bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials
Authors: Qin Jing , Song Li 
Published: May 2022

Abstract
Background
The cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.

Methods
PubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.

Results
We included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).

Conclusion
We concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.
Late initiation of antenatal care and associated factors among pregnant women in Jimma Zone Public Hospitals, Southwest Ethiopia, 2020
Authors: Tadele Fetlework , Getachew Nigusu , Fentie Kelemu , Amdisa Demuma 
Published: May 2022

Abstract
Background
Late antenatal care initiation is linked to a higher risk of maternal death. Women who do not start ANC at an early stage may experience the effects of pregnancy-related health difficulties, as well as long-term health issues and pregnancy complications. Therefore, our study aimed to determine the prevalence of late initiation of antenatal care and associated factors among pregnant women in Jimma Zone public Hospitals.

Methods
A facility-based cross-sectional study design was employed in Jimma zone public hospitals from February 1 up to 30 March 2020 and 409 pregnant women were participated in the study by using a systematic random sampling method. Structured questionnaire was used to collect data that contain socio demographic variables, socio cultural variables, pregnancy related factors and predisposing factor related variables. The data was entered into EPI data version 3.1 and exported to SPSS version 20 for statistical analysis. Binary and multivariable logistic regression analysis were performed by using 95%CI and significance was declared at P < 0.05.

Result
Forty-eight percent of pregnant women were initiated their first ANC late. Primary education (AOR = 0.242; 95% CI, 0.071–0.828) and college diploma and above was (AOR = 0.142; 95% CI, 0.040- 0.511), mothers with an unplanned pregnancy (AOR = 11.290; 95%CI, 4.109–31.023), time taken to arrive the health facility greater than sixty (60) minutes (AOR = 8.285; 95% CI, 2.794–24.564) and inadequate knowledge about ANC service (AOR = 4.181; 95%CI, 1.693–10.348) were associated with late first Antenatal care initiating.

Conclusion
The prevalence of late initiation of ANC still remains a major public health concern in the study area. Level of education, unplanned pregnancy, distance from house to health facility, and lack of understanding about ANC services were all found to be significant variables in late ANC starting. As a result, healthcare workers can provide ongoing health education on the need of starting antenatal care visits early to avoid unfavorable pregnancy outcomes by considering all identified factors.
Decreasing dorsal cochlear nucleus activity ameliorates noise-induced tinnitus perception in mice
Authors: Malfatti Thawann , Ciralli Barbara , Hilscher Markus M. , Leao Richardson N. , Leao Katarina E. 
Published: May 2022

Abstract
Background
The dorsal cochlear nucleus (DCN) is a region known to integrate somatosensory and auditory inputs and is identified as a potential key structure in the generation of phantom sound perception, especially noise-induced tinnitus. Yet, how altered homeostatic plasticity of the DCN induces and maintains the sensation of tinnitus is not clear. Here, we chemogenetically decrease activity of a subgroup of DCN neurons, Ca2+/Calmodulin kinase 2 α (CaMKII α)-positive DCN neurons, using Gi-coupled human M4 Designer Receptors Exclusively Activated by Designer Drugs (hM4Di DREADDs), to investigate their role in noise-induced tinnitus.

Results
Mice were exposed to loud noise (9–11kHz, 90dBSPL, 1h, followed by 2h of silence), and auditory brainstem responses (ABRs) and gap prepulse inhibition of acoustic startle (GPIAS) were recorded 2 days before and 2 weeks after noise exposure to identify animals with a significantly decreased inhibition of startle, indicating tinnitus but without permanent hearing loss. Neuronal activity of CaMKII α+ neurons expressing hM4Di in the DCN was lowered by administration of clozapine-N-oxide (CNO). We found that acutely decreasing firing rate of CaMKII α+ DCN units decrease tinnitus-like responses (p = 3e −3, n = 11 mice), compared to the control group that showed no improvement in GPIAS (control virus; CaMKII α-YFP + CNO, p = 0.696, n = 7 mice). Extracellular recordings confirmed CNO to decrease unit firing frequency of CaMKII α-hM4Di+ mice and alter best frequency and tuning width of response to sound. However, these effects were not seen if CNO had been previously administered during the noise exposure (n = 6 experimental and 6 control mice).

Conclusion
We found that lowering DCN activity in mice displaying tinnitus-related behavior reduces tinnitus, but lowering DCN activity during noise exposure does not prevent noise-induced tinnitus. Our results suggest that CaMKII α-positive cells in the DCN are not crucial for tinnitus induction but play a significant role in maintaining tinnitus perception in mice.
Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs
Authors: Lorzadeh A. , Hammond C. , Wang F. , Knapp D. J. H. F. , Wong J. CH. , Zhu J. Y. A. , Cao Q. , Heravi-Moussavi A. , Carles A. , Wong M. , Sharafian Z. , Steif J. , Moksa M. , Bilenky M. , Lavoie P. M. , Eaves C. J. , Hirst M. 
Published: May 2022

Abstract
Background
Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. To address this gap, we generated comprehensive reference epigenomes of 8 phenotypically defined subsets of normal human cord blood.

Results
We describe a striking contraction of H3K27me3 density in differentiated myelo-erythroid cells that resembles a punctate pattern previously ascribed to pluripotent embryonic stem cells. Phenotypically distinct progenitor cell types display a nearly identical repressive H3K27me3 signature characterized by large organized chromatin K27-modification domains that are retained by mature lymphoid cells but lost in terminally differentiated monocytes and erythroblasts. We demonstrate that inhibition of polycomb group members predicted to control large organized chromatin K27-modification domains influences lymphoid and myeloid fate decisions of primary neonatal hematopoietic progenitors in vitro. We further show that a majority of active enhancers appear in early progenitors, a subset of which are DNA hypermethylated and become hypomethylated and induced during terminal differentiation.

Conclusion
Primitive human hematopoietic cells display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in monocytes and erythroblasts. Intervention data implicate that control of this chromatin state change is a requisite part of the process whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions.
Spatiotemporal analysis of highly pathogenic avian influenza (H5N1) outbreaks in poultry in Egypt (2006 to 2017)
Authors: Elsobky Yumna , El Afandi Gamal , Salama Akram , Byomi Ahmed , Omar Muhammad , Eltholth Mahmoud 
Published: May 2022

Abstract
Background
In Egypt, the highly pathogenic avian influenza (HPAI) subtype H5N1 is endemic and possesses a severe impact on the poultry. To provide a better understanding of the distributional characteristics of HPAI H5N1 outbreaks in Egypt, this study aimed to explore the spatiotemporal pattern and identify clusters of HPAI H5N1 outbreaks in Egypt from 2006 to 2017.

Results
The Epidemic curve (EC) was constructed through time series analysis; in which six epidemic waves (EWs) were revealed. Outbreaks mainly started in winter peaked in March and ended in summer. However, newly emerged thermostable clades (2.2.1.1 and 2.2.1.2) during the 4th EW enabled the virus to survive and cause infection in warmer months with a clear alteration in the seasonality of the epidemic cycle in the 5th EW. The endemic situation became more complicated by the emergence of new serotypes. As a result, the EC ended up without any specific pattern since the 6th EW to now. The spatial analysis showed that the highest outbreak density was recorded in the Nile Delta considering it as the ‘Hot spot’ region. By the 6th EW, the outbreak extended to include the Nile valley. From spatiotemporal cluster epidemics, clustering in the Delta was a common feature in all EWs with primary clusters consistently detected in the hot-spot region, but the location and size varied with each EW. The highest Relative Risk (RR) regions in an EW were noticed to contain the primary clusters of the next EW and were found to include stopover sites for migratory wild birds. They were in Fayoum, Dakahlia, Qalyobiya, Sharkia, Kafr_Elsheikh, Giza, Behera, Menia, and BeniSuef governorates. Transmission of HPAI H5N1 occurred from one location to another directly resulted in a series of outbreaks forming neighboring secondary clusters. The absence of geographical borders between the governorates in addition to non-restricted movements of poultry and low vaccination and surveillance coverage contributed to the wider spread of infection all over Egypt and to look like one epidemiological unit.

Conclusion
Our findings can help in better understanding of the characteristics of HPAI H5N1 outbreaks and the distribution of outbreak risk, which can be used for effective disease control strategies.

Graphical abstract
Comparative craniometric measurements of two Canid species in Egypt: the Egyptian red fox and the Egyptian Baladi dog
Authors: Mahdy Mohamed A. A. , Mohamed Walid Fathy 
Published: May 2022

AbstractThe Egyptian red fox (Vulpes vulpes aegyptiaca) and Egyptian Baladi dog (Canis familiaris) are two members of the Family Canidae that are widely distributed in Egypt. The skulls of different Canid species vary greatly in their size and shape; therefore, they can be used as a tool to study the evolution and evolutionary history of these animals. The craniometric measurements are crucial for species identification and determination of the specific sites for nerve blocks. The present study compared the craniometric measurements of the red fox and Baladi dog skulls by measuring 47 parameters on each skull and calculation of 8 indices. The red fox skull had significantly lower values of 41 craniometric measurements (approximately 87% of the measurements done), including skull length, width, and height, cranial length and width, palatal and mandibular length, and dental measurements. In contrast, the red fox had significantly higher values of only 3 measurements (approximately 6% of the measurements done) including the tympanic bulla measurement. While only three skull measurements did not differ significantly between the red fox and dog. Statistics revealed that domestic dog had significantly higher values of foramen magnum and palatine indices, and significantly lower value of nasal index than those of red fox. The present work reported variations in the gross and craniometric measurements of skull between the red fox and dog. The measured cranial parameters of both adult animals provide valuable information that can be used in ecological studies, comparative anatomy, and clinical veterinary sciences.
Identifying key genes and functionally enriched pathways in Th2-high asthma by weighted gene co-expression network analysis
Authors: Cao Yao , Wu Yi , Lin Li , Yang Lin , Peng Xin , Chen Lina 
Published: May 2022

Abstract
Background
Asthma is a chronic lung disease characterized by reversible inflammation of the airways. The imbalance of Th1/Th2 cells plays a significant role in the mechanisms of asthma. The aim of this study was to identify asthma-related key genes and functionally enriched pathways in a Th2-high group by using weighted gene coexpression network analysis (WGCNA).

Methods
The gene expression profiles of GSE4302, which included 42 asthma patients and 28 controls, were selected from the Gene Expression Omnibus (GEO). A gene network was constructed, and genes were classified into different modules using WGCNA. Gene ontology (GO) was performed to further explore the potential function of the genes in the most related module. In addition, the expression profile and diagnostic capacity (ROC curve) of hub genes of interest were verified by dataset GSE67472.

Results
In dataset GSE4302, subjects with asthma were divided into Th2-high and Th2-low groups according to the expression of the SERPINB2, POSTN and CLCA1 genes. A weighted gene coexpression network was constructed, and genes were classified into 7 modules. Among them, the red module was most closely associated with Th2-high asthma, which contained 60 genes. These genes were significantly enriched in different biological processes and molecular functions. A total of 8 hub genes (TPSB2, CPA3, ITLN1, CST1, SERPINB10, CEACAM5, CHD26 and P2RY14) were identified, and the expression levels of these genes (except TPSB2) were confirmed in dataset GSE67472. ROC curve analysis validated that the expression of these 8 genes exhibited excellent diagnostic efficiency for Th2-high asthma and Th2-low asthma.

Conclusions
The study provides a novel perspective on Th2-high asthma by WGCNA, and the hub genes and potential pathways involved may be beneficial for the diagnosis and management of Th2-high asthma.
Influence of exercise duration on respiratory function and systemic immunity among healthy, endurance-trained participants exercising in sub-zero conditions
Authors: Gavrielatos Angelos , Ratkevica Iluta , Stenfors Nikolai , Hanstock Helen G. 
Published: May 2022

AbstractBackgroundStrenuous endurance exercise in sub-zero temperatures can cause airway damage that may lead to EIB. Prolonged exercise can also elicit greater immune perturbations than short-duration exercise. However, the influence of exercise duration on lung function and systemic immunity in sub-zero temperatures has not been established. Additionally, it is currently unknown whether atopic disposition, which is risk factor for EIB, influences respiratory responses in a sub-zero climate. The aim of this study was to compare respiratory and systemic immune responses to two cold air running trials of short and long duration, as well as to examine whether the responses differed between atopic and non-atopic subjects.MethodsEighteen healthy, endurance-trained subjects (males/females: 14/4; age: 29.4 ± 5.9 years old; BMI: 23.1 ± 1.7; atopic/non-atopic: 10/8) completed two moderate-intensity climate chamber running trials at − 15 °C, lasting 30 and 90 min, in a randomized, cross-over design. Lung function (spirometry and impulse oscillometry), serum CC16, respiratory symptoms, and blood leukocyte counts were examined before and after the trials.ResultsLung function was not significantly affected by exercise or exercise duration. CC16 concentration increased after both trials (p = 0.027), but the response did not differ between trials. Respiratory symptom intensity was similar after each trial. There was a greater increase in neutrophils (p < 0.001), and a decrease in eosinophils (p < 0.001) after the 90-min bout. The 90-min protocol increased X5 compared to the 30-min protocol only in atopic subjects (p = 0.015) while atopy increased lower airway symptoms immediately after the 90-min session (p = 0.004).ConclusionsOur results suggest that a 90-min bout of moderate-intensity exercise at − 15 °C does not cause substantial lung function decrements, airway epithelial damage or respiratory symptoms compared to 30 min running in the same environment, despite a heightened redistribution of white blood cells. However, exercise at − 15 °C may cause airway injury and evoke respiratory symptoms, even at moderate intensity. Atopic status may lead to greater peripheral bronchodilation and higher frequency of respiratory symptoms after long-duration exercise in cold.Trial registration:01/02/2022 ISRCTN13977758. This trial was retrospectively registered upon submission to satisfy journal guidelines. The authors had not initially registered the study, as the intervention was considered to be a controlled simulation of exercise in a naturally occurring environment (i.e. sub-zero air) for healthy volunteers.
Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease
Authors: Zhan Yuan , Chen Jinkun , Wu Jixing , Gu Yiya , Huang Qian , Deng Zhesong , Chen Shanshan , Wu Xiaojie , Lv Yongman , Zeng Zhilin , Xie Jungang 
Published: May 2022

Abstract
Background
Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by chronic inflammation and airway remodeling. Human epididymis protein 4 (HE4) plays a critical role in various inflammatory or fibrotic diseases. However, the role of HE4 in COPD remains unidentified.

Methods
HE4 expression was determined in the lung tissues from COPD patients and cigarette smoke (CS)-exposed mice using immunohistochemical staining, qPCR, or western blot. The plasma level of HE4 was detected by ELISA. The regulations of HE4 in the expressions of CS extract (CSE)-induced inflammatory cytokines in human bronchial epithelial cells (HBE) were investigated through knockdown or overexpression of HE4. The role of secretory HE4 (sHE4) in the differentiation and proliferation in human pulmonary fibroblast cells (HPF) was explored via qPCR, western blot, CCK8 assay or 5-ethynyl-2′-deoxyuridine (EdU) staining. The probe of related mechanism in CSE-induced HE4 increase in HBE was conducted by administrating N-acetylcysteine (NAC).

Results
HE4 was up-regulated in both the lung tissue and plasma of COPD patients relative to controls, and the plasma HE4 was negatively associated with lung function in COPD patients. The same enhanced HE4 expression was verified in CS-exposed mice and CSE-induced HBE, but CSE failed to increase HE4 expression in HPF. In vitro experiments showed that reducing HE4 expression in HBE alleviated CSE-induced IL-6 release while overexpressing HE4 facilitated IL-6 expression, mechanistically through affecting phosphorylation of NFκB-p65, whereas intervening HE4 expression had no distinctive influence on IL-8 secretion. Furthermore, we confirmed that sHE4 promoted fibroblast-myofibroblast transition, as indicated by promoting the expression of fibronectin, collagen I and α-SMA via phosphorylation of Smad2. EdU staining and CCK-8 assay demonstrated the pro-proliferative role of sHE4 in HPF, which was further confirmed by enhanced expression of survivin and PCNA. Pretreatment of NAC in CSE or H2O2-induced HBE mitigated HE4 expression.

Conclusions
Our study indicates that HE4 may participate in airway inflammation and remodeling of COPD. Cigarette smoke enhances HE4 expression and secretion in bronchial epithelium mediated by oxidative stress. Increased HE4 promotes IL-6 release in HBE via phosphorylation of NFκB-p65, and sHE4 promotes fibroblastic differentiation and proliferation.
Multi-omics analysis revealed TEK and AXIN2 are potential biomarkers in multifocal papillary thyroid cancer
Authors: Kim Ga Hyun , Heo Hye Jin , Kang Ji Wan , Kim Eun-Kyung , Baek Seung Eun , Kim Keunyoung , Kim In Joo , Suh Sunghwan , Lee Byung-Joo , Kim Yun Hak , Pak Kyoungjune 
Published: May 2022

Abstract
Background
Papillary thyroid carcinoma (PTC), the most common endocrine cancer, accounts for 80–85% of all malignant thyroid tumors. This study focused on identifying targets that affect the multifocality of PTC. In a previous study, we determined 158 mRNAs related to multifocality in BRAF-mutated PTC using The Cancer Genome Atlas.

Methods
We used multi-omics data (miRNAs and mRNAs) to identify the regulatory mechanisms of the investigated mRNAs. miRNA inhibitors were used to determine the relationship between mRNAs and miRNAs. We analyzed the target protein levels in patient sera using ELISA and immunohistochemical staining of patients’ tissues.

Results
We identified 44 miRNAs that showed a negative correlation with mRNA expression. Using in vitro experiments, we identified four miRNAs that inhibit TEK and/or AXIN2 among the target mRNAs. We also showed that the downregulation of TEK and AXIN2 decreased the proliferation and migration of BRAF ( +) PTC cells. To evaluate the diagnostic ability of multifocal PTC, we examined serum TEK or AXIN2 in unifocal and multifocal PTC patients using ELISA, and showed that the serum TEK in multifocal PTC patients was higher than that in the unifocal PTC patients. The immunohistochemical study showed higher TEK and AXIN2 expression in multifocal PTC than unifocal PTC.

Conclusions
Both TEK and AXIN2 play a potential role in the multifocality of PTC, and serum TEK may be a diagnostic marker for multifocal PTC.