bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Effectiveness and Safety of Infliximab and Golimumab in Ankylosing Spondylitis Patients from a Canadian Prospective Observational Registry
Authors: Rahman Proton , Starr Michael , Haaland Derek , Bessette Louis , Teo Michelle , Rampakakis Emmanouil , Lehman Allen J , Nantel Francois
Published: August 2020

Background: The objectives of this study were to describe the profile of ankylosing spondylitis (AS) patients treated with either infliximab (IFX) or subcutaneous golimumab (GLM) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety. Methods: AS patients who were eligible for treatment with IFX or subcutaneous GLM as per their respective Canadian product monographs were enrolled into the BioTRAC registry from 2005-2017. The study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in clinical outcomes and acute phase reactants. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates. Results: A total of 389 IFX- and 421 GLM-treated patients were enrolled. A significant decrease in disease duration at baseline was observed in the IFX cohort, from a median of 8.0 in 2005-2008 to 1.0 years in 2009-2015 (p<0.001). A reduction in baseline BASFI score (p=0.011) and proportion of patients in ASDAS very high disease activity (p=0.004) was also observed over time. Meanwhile, in the GLM cohort, most disease parameters remained similar from 2010-2017.Treatment with both agents significantly improved all disease parameters over time with similar efficacy between the two agents. The incidence of AEs and SAEs were 136 and 131 events/100 PYs and 10.5 and 8.45 events/100 PYs for IFX- and GLM-treated patients, respectively. Conclusion: Both IFX and GLM treatment in AS significantly reduced disease activity in most outcome measures in a similar fashion and were well tolerated in Canadian routine care. Trial Registration: NCT00741793
Host phylogeny matters: Examining sources of variation in infection risk by blood parasites across a tropical montane bird community in India
Authors: Gupta Pooja , Vishnudas C.K. , Robin V.V. , Dharmarajan Guha
Published: August 2020

Background: Identifying patterns and drivers of infection risk among host communities is crucial to elucidate disease dynamics and predict infectious disease risk in wildlife populations. Blood parasites of genera Plasmodium and Haemoproteus are a diverse group of vector-borne protozoan parasites that affect bird populations globally. Despite their widespread distribution and exceptional diversity, factors underlying haemosporidian infection risk in wild bird communities remain poorly understood. While some studies have examined variation in avian haemosporidian risk, researchers have primarily focused on host ecological traits without considering host phylogenetic relationships. In this study, we employ a phylogenetically informed approach to examine the association between host ecological traits and haemosporidian infection risk in endemic bird communities in the Western Ghats Sky Islands.Methods: We used parasite sequence data based on partial mitochondrial cytochrome b gene, that was amplified from genomic DNA extracted from 1177 birds (28 species) across the Western Ghats to assess infection of birds with haemosporidian parasites. We employed a Bayesian phylogenetic mixed effect modelling approach to test whether haemosporidian infection risk was affected by seven species-specific and four individual level ecological predictors. We also examined the effect of host phylogenetic relationships on the observed patterns of variation in haemosporidian infection risk by estimating phylogenetic signal.Results: Our study shows that host ecological traits and host phylogeny differentially influence infection risk by Plasmodium (generalist parasite) and Haemoproteus (specialist parasite). For Plasmodium, we found that sociality, sexual dimorphism and feeding strata were important ecological predictors. For Haemoproteus, patterns of infection risk among host species were associated with sociality, elevation and individual body condition. Interestingly, variance in infection risk explained by host phylogeny was higher for Haemoproteus parasites compared to Plasmodium. Conclusion: Our study highlights that while host ecological traits promoting parasite exposure and host susceptibility are important determinants of infection risk, host phylogeny also contributes substantially to predicting patterns of haemosporidian infection risk in multi- host communities. Importantly, infection risk is driven by joint contributions of host ecology and host phylogeny and studying these effects together could increase our ability to better understand the drivers of infection risk and predict future disease threats.
Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis
Authors: Yan Feili , Zhong Zhirong , Wang Yao , Feng Yue , Mei Zhiqiang , Li Hui , Chen Xiang , Cai liang , Li Chunhong
Published: August 2020

Background: Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration and serious adverse reactions during long-term administration. To achieve better treatment and reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. Results: The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was -22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility.Conclusion: The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.
LncRNA LINC00342 contributes to the growth and metastasis of colorectal cancer via targeting miR-19a-3p/NPEPL1
Authors: Shen Peng , Qu Lili , Wang Jingjing , Ding Quchen , Zhou Chuanwen , Xie Rui , Wang Honggang , Ji Guozhong
Published: August 2020

Background Long intergenic non-protein coding RNA 00342 (LINC00342) has been identified as a novel oncogene. However, the functional role of LINC00342 in colorectal cancer (CRC) remains unclear. Methods The expression of LINC00342 was detected by real-time PCR. Cell proliferation, migration and invasion and xenograft model were examined to analyze the biological functions of LINC00342 in vitro and in vivo. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to identify the target interactions between LINC00342, miR-19a-3p and aminopeptidase like 1 (NPEPL1). Results LINC00342 was highly expressed in CRC. Downregulation of LINC00342 inhibited cell proliferation and metastasis of CRC cells. Moreover, knocking down LINC00342 could weaken the tumor growth in vivo. Mechanistic investigation revealed that LINC00342 might sponge miR-19a-3p to regulate NPEPL1 expression. Further investigation indicated that the oncogenesis facilitated by LINC00342 was inhibited due to the depletion of NPEPL1.Conclusion LINC00342 promoted CRC progression by competitively binding miR-19a-3p with NPEPL1.
Implementation and evaluation of nonclinical interventions for appropriate use of cesarean section in low- and middle-income countries: protocol for a multisite hybrid effectiveness-implementation type III trial
Authors: Dumont Alexandre , Betrán Ana Pilar , Kabore Charles , De Loenzien Myriam , Lumbiganon Pisake , Bohren Meghan , Nhu Hung Mac Quoc , Ph.D. Newton , Carroli Guillermo , Annerstedt Kristi Sidney , Ridde Valery , Escuriet Ramon , Robson Michael , Hansen Claudia , group QUALI-DEC Research
Published: August 2020

Background: While cesarean sections (CSs) are a life-saving intervention, an increasing number are performed without medical reasons in low- and middle-income countries (LMICs). Unnecessary CS diverts scarce resources and thereby reduces access to healthcare for women in need. Argentina, Burkina Faso, Thailand and Vietnam are committed to reducing unnecessary CS, but many individual and organizational factors in healthcare facilities obstruct this aim. Nonclinical interventions can overcome these barriers by helping providers improve their practices and supporting women’s decision-making regarding childbirth. Existing evidence has shown only a modest effect of single interventions on reducing CS rates, arguably because of the failure to design multifaceted interventions effectively tailored to the context. The aim of this study is to design, adapt and test a multifaceted intervention for the appropriate use of CS in Argentina, Burkina Faso, Thailand and Vietnam. Methods: We designed an intervention (QUALIty DECision-making - QUALI-DEC) with four components: (1) opinion leaders at heath care facilities to improve adherence to best practices among clinicians, (2) CS audits and feedback to help providers identify potentially avoidable CS, (3) a decision analysis tool to help women make an informed decision on the mode of birth, and (4) companionship to support women during labor. QUALI-DEC will be implemented and evaluated in 32 hospitals (8 sites per country) using a pragmatic hybrid effectiveness-implementation design to test our implementation strategy, and information regarding its impact on relevant maternal and perinatal outcomes will be gathered. The implementation strategy will involve the participation of women, healthcare professionals and organizations and account for the local environment, needs, resources and social factors in each country.Discussion: There is urgent need for interventions and implementation strategies to optimize the use of CS while improving health outcomes and satisfaction in LMICs. This can only be achieved by engaging all stakeholders involved in the decision-making process surrounding birth and addressing their needs and concerns. The study will generate robust evidence about the effectiveness and the impact of this multifaceted intervention. It will also assess the acceptability and scalability of the intervention and the capacity for empowerment among women and providers alike. Trial registration: ISRCTN67214403
Risk factors for the critical illness in SARS-CoV-2 infection: a multicenter retrospective cohort study
Authors: Cheng Sijing , Wu Dingfeng , Li Jie , Zou Yifeng , Wan Yunle , Shen Lihan , Zhu Lixin , Shi Mang , Hou Linlin , Xu Tao , Jiao Na , Li Yichen , Huang Yibo , Tang Zhipeng , Xu Mingwei , Jiang Shusong , Li Maokun , Yan Guangjun , Lan Ping , Zhu Ruixin
Published: August 2020

Background

Prior studies reported that 5~32% COVID-19 patients were critically ill, a situation that poses great challenge for the management of the patients and ICU resources. We aim to identify independent risk factors to serve as prediction markers for critical illness of SARS-CoV-2 infection.

Methods

Fifty-two critical and 200 non-critical SARS-CoV-2 nucleic acid positive patients hospitalized in 15 hospitals outside Wuhan from January 19 to March 6, 2020 were enrolled in this study. Multivariable logistic regression and LASSO logistic regression were performed to identify independent risk factors for critical illness.

Results

Age older than 60 years, dyspnea, respiratory rate > 24 breaths per min, leukocytosis >9.5 X10 9 /L, neutrophilia >6.3 X10 9 /L, lymphopenia <1.1 X10 9 /L, neutrophil-to-lymphocyte ratio >3.53, fibrinogen >4g/L, d-dimer >0.55 µg/mL, blood urea nitrogen >7.1 mM, elevated aspartate transaminase, elevated alanine aminotransferase, total bilirubin >21 µM, and Sequential Organ Failure Assessment (SOFA) score ≥2 were identified as risk factors for critical illness. LASSO logistic regression identified the best combination of risk factors as SOFA score, age, dyspnea, and leukocytosis. The Area Under the Receiver-Operator Curve values for the risk factors in predicting critical illness were 0.921 for SOFA score, 0.776 for age, 0.764 for dyspnea, 0.658 for leukocytosis, and 0.960 for the combination of the four risk factors.

Conclusions

Our findings advocate the use of risk factors SOFA score ≥2, age >60, dyspnea and leukocytosis >9.5 X10 9 /L on admission, alone or in combination, to determine the optimal management of the patients and health care resources.
Unrecognized Geriatric Depression in the Emergency Department of a Teaching Hospital in Nepal: Prevalence, Contributing Factors, and Metric Properties of 5 item Geriatric Depression Scale in this Population
Authors: Shrestha Roshana , Shrestha Anmol Purna , Shrestha Abha , Kamholz Barbara
Published: August 2020

Background: Depression is prevalent but poorly recognized in the Emergency Department (ED). We aimed to identify the frequency of unrecognized geriatric depression and its possible determinants in the ED using the 15-item geriatric depression scale (GDS). We also aimed to explore the performance of the shorter, five-item GDS as compared to the 15-item GDS.Methods: This was a cross-sectional study of the ED patients ≥ 60 years. The previously validated Nepali version of GDS-15 screened the sample into “no”, “mild-moderate” and “severe" depression using cutoff values of 4/5, and 8/9 respectively. Demographic and socioeconomic factors, comorbidities and health seeking behaviors were studied and the relation was assessed with binary (Chi-square and Kruskal-Wallis test) and multinomial regression analysis. The performance of GDS-5 was compared with the GDS-15 as standard. Cronbach’s alpha was calculated to investigate reliability. Validity was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, Spearman’s correlation, receiver operating characteristic curve, and kappa coefficient.Results: 280 patients were enrolled with an overall prevalence of unrecognized depression of 45.7 % [104 (81.3%) mild-moderate depression, and 24 (18.8%) severe depression]. The mean age of the sample was 71.36 with female predominance (61%), and 82.5% were illiterate. In the binary analysis, those who had more pain, visited the ED more often, had musculoskeletal diseases and sleep problems, mobility problems, visited local healers previously, and who reported self-perceived “heart and mind” disease showed statistically significant differences among the three categories. In multinomial regression analysis, visits to local healers, sleep problems and frequency of pain were significantly related to depression. The sensitivity, specificity, area under curve and Spearman’s correlation of GDS-5 were 75.8%, 96%, 0.919, and 0.827 respectively. Cronbach's alpha for GDS-5 was low (0.416), therefore a new version was proposed which improved the sensitivity to 90.6% and Cronbach’s alpha to 0.623.Conclusions: Unrecognized geriatric depression was highly prevalent which urges the need for ED-based interventions for screening and referral. The proposed brief GDS-5 correlated well with the GDS-15 with better validity and internal reliability and offers a more expeditious form of screening for geriatric depression in emergency settings in Nepal.
Association between Growth Differentiation Factor 5 rs143383 Genetic Polymorphism and the Risk of Knee Osteoarthritis among Caucasian But Not Asian: A Meta-analysis
Authors: lei peng , Jin Song , Lu Jiping , Ouyang Chao , Gou Jiang , Xie Zhongyu , Shen Huiyong , Wang Peng
Published: August 2020

Background

A few months ago, the Bioscience Reports journal showed that Growth Differentiation Factor 5 (GDF5) rs143383 genetic polymorphism increases the susceptibility of knee osteoarthritis (KOA), but previous studies’ results have debates about available data. Considering the availability of more recent data, we focus on clarifying the relationship of KOA and GDF5 rs143383 genetic polymorphism by a meta-analysis of case-control trial data.

Methods

The eligible studies from the time of database established to Oct. 2019 were collected from PubMed, Springer, Cochrane library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang library. The meta-analysis was completed by STATA 18.0 software. Two independent authors extracted the data and assessed case-control trial quality.

Results

A total of 196 studies were collected, 16 of them including in final meta-analysis (7997 cases and 12684 controls). There was significant association between GDF 5 rs143383 polymorphism and KOA in all genetic models (for Allele model (C versus T): OR = 0.84 (95% CI = 0.76-0.91); dominate model (CC+CT versus TT): OR = 0.80(95% CI = (0.72-0.90); recessive model (CC versus CT+TT): OR= 0.79 (95% CI = 0.68-0.92); heterozygote model (CT versus CC+TT): OR = 0.89 (95% CI=0.80-0.97); homozygous model (CC versus TT): OR = 0.71 (95% CI=0.60-0.85). In the subgroup analysis by ethnicity, we obtained the results is no significant among Asians.

Conclusion

GDF5 rs143383 genetic polymorphism increases the risk of KOA among Caucasians; CC genotype and C allele are protective factors for the susceptibility of KOA among Caucasians.
Long non-coding RNA H19 deficiency ameliorates bleomycin-induced pulmonary inflammation and fibrosis
Authors: WAN XIAOYU , TIAN XINBEI , DU JUN , LU YING , XIAO YONGTAO
Published: August 2020

Background: The poor understanding of pathogenesis in idiopathic pulmonary fibrosis (IPF) impaired development of effective therapeutic strategies. The aim of the current study is to investigate the roles of long non-coding RNA H19 (lncRNA H19 ) in the pathogenesis of IPF. Methods: Bleomycin was used to induce pulmonary inflammation and fibrosis in mice. The mRNAs and proteins expression in lung tissues was determined by quantitative real-time polymerase chain reaction and western blot. H19 knockout ( H19 -/- ) mice were generated by CRISPR/Cas9 and used to investigate the roles of H19 in the pulmonary inflammation and fibrosis in vivo . Results: The expression of H19 mRNA was up-regulated in fibrotic lungs patients with IPF as well as in lungs tissues that obtained from bleomycin-treated mice. H19 -/- mice suppressed bleomycin-mediated pulmonary inflammation and inhibited the Il6/Stat3 signaling. H19 deficiency ameliorated bleomycin-induced pulmonary fibrosis and repressed the activation of TGF-β/Smad and S1pr2/Sphk2 in the lungs of bleomycin-treated mice. Conclusions : Our data suggests that H19 is a profibrotic lncRNA and a potential therapeutic target for pulmonary fibrosis.
Asymptomatic “Exposers” and “Infectors” are Sources of Infection by SARS-CoV-2: Analysis based on Family Clustering
Authors: He Yu , Guo Yuanyuan , Liu Ping , Li Rui , Ouyang Liu , Wang Siyuan , Fu Dehao
Published: August 2020

Background: Previous studies have documented the clinical characteristics of patients with Coronavirus disease 2019(COVID-19) and presented evidence of person-to-person transmission. Limited data are available for patients with asymptomatic infections. Some asymptomatic carriers, whom we characterize as “exposers” or “infectors”, may be responsible for family clustering of COVID-19.Methods: A questionnaire survey and follow-up survey based on media reports were used to assess familial clustering of SARS-CoV-2 infection induced by asymptomatic exposers/infectors. Individual data were collected for all members of each tracked family. A transmission map was then drawn for each family.Results: Our study of 5 families indicated that individuals with no obvious symptoms of COVID-19, regardless of the PCR results, transmitted the virus to other family members who were community contained at home and had no contact with other infected individuals. There was one death case in Family No.3. Conclusion: Asymptomatic exposers/infectors of SARS-CoV-2 were all middle-aged (average age: 44.4 ± 14.9 years) who had no symptoms but had the ability to disseminate the virus. Medical staff participating in treatment of COVID-19 cases all had a high risk of infection, they should be quarantined so as to protect their families. The morbidity and mortality of Case 3.2 remind us that although these asymptomatic infected people have no symptoms, they are also infectious. It is not ruled out that the subsequent infected people are seriously ill or even die. Therefore, we should not take it lightly.
Scaling-up Community Self-reporting Rate for COVID-19: Implication for Assessing the Perceived Stigmatization of COVID-19 Survivors Among Residents of Agege Local Government, Lagos, Nigeria
Authors: Babatunde Olaniyan Akintunde , Amifofun Owoicho Samuel , Sola Sunday Thomas , Akande Abayomi , Besong Mathias , Yesufu Baqiah Morenike , Akanbi Ibukun Mary , Dairo Magbagbeola David
Published: August 2020

Objective: Coronavirus disease 2019 (COVID-19) is an emerging public health problem with over two million confirmed infections globally. Previous studies show that stigma impede the response activities. Therefore, this study was conducted to assess the perceived stigmatization of COVID-19 survivors among residents of Agege local government, Lagos State, Nigeria. We conducted a cross-sectional survey among 333 consenting residents recruited from Agege local government using multi-stage sampling technique. An interviewer-administered questionnaire was used to collect data on perceived stigmatization. Bivariate and multivariate analyses were done using Chi-square and logistic regression respectively.Results: The mean age of the respondents was 35.7 ± 13.6 years. The proportion of respondents with poor knowledge was 50.5% and awareness for COVID-19 was 95.2%. Television and radio were the two major sources of awareness for COVID-19. Higher likelihood of perceived stigmatization was found among those aged 25 – 49 years (aOR= 3.1, 95% CI = 1.4 – 6.7), ≥ 50 years (aOR= 2.1, 95% CI = 1.1 – 3.9) and married respondents (aOR= 1.8, 95% CI = 1.1 – 2.9). To reduce the effect of stigmatization, we recommend a holistic response plan designed with basic facts about COVID-19 using programmes targeting married respondents as well as the adults.
Incidence of Alzheimer’s Disease and Other Dementias: Results from the 2017 Global Burden of Disease Study
Authors: Guo Xiaojuan , He Hairong , Qu Yan , Liu Jie , Qu Qiumin , Lyu Jun
Published: August 2020

Background

The aim is to reveal the trends in the incidence of Alzheimer’s disease (AD) and other dementias at the global, region, and national levels using data from 2017 Global Burden of Disease Study (GBD 2017).
Methods

We collected information on the number of incident cases and on the age-standardized incidence rate (ASIR) of AD and other dementias during 1990–2017 from the GBD 2017. We also analyzed differences in the incidence among different age groups. The association of ASIR with the development level was explored using Pearson correlation analysis.
Results

In 2017, the number of incident cases of AD and other dementias was 73.01 million (95% uncertainty interval [CI] = 65.16–81.33 million). This represented an increase of 113.17% from 1990, and an ASIR of 97.46 per 100,000 persons (95% CI = 86.80–108.89 per 100,000 persons). The ASIR was highest in countries in the high-middle sociodemographic index (SDI) quintile, and lowest in low-SDI-quintile countries. The number of incident cases increased from 1990 to 2017, whereas ASIR showed a slight downward trend in most countries. Japan had the highest ASIR in 2017 and showed the largest increase in ASIR over the preceding 28 years. The ASIR increased rapidly with age among those older than 70 years, and was significantly associated with the SDI (P < 0.0001, ρ = 0.68).
Conclusion

The incidence rate of AD and other dementias has declined in recent decades, but the incidence still remains high. The present findings should be useful for resource allocation and planning health services for AD and other dementias.
The Association between Frequency of Eating Out with Overweight and Obesity Among Children Aged 6-17 in China: A National Cross-Sectional Study
Authors: Ma Yanning , Gong Weiyan , Ding Caicui , Song Chao , Yuan Fan , Fan Jing , Feng Ganyu , Chen Zheng , Liu Ailing
Published: August 2020

Background: In parallel with the increased prevalence of childhood overweight and obesity, the rate of eating out in China has increased dramatically in recent years. The purpose of the study was to explore the association between frequency of eating out with overweight and obesity among Chinese children.Methods: The representative sample of Chinese children aged 6-17 years (7685 boys; 7576 girls) was recruited from Chinese National Nutrition and Health Survey (CNNHS) in 2010-2012. Frequency of eating out was collected by interview-administered questionnaire and categorized as: less than once per week, once and twice per week, and three times or more per week. Height and weight were measured (body mass index was consequently calculated). Results：The prevalence of eating out among Chinese children aged 6-17 years old was 23.2%. Children who ate out 0, 1-2, ≥3 times per week were accounted for 76.8%, 10.9% and 12.3% respectively. Findings revealed that eating out three times per week or more was statistically significant associated with higher prevalence of overweight and obesity among boys (OR=1.20,95CI:1.04-1.38) compared with those ate out less than three times per week. However, no significantly association was observed among girls (OR=0.91, 95CI:0.78-1.01). In additional, Younger children, rural children, children from high income family, those with leisure exercises, leisure SB(>2h/d) were relatively more likely to eat out.Conclusions: The results illustrated that eating out three times or more had a significantly positive effect on overweight and obesity among boys in China.
Whole-Genome Sequencing of Bamei Mutton Sheep for Screening the Genes and SNPs Associated with Litter Size under Selection
Authors: Yao Yaxin , Pan Zhangyuan , Di Ran , Liu Qiuyue , Hu Wenping , Guo Xiaofei , He Xiaoyun , Gan Shangquan , Wang Xiangyu , Chu Mingxing
Published: August 2020

Background: Bamei mutton sheep is a Chinese domestic sheep breed developed by crossing German Mutton Merino sheep and indigenous Mongolian sheep for meat production. Here, we focused on increasing the litter size of this breed to improve the efficiency of mutton production.Results: We selected five high- and five low-fecundity Bamei mutton sheep for whole-genome resequencing to identify candidate genes for sheep prolificacy. We used the FST and XP-EHH statistical approach to detect the selective sweeps between these two groups. Combining the two selective sweep methods, the reproduction-related genes JUN, ITPR3, PLCB2, HERC5, and KDM4B were detected. JUN, ITPR3, and PLCB2 play vital roles in GnRH, oxytocin, and estrogen signaling pathway. Moreover, KDM4B, which had the highest FST value, exhibits demethylase activity. It can affect reproduction by binding the promoters of estrogen-regulated genes, such as FOXA1 and ESR1. Notably, one nonsynonymous mutation (p.S936A) specific to the high-prolificacy group was identified at the TUDOR domain of KDM4B.Conclusion: These observations provide a new opportunity to research the genetic variation influencing fecundity traits within a population evolving under artificial selection. The identified genomic regions of KDM4B that are responsible for litter size can in turn be used for further selection.
A Qualitative Content Analysis of "Problem Students": How Can We Identify and Manage Them?
Authors: Ahmady Soleiman , Khajeali nasrin , Kalantarion Masomeh , Amini Mitra
Published: August 2020

Objectives: Problem students is one of the important issues in medical education. This qualitative study aimed to identify the problem students and the ways for managing these students from the educational experts view. Purposive sampling was used, and data collection continued until data saturation was achieved. The participants were 12 higher education experts and policymakers. Data analysis was performed by the content analysis method based on the Heidegger approach.Results: After data analysis, five main themes and 28 categories, and 164 codes were extracted. The reasons for changing a student to a problem students was: student self-regulation skills, multilayer interactions, curriculumfailure, identification policy and supportive solutions. The results indicated that despite revision in the curriculum, there were shortcomings in identification and management of problem students. This study emphasized that we could identify and manage this type of students with the best approach by faculty development, reviewing the faculty member recruitment, strengthening counseling centers, improving the exams, and screening the students on arrival.
CircRNA UBAP2 Serves as a Sponge of miR-1294 to Increase Tumorigenesis in Hepatocellular Carcinoma through Regulating c-Myc Expression
Authors: Yu Min-Cheng , Ding Guang-Yu , Fu Pei-Yao , Ma Peng , Zhu Xiao-Dong , Cai Jia-Bin , Shen Ying-Hao , Zhou Jian , Fan Jia , Sun Hui-Chuan , Kuang Ming , Huang Cheng
Published: August 2020

The authors have withdrawn this preprint due to author disagreement.
Blockage of AMPK-ULK1 pathway mediated autophagy promotes cell apoptosis to increase doxorubicin sensitivity in breast cancer (BC) cells: an in vitro study
Authors: Yu Libo , Shi Qingtao , Jin Yan , Liu Zhixin , Li Jiaxin , Sun Wenzhou
Published: August 2020

Background: Activation of autophagy flux contributed to resistance of breast cancer (BC) cells to current chemotherapeutic drugs, which seriously limited their therapeutic efficacy and facilitated BC recurrence in clinic. However, the detailed mechanisms are still not fully understood. In the present study, we identified that inactivation of AMPK-ULK1 signaling cascade mediated protective autophagy sensitized BC cells to doxorubicin in vitro. Methods: Cell counting kit-8 (CCK-8) assay and colony formation assay were performed to evaluate cell proliferation abilities. Trypan blue staining assay was used to examine cell viability, and Annexin V-FITC/PI double staining method was conducted to determine cell apoptosis. The autophagosomes in BC cells were observed and photographed by electronic microscope (EM). Western Blot analysis was employed to examine genes expressions at protein levels.Results: The parental doxorubicin-sensitive BC (DS-BC) cells were exposed to increasing concentrations of doxorubicin to establish doxorubicin-resistant BC (DR-BC) cells, and the DR-BC cells were much more resistant to high-dose doxorubicin stimulation compared to the DS-BC cells (P < 0.05). Interestingly, high-dose doxorubicin specifically increased LC3B-II/I ratio, promoted autophagosomes formation and decreased p62 expression levels to facilitate autophagy in DR-BC cells, instead of DS-BC cells (P < 0.05), and the autophagy inhibitor 3-methyladenine (3-MA) enhanced the cytotoxic effects of high-dose doxorubicin on DR-BC cells (P < 0.05). In addition, we proved that high-dose doxorubicin triggered protective autophagy in DR-BC cells by activating AMPK-ULK1 pathway. Functionally, high-dose doxorubicin increased the expression levels of phosphorylated AMPK (p-AMPK) and ULK1 (p-ULK1) to activate AMPK-ULK1 pathway in DR-BC cells (P < 0.05), and the inhibitors for AMPK (compound C) and ULK1 (SBI-0206965) blocked autophagy to promote cell death and slow down cell growth in DR-BC cells treated with high-dose doxorubicin (P < 0.05). Conclusions: Collectively, our in vitro data indicated that blockage of AMPK-ULK1 signaling cascade mediated protective autophagy might be a promising strategy to increase doxorubicin sensitivity for BC treatment.
Identification of Novel Transcription Factor-microRNA-mRNA Co-regulatory Networks in Pulmonary Large-cell Neuroendocrine Carcinomas
Authors: Cai Cunliang , Zhang Mingqiang , Mu Xiangdong
Published: August 2020

Background: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare neuroendocrine neoplasm. Previous studies have shown that microRNAs can be widely involved in tumor regulation through targeting critical genes. However, it is unclear about which miRNAs play vital roles in LCNEC’s pathogenesis and how they interact with transcription factors (TFs) to regulate the cancer-related genes. Methods: To clarify the new TFs-miRNA-target gene feed-forward loops (FFLs) model of LCNEC, we integrated multi-omics data from GEO, TRRUST, TRED, and miRTarBase database. First, expression profile datasets for mRNAs (GSE1037) and miRNAs (GSE19945) were downloaded from the GEO database. Overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified through integrative analysis. The target genes of the FFL being obtained from the mirTarBase database, the GO and KEGG functional enrichment analysis was performed on the target gene. Then, we screened for key miRNAs in the FFL and perform gene regulatory network analysis based on key miRNAs. Finally, the TF-miRNA-target gene FFLs were constructed by the hypergeometric test.Results: A total of 343 DEGs and 60 DEMs were identified in LCNECs compared to normal tissues, including 210 downregulated, 133 upregulated genes and 29 downregulated, 31 upregulated miRNAs. Additionally, 55 DEMs were predicted through miRanda, mirDB, and TargetScan to be associated with the LCNEC 77 key genes. Finally, ETS1-miR195-CD36 and E2F3-miR195-CD36 from the TF-miRNA-mRNA FFLs were constructed and are significantly enriched in focal adhesion, cytokine-receptor interaction, hematopoietic cell lineage, and transforming growth factor (TGF)-β signaling pathways. Survival analysis showed that the differential expression of the multi-effect factors ETS1, CD36, and hsa-miR-195 in the FFL significantly affected the survival time of LCNEC patients.Conclusion: In summary, we construct the TF-miRNA-target regulatory network, which is helpful to understand the complex LCNEC regulatory mechanisms. The expression difference of regulated multi-effect target factors ETS1, CD36, and hsa-miR-195 has a significant impact on the survival and development of LCNEC.
Risk Factors for Unplanned Reintubation Caused by Acute Airway Compromise After General Anesthesia: A Case-control Study
Authors: CHEN SI , Zhang Yuelun , Che Lu , Shen Le , Huang Yuguang
Published: August 2020

Background: This study aimed to identify the risk factors and evaluate the prognosis of unplanned reintubation caused by acute airway compromise (AAC) after general anesthesia.Methods: This case-control study included surgical patients who underwent unplanned reintubation after general anesthesia during five years. Cases due to AAC were matched 1:4 with randomly selected controls.Results: Univariate analysis revealed that male sex, age >65, ASA physical status 3, heart disease history, cerebral infarction history, Cormack Lehane grade, surgery type, fresh frozen plasma infusion, increased intubation duration, white blood cell count, and creatinine clearance rate were significantly associated with AAC-caused unplanned reintubation. Multivariate analysis revealed that age >65 (OR=7.50, 95% CI=2.47-22.81, P<0.001), ASA physical status 3 (OR=6.51, 95% CI=1.18-35.92, P=0.032), head-neck surgery (OR=4.94, 95% CI=1.33-18.36, P=0.017) or thoracic surgery (OR=12.56, 95% CI=2.93-53.90, P<0.001), and a high fluid load (OR=3.04, 95% CI=1.16-7.99, P=0.024) were independent risk factors for AAC-caused unplanned reintubation. AAC-caused unplanned reintubation patients had longer postoperative hospital (OR=5.26, 95% CI=1.57-8.95, P<0.001) and intensive care unit days (OR=3.94, 95% CI=1.69-6.18, P<0.001).Conclusions: Age>65, ASA physical status 3, head-neck or thoracic surgery, and high fluid load were risk factors for AAC-caused unplanned reintubation, which was associated with increased postoperative hospital and ICU days.
Conservation Status and Historical Relatedness of South African Communal Indigenous Goat Populations Using Genome-Wide Snp Marker
Authors: Chokoe Tlou Caswell , Hadebe Khanyi , Muchadeyi Farai , Nephawe Khathutshelo , Dzomba Edgar , Mphahlele Tumudi , Matelele Tlou , Mtileni Bohani
Published: August 2020

Background: Indigenous goats forms the majority of populations in smallholder; low input, low output production systems and are considered an important genetic resource due to their adaptability to different production environments and support communal farming. Effective population size (Ne), inbreeding levels, and the runs of homozygosity (ROHs) are effective tools for exploring the genetic diversity and understanding the demographic history in efforts to support breeding strategies to use and conserve genetic resources. Results: Across populations, the current Ne of Gauteng was the lowest at 371 animals, while the historical Ne across populations suggests that the ancestor Ne has decreased by 53.86%, 44.58%, 42.16% and 41.16% in Free State (FS), North West (NW), Limpopo (LP) and Gauteng (GP), respectively, over the last 971 generations. Genomic inbreeding levels related to ancient kinship (FROH >5Mb) was highest in FS (0.08±0.09) and lowest for Eastern Cape (EC) (0.02±0.02). A total of 871 ROH island regions which include important environmental adaptation and hermo-tolerance genes such as IL10RB, IL23A, FGF9, IGF1, EGR1, MTOR and MAPK3 were identified (occurring in over 20% of the samples) in FS (n = 37), GP (n = 42), NW (n = 2) populations only. The mean length of ROH across populations was 7.76Mb and ranged from 1.61Mb KwaZulu-Natal (KZN) to 98.05Mb (GP and NW). Distribution of ROH according to their size showed that the majority (n = 1949) of the detected ROH were >5Mb in length than the other categories. Assuming two hypothetical ancestral populations, the population from KZN and LP are revealed, supporting PC 1. The genomes of KZN and LP shared an origin but have substantial admixture from the EC and NW populations.Conclusions: These findings indicated a greater negative impact of inbreeding in recent times which is important for planning conservation strategies. It was revealed that the occurrence of high Ne and autozygosity varied largely across breeds in communal indigenous goat populations at different recent and ancient events when a genome-wide SNP marker was used.
In Vivo Vaccination with Cell Line-Derived Whole Tumor Lysates – Neoantigen Quality, Not Quantity Matters
Authors: Salewski Inken , Gladbach Yvonne Saara , Kuntoff Steffen , Irmscher Nina , Hahn Olga , Junghanss Christian , Maletzki Claudia
Published: August 2020

Background: Cancer vaccines provide a complex source of neoantigens. Still, increasing evidence reveals that the neoantigen quality rather than the quantity is predictive for treatment outcome. Methods: Using the preclinical Mlh1-/- tumor model, we performed a side-by side comparison of two autologous cell-line derived tumor lysates (namely 328 and A7450 T1 M1) harboring different tumor mutational burden (TMB; i.e. ultra-high: 328; moderate-high: A7450 T1 M1). Mice received repetitive prophylactic or therapeutic applications of the vaccine. Tumor incidence, immune responses and tumor microenvironment was examined.Results: Both tumor cell lysates delayed tumor formation in the prophylactic setting, with the A7450 T1 M1 lysate being more effective in decelerating tumor growth than the 328 lysate (median overall survival: 37 vs. 25 weeks). Comparable results were achieved in therapeutic setting and could be traced back to antigen-driven immune stimulation. Reactive T cells isolated from A7450 T1 M1-treated mice recognized autologous Mlh1−/− tumor cells in IFNγ ELISpot, but likewise YAC-1 cells, indicative for stimulation of both arms of the immune system. By deciphering local effects, vaccines shaped the tumor microenvironment differently. While A7450 T1 M1 prophylactically vaccinated tumors harbored low numbers of myeloid-derived suppressor cells (MDSC) and elevated CD8-T cell infiltrates, vaccination with the 328 lysate evoked MDSC infiltration. Similar effects were seen in the therapeutic setting with stable disease induction only upon A7450 T1 M1 vaccination. Untangling individual response profiles revealed strong infiltration with LAG3+ and PD-L1+ immune cells when treatments failed, but almost complete exclusion of checkpoint-expressing lymphocytes in long-term survivors. Conclusions: By applying two tumor cell lysates we demonstrate that neoantigen quality outranks quantity. This should be considered prior to designing cancer vaccine-based combination approaches.
Neurological Presentation of Severe Dengue in Children From a Colombian Hyperendemic Area
Authors: Castellanos Jaime E. , Esteban Paula , Panqueba-Salgado Juanita , Benavides-del-Castillo Daniela , Pastrana Valentina , Acosta Gladys , Salgado Doris , Narvaez Carlos F. , Camacho-Ortega Sigrid , Calvo Eliana , Velandia-Romero Myriam L.
Published: August 2020

Objective: Dengue transmission is sustained in Colombia with increasing prevalence mainly in children. This work was aimed to describe a cases series of children diagnosed with dengue presenting neurological disease in the Huila province of Colombia. Eleven pediatric febrile patients confirmed to dengue disease and presenting neurological signs were studied in the University Hospital of Neiva, Huila province. Clinical and laboratory findings, CSF cytochemical analysis, neurology images, and serology and molecular studies were performed. Results. Viral RNA was detected in all patients’ sera by RT-PCR. Nine out of 11 were primary infections. Tonic-clonic seizures (73%), consciousness alterations (27%), irritability (27%) and ataxia (18%) were the most frequent neurological signs. None of the patients had plasma leakage, hypovolemic shock or liver disease, confirming the encephalitis diagnosis. Diagnostic images did not show abnormal findings neither bacterial or fungal infections were detected in CSF analysis. All patients survived without sequelae except in one patient that presented ataxia for months. In conclusion, we described a group of children with neurological signs during severe dengue disease as the main finding, indicating the importance of include dengue as a differential diagnosis in neurological patients from endemic areas.
Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single cell transcriptomics in real-world pancreatic cancer biopsies
Authors: Lee Jaewon , Bernard Vincent , Semaan Alexander , Monberg Maria , Huang Jonathan , Stephens Bret , Lin Daniel , Weston Brian , Bhutani Manoop , Haymaker Cara , Bernatchez Chantale , Taniguchi Cullen , Maitra Anirban , Guerrero Paola
Published: August 2020

Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployed ex vivo preclinical platforms, such as patient-derived organoids (PDOs), remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast (CAF) subclasses, and predict a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. While PDOs continue to enable prospective therapeutic prediction, our analysis also demonstrates the complementarity of using orthogonal de novo biopsies from PDAC patients paired with scRNA-seq to inform clinical decision-making.
“Z” Chest Drainage and Modified Incision and Closure Techniques for Uniportal VATS
Authors: Zhang Ruijie , Hao Zhipeng , Zhang Ni , Fu Xiangning
Published: August 2020

BACKGROUND: To research the application of “Z” chest drainage and modified incision and closure techniques for uniportal VATS.METHODS: The 422 patients by uniportal VATS were divided into three groups:282 in experimental group(“Z” Chest drainage with two 16 F chest tube),male 156,female 126, medianage is 55 years old;100 in control group1(traditional Chest drainage with two 16 F chest tube) , male 58,female 42, medianage is 53 years old;;40 in control group2(traditional Chest drainage with two 34 F chest tube), male 24,female 16, medianage is 52 years old. The age,sex and surgical method of the three groups has no statistical significance. To compare the incidence rate of Incision exudating、Poor healing of incision and debridement between the 3 groups.RESULTS: Incidence rate of Incision exudating of experimental group, control group1 and control group2: 5（1.8%,5/282），5（5%,5.0/100） and 6（15.0%，6/40）; Poor healing of incision of the three groups: 0，1（1%,1/100） and 3（7.5%,3/40）; debridement of the three groups: 0，0 and 3（7.5%,3/40）. For the healing of incision, control group1was better than control group2;and experimental group was better than control group1.CONCLUSIONS: “Z” Chest drainage and Modified Incision and Closure Techniques decreased the incidence rate of Incision exudating、Poor healing of incision and debridement,which would be useful to obtain a better cosmetic effect after uniportal VATS .
Clinical Impact of Interferon-γ in Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis
Authors: Lee Kijun , Min Hong Ki , Ko Seong-Hee , Lee Sang-Heon , Kim Hae-Rim , Ju Ji Hyeon , Kim Ho-Youn
Published: August 2020

Background: CD4+ T cells are crucial for the pathogenesis of rheumatoid arthritis (RA). The roles of gene overexpression in CD4+ T cells and the predictive roles of Th1- and Th17-related cytokines have not been clearly defined in patients with RA. Here, we investigated gene expression levels in CD4+ T cells in methotrexate (MTX)-naïve early RA (eRA) and evaluated changes in CD4+ T-cell-related cytokines during eRA. Methods: Patients with anti-citrullinated protein antibody (ACPA)-positive MTX-naïve eRA were recruited. Patients with osteoarthritis were evaluated as controls. Microarray analysis was used to identify overexpressed genes in CD4+ T cells, and reverse transcription quantitative polymerase chain reaction was used to validate the identified genes. Plasma cytokine levels were measured, and correlations with disease activity were assessed.Results: Thirty-four genes showed overexpression in CD4+ T cells from patients with ACPA-positive MTX-naïve eRA compared with controls. Nineteen were related to interferon (IFN)-γ, and nine were related to interleukin (IL)-17A; five were related to both IFN-γ and IL-17A. Plasma levels of five cytokines were elevated in the ACPA-positive MTX-naïve eRA group compared with those in the control group, and C-X-C motif chemokine ligand 10 was significantly elevated in the ACPA-positive MTX-naïve eRA group compared with that in the established active RA and OA groups. In established RA with low disease activity, the drug-free remission group/drug reduction group showed significantly lower IFN-γ and IL-17A levels than the drug maintenance group and relapse after drug reduction group. Conclusion: Our T2 research of IFN-γ emphasized that, not only the Th17 immune response, but the Th1 immune response is also very important for the RA pathogenesis. Concurrent increase in IFN-γ and IL-17 were observed in active stage of ACPA-positive MTX-naïve eRA, and the plasma levels of them could be useful for new clinical biomarkers before and/or after treatment of RA.