pharmacist-driven patient education has the potential to reduce adverse events. The University of New Mexico Comprehensive Cancer Center (UNM CCC) initiated a patient education and consent process for oral oncolytics in our minority, rural, and economically disadvantaged population.

PATIENTS AND METHODS:

The UNM CCC initiated a pharmacist-driven education and consent process from August 2016 to October 2018. The process metric measured via statistical process control charts was the percentage of patients receiving oral oncolytic therapy who were educated and consented. The balancing metric was time for benefit investigation. The intervention was pharmacy team members providing standardized education for and obtaining consent from each patient, supported by electronic medical record orders, physician education, pharmacy notifications, and hospital discharge planning.

RESULTS:

The initial monthly education and consent rate was 17.9%, followed by 45.5% the subsequent month. This quickly grew to an average of 87.0% (95% CI, 81.5% to 92.4%) for the subsequent 15 months in which control was achieved. Additional changes increased the education rate to 95.7% (95% CI, 93.4% to 98.1%). These 2 periods were statistically different ( P = .0025). There was no change in time for benefit investigation (5.60 v 5.52 days; P = .75).

CONCLUSION:

A pharmacist-driven program for education and consent upon initiation of oral oncolytics is possible and can successfully educate a majority of patients. Future directions will include ensuring patient adherence and educating patients who fill oral oncolytic prescriptions outside UNM CCC.
EV PD-L1 is Correlated With Clinical Features and Contributes to T Cell Suppression in Pediatric Thyroid Cancer
Authors: Wang Guoliang , He Lejian , Wang Shengcai , Zhang Meng , Li Yanzhen , Liu Qiaoyin , Sun Nian , Zhang Xuexi , Liu Yuwei , Zhang Jie , Tai Jun , Ni Xin
Published: May 2020

Context

The contribution of blood extracellular vesicular (EV) programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) in papillary thyroid cancer (PTC) is uncertain.

Objective

We sought to determine the relationship of EV PD-L1/PD-1 with the clinical features of pediatric PTC and the role of EV PD-L1 in immunosuppression.

Main Outcome Measures

Plasma levels of EV and soluble PD-L1 and PD-1 and levels of plasma cytokines in children with PTC and controls were determined by enzyme-linked immunosorbent assay. Levels of tumor PD-L1 and the tumor-infiltrating lymphocyte (TIL) score were determined by immunohistochemistry. Correlations of the plasma PD-L1/PD-1 level with clinicopathological characteristics, levels of plasma cytokines, tumor PD-L1 expression, and TIL score were analyzed. T-cell suppression by EVs from PTC patients was determined by incubation of PD-L1high or PD-L1low EVs with activated CD8+ T cells. Changes in CD69 and PD-1 expression and changes in tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) secretion were measured by flow cytometry.

Results

The levels of plasma PD-L1/PD-1 were significantly higher in children with PTC than in controls. The levels of plasma EV PD-L1 significantly correlated with tumor T stage, tumor PD-L1 expression, TIL score, and plasma cytokine content. Levels of plasma soluble PD-1 significantly correlated with patient age, plasma EV PD-L1, and IFNα concentration. PD-L1high EVs significantly inhibited the activation of CD8+ T cells.

Conclusions

Plasma levels of EV PD-L1, but not soluble PD-L1, were associated with tumor T stage in children with PTC. Plasma EV PD-L1 emerges as a useful metric for assessing tumor T stage and T cell suppression in PTC.
GIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists
Authors: Holst Jens Juul , Rosenkilde Mette Marie
Published: May 2020

The 2 hormones responsible for the amplification of insulin secretion after oral as opposed to intravenous nutrient administration are the gut peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, whereas GLP-1 also inhibits appetite and food intake and improves glucose regulation in patients with type 2 diabetes (T2DM), GIP seems to be devoid of these activities, although the 2 hormones as well as their receptors are highly related. In fact, numerous studies have suggested that GIP may promote obesity. However, chimeric peptides, combining elements of both peptides and capable of activating both receptors, have recently been demonstrated to have remarkable weight-losing and glucose-lowering efficacy in obese individuals with T2DM. At the same time, antagonists of the GIP receptor have been reported to reduce weight gain/cause weight loss in experimental animals including nonhuman primates. This suggests that both agonists and antagonist of the GIP receptor should be useful, at least for weight-losing therapy. How is this possible? We here review recent experimental evidence that agonist-induced internalization of the two receptors differs markedly and that modifications of the ligand structures, as in co-agonists, profoundly influence these cellular processes and may explain that an antagonist may activate while an agonist may block receptor signaling.