bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating causal effects of atherogenic lipid-related traits on COVID-19 susceptibility and severity using a two-sample Mendelian randomization approach
Authors: Yoshikawa Masahiro , Asaba Kensuke , Nakayama Tomohiro 
Published: November 2021

Abstract
Background
As the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach.

Methods
We used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant.

Results
This MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001–1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04–1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08–1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely.

Conclusions
Our MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.
CYP2J2 and EETs protect against pulmonary arterial hypertension with lung ischemia–reperfusion injury in vivo and in vitro
Authors: Ding Yun , Tu Pengjie , Chen Yiyong , Huang Yangyun , Pan Xiaojie , Chen Wenshu 
Published: November 2021

Abstract
Background
Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. However, the role of CYP2J2 and EETs in pulmonary arterial hypertension (PAH) with lung ischemia–reperfusion injury (LIRI) remains unclear. In the present study, we investigated the effects of CYP2J2 overexpression and exogenous EETs on PAH with LIRI in vitro and in vivo.

Methods
CYP2J2 gene was transfected into rat lung tissue by recombinant adeno-associated virus (rAAV) to increase the levels of EETs in serum and lung tissue. A rat model of PAH with LIRI was constructed by intraperitoneal injection of monocrotaline (50 mg/kg) for 4 weeks, followed by clamping of the left pulmonary hilum for 1 h and reperfusion for 2 h. In addition, we established a cellular model of human pulmonary artery endothelial cells (HPAECs) with TNF-α combined with anoxia/reoxygenation (anoxia for 8 h and reoxygenation for 16 h) to determine the effect and mechanism of exogenous EETs.

Results
CYP2J2 overexpression significantly reduced the inflammatory response, oxidative stress and apoptosis associated with lung injury in PAH with LIRI. In addition, exogenous EETs suppressed inflammatory response and reduced intracellular reactive oxygen species (ROS) production and inhibited apoptosis in a tumor necrosis factor alpha (TNF-α) combined hypoxia-reoxygenation model of HPAECs. Our further studies revealed that the anti-inflammatory effects of CYP2J2 overexpression and EETs might be mediated by the activation of PPARγ; the anti-apoptotic effects might be mediated by the PI3K/AKT pathway.

Conclusions
CYP2J2 overexpression and EETs protect against PAH with LIRI via anti-inflammation, anti-oxidative stress and anti-apoptosis, suggesting that increased levels of EETs may be a promising strategy for the prevention and treatment of PAH with LIRI.

Graphical Abstract
NAP1L1 interacts with hepatoma-derived growth factor to recruit c-Jun inducing breast cancer growth
Authors: Liu Shu , Zhang Yewei , Cui Shien , Song Dajiang , Li Bo , Chen Qian , Yao Guangyu , Gong Bin 
Published: November 2021

Abstract
Background
Breast cancer is a common cancer among women in the world. However, its pathogenesis is still to be determined. The role and molecular mechanism of Nucleosome Assembly Protein 1 Like 1 (NAP1L1) in breast cancer have not been reported. Elucidation of molecular mechanism might provide a novel therapeutic target for breast cancer treatment.

Methods
A bioinformatics analysis was conducted to determine the differential expression of NAP1L1 in breast cancer and find the potential biomarker that interacts with NAP1L1 and hepatoma-derived growth factor (HDGF). The expression of NAP1L1 in tissues was detected by using immunohistochemistry. Breast cancer cells were transfected with the corresponding lentiviral particles and siRNA. The efficiency of transfection was measured by RT-qPCR and western blotting. Then, MTT, Edu, plate clone formation, and subcutaneous tumorigenesis in nude mice were used to detect the cell proliferation in breast cancer. Furthermore, coimmunoprecipitation (Co-IP) assay and confocal microscopy were performed to explore the detailed molecular mechanism of NAP1L1 in breast cancer.

Results
In this study, NAP1L1 protein was upregulated based on the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Consistent with the prediction, immunohistochemistry staining showed that NAP1L1 protein expression was significantly increased in breast cancer tissues. Its elevated expression was an unfavorable factor for breast cancer clinical progression and poor prognosis. Stably or transiently knocking down NAP1L1 reduced the cell growth in vivo and in vitro via repressing the cell cycle signal in breast cancer. Furthermore, the molecular basis of NAP1L1-induced cell cycle signal was further studied. NAP1L1 interacted with the HDGF, an oncogenic factor for tumors, and the latter subsequently recruited the key oncogenic transcription factor c-Jun, which finally induced the expression of cell cycle promoter Cyclin D1(CCND1) and thus the cell growth of breast cancer.

Conclusions
Our data demonstrated that NAP1L1 functions as a potential oncogene via interacting with HDGF to recruit c-Jun in breast cancer.
Comprehensive economic evaluation of enhanced recovery after surgery in hepatectomy
Authors: Dong Yihan , Zhang Yan , Jin Chengcheng 
Published: November 2021

AbstractBackgroundEnhanced recovery after surgery (ERAS) is attracting extensive attention and being widely applied to reduce postoperative stress and accelerate recovery. However, the economic benefits of ERAS are less clarified at the social level. We aimed to assess the economic impact of ERAS in hepatectomy from the perspectives of patients, hospitals and society, as well as identify the approach to create the economic benefits of ERAS.MethodsBy combining the literature and national statistical data, the cost-effectiveness framework was clarified, and parameter values were determined. Cost-effectiveness analysis, cost–benefit analysis and cost-minimisation analysis were used to compare ERAS and conventional treatment from the perspectives of patients, hospitals and society. The capital flow diagram was used to analyse the change between them.ResultsERAS significantly reduced the economic burden of disease on patients ($8935.02 vs $10,470.02). The hospital received an incremental benefit in ERAS (the incremental benefit cost ratio value is 1.09), and the total social cost was reduced ($5958.67 vs $6725.80). Capital flow diagram analysis demonstrated that the average daily cost per capita in the ERAS group increased ($669.51 vs $589.98), whereas the benefits depended on the reduction of hospital stay and productivity loss.ConclusionThe mechanism by which ERAS works is to reduce the average length of stay, thereby reducing the economic burden and productivity loss on patients and promoting the hospital bed turnover rate. Therefore, ERAS should further focus on accelerating the rehabilitation process, and more economic support (such as subsidies) should be given to hospitals to carry out ERAS.
Gene profiling of Toll-like receptor signalling pathways in neutrophils of patients with acute-on-chronic liver failure
Authors: Zhang Yi , Wu Wei , Wang Yijie , Tong Lingjia , Hong Meng , Xia Qi , Chen Zhi 
Published: November 2021

Abstract
Objectives
Toll-like receptors (TLRs) on neutrophils play a crucial role in detecting pathogens and organ/tissue injury in acute-on-chronic liver failure (ACLF). However, little is known about the exact mechanisms and potential signalling pathways. The aim of this study was to investigate alterations in TLR signalling pathways in neutrophils of ACLF patients.

Methods
Twenty-seven patients with compensated cirrhosis (n = 9), decompensated cirrhosis (n = 9) and ACLF (n = 9) were enrolled in the study. Neutrophils were isolated, and alterations in TLR signalling pathways were evaluated using an RT2 Profiler™ PCR Array. The fold change for each gene (2(−∆∆CT)) was compared among the groups. Genes with a fold change ratio of ≥ 2 or ≤ 0.5 along with a p value of < 0.05 were considered to be differentially expressed.

Results
A total of 17 genes were upregulated in neutrophils from patients with compensated cirrhosis and were mainly distributed in adaptors, TLR-interacting proteins and downstream pathways. Six genes were detected in patients with decompensated cirrhosis. A trend of downregulation of genes in the TLR signalling pathway was observed in neutrophils of patients with cirrhosis and ACLF. TLR3, IFNG, IL1B, TBK1, CCL2 and LTA were downregulated in neutrophils. Moreover, CD14 and IL10 were upregulated in neutrophils of ACLF patients.

Conclusions
TLR signalling pathway genes were differentially regulated in neutrophils between cirrhosis and ACLF. In ACLF patients, defective expression of TLR3 and IFN, along with enhanced CD14 and IL10 expression, was characterized by transcriptional alterations of neutrophils.
Home-based exercise program for adolescents with juvenile dermatomyositis quarantined during COVID-19 pandemic: a mixed methods study
Authors: Astley Camilla , Sieczkowska Sofia Mendes , Marques Isabela Gouveia , Ihara Bianca Pires , Lindoso Livia , Lavorato Sofia Simão Martins , Campos Lucia Maria Arruda , Pereira Rosa Maria Rodrigues , Elias Adriana Maluf , Aikawa Nadia Emi , Kozu Katia , Iraha Amanda Yuri , Franco Tathiane Christine , Roschel Hamilton , Queiroz Ligia Bruni , Polanczyk Guilherme Vanoni , Silva Clovis Artur , Gualano Bruno 
Published: November 2021

Abstract
Background
Exercise has been suggested to prevent deterioration of health-related quality of life (HRQL) and overall health in pediatric rheumatologic diseases during the COVID-19 pandemic. Herein we describe the effects of a 12-week, home-based, exercise program on overall health and quality of life among quarantined patients with juvenile dermatomyositis (JDM).

Method
This prospective, quasi-experimental, mixed methods (qualitative and quantitative) study was conducted between July and December 2020, during the most restricted period of COVID-19 pandemic in Brazil. The home-based exercise program consisted of a 12-week, three-times-a-week, aerobic and strengthening (bodyweight) training program. Qualitative data were systematically evaluated. Strengths and Difficulties Questionnaire (SDQ), Pediatric Quality of Life Inventory (PedsQOL) and Pittsburgh Sleep Quality Index (PSQI) evaluate symptoms of mental health disorder, HRQL, and quality of sleep.

Findings
11 patients (out of 27) met the inclusion criteria (91% female; mean ± SD age: 13.5 ± 3.2 years). Adherence to the intervention was 72.6%. Barriers to exercise involved poor internet connectivity, excessive weekly sessions, and other commitments. Even though not statistically significant, Self-report SDQ subscales Total Difficulties Score, Emotional Problems Score, and PedsQOL School Functioning Score improved after intervention (− 2.4; 95%confidence interval [CI] -5.1; 0.2, p = 0.06; − 1.0; 95%CI -2.2; 0.2, p = 0.09 and; 11.7; 95%CI -2.5; 25.8, p = 0.09, respectively). Remaining SDQ subscales were not altered. Six themes emerged from patients’ and parents’ comments (qualitative results). Patients engaged in exercise reported other health-related benefits including increased motivation, concentration and strength.

Interpretation
A home-based exercise program was associated with qualitative perceptions of improvements in overall health and HRQL by quarantined adolescents with JDM during COVID-19 pandemic. Lessons from this trial may help developing interventions focused on tackling physical inactivity in JDM.
Hypothermia modulates myeloid cell polarization in neonatal hypoxic–ischemic brain injury
Authors: Seitz Marina , Köster Christian , Dzietko Mark , Sabir Hemmen , Serdar Meray , Felderhoff-Müser Ursula , Bendix Ivo , Herz Josephine 
Published: November 2021

Abstract
Background
Neonatal encephalopathy due to hypoxia–ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice.

Methods
Nine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry.

Results
Immediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT.

Conclusion
Our data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.
Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders
Authors: Luo Gang , Wang Xiaofeng , Cui Yongchen , Cao Yue , Zhao Zhe , Zhang Junfeng 
Published: November 2021

Abstract
Background
Microglial polarization toward pro-inflammatory M1 phenotype are major contributors to the development of perioperative neurocognitive disorders (PNDs). Metabolic reprogramming plays an important role in regulating microglial polarization. We therefore hypothesized that surgical trauma can activate microglial M1 polarization by metabolic reprogramming to induce hippocampal neuroinflammation and subsequent postoperative cognitive impairment.

Methods
We used aged mice to establish a model of PNDs, and investigated whether surgical trauma induced metabolic reprograming in hippocampus using PET/CT and GC/TOF–MS based metabolomic analysis. We then determined the effect of the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) on hippocampal microglial M1 polarization, neuroinflammation, and cognitive function at 3 d after surgery.

Results
We found that surgery group had less context-related freezing time than either control or anesthesia group (P < 0.05) without significant difference in tone-related freezing time (P > 0.05). The level of Iba-1 fluorescence intensity in hippocampus were significantly increased in surgery group than that in control group (P < 0.05) accompanied by activated morphological changes of microglia and increased expression of iNOS/CD86 (M1 marker) in enriched microglia from hippocampus (P < 0.05). PET/CT and metabolomics analysis indicated that surgical trauma provoked the metabolic reprogramming from oxidative phosphorylation to glycolysis in hippocampus. Inhibition of glycolysis by 2-DG significantly alleviated the surgical trauma induced increase of M1 (CD86+CD206−) phenotype in enriched microglia from hippocampus and up-regulation of pro-inflammatory mediators (IL-1β and IL-6) expression in hippocampus. Furthermore, glycolytic inhibition by 2-DG ameliorated the hippocampus dependent cognitive deficit caused by surgical trauma.

Conclusions
Metabolic reprogramming is crucial for regulating hippocampal microglial M1 polarization and neuroinflammation in PNDs. Manipulating microglial metabolism might provide a valuable therapeutic strategy for treating PNDs.
Administration of anti-ERMAP antibody ameliorates Alzheimer’s disease in mice
Authors: Liu Haiyan , Zhao Jin , Lin Yujun , Su Min , Lai Laijun 
Published: November 2021

Abstract
Background
Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques. Immune cells play an important role in the clearance of Aβ deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions.

Methods
We produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice.

Results
We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aβ in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aβ plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aβ antibodies in the serum and the macrophage phagocytosis of Aβ are enhanced in the anti-ERMAP mAb-treated AD mice.

Conclusions
Our results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.
Postpartum intrauterine contraceptive device use and its associated factors in Ethiopia: systematic review and meta-analysis
Authors: Kassa Bekalu Getnet , Ayele Alemu Degu , Belay Habtamu Gebrehana , Tefera Adanech Getie , Tiruneh Gebrehiwot Ayalew , Ayenew Netsanet Temesgen , Mihiretie Gedefaye Nibret , Tenaw Lebeza Alemu , Semahegn Abenezer Melkie , Worku Mulugeta Dilie 
Published: November 2021

Abstract
Background
The intrauterine contraceptive device, a type of long-acting reversible contraception, is one of the most effective and safe contraceptive methods. In Ethiopia, intrauterine contraceptive device is little known and practised to delay pregnancy. Therefore, this study aimed to assess post-partum intrauterine contraceptive device utilisation and its associated factors among women in Ethiopia.

Method
In the current meta-analysis, variables were searched from different electronic database systems, including PubMed, Google Scholar, EMBASE, HINAR, Scopus, Web of Sciences, and Grey literature. Data were extracted using a standardised data collection measurement tool. The data were also analysed by using STATA 16 statistical software. I2 tests assessed heterogeneity between the studies. A random-effect model was used to forecast the pooled utilisation of postpartum intrauterine contraceptive device.

Results
Twelve full-article studies were included. The pooled prevalence of post-partum intrauterine contraceptive device among women in Ethiopia was 21.63%. Occupation (OR = 4.44, 95% CI, 2.24–8.81), educational level of college and above (OR = 5.93, 95% CI, 2.55–13.8), antenatal care (OR = 2.09, 95% CI, 1.4–3.12), age (OR = 4.8, 95% CI, 2.3–10.04), good knowledge (OR = 4.16, 95% CI, 1.65–10.49), counseling (OR = 3.05, 95%CI, 1.41–6.63), husband support (OR = 11.48, 95% CI, 6.05–21.79) and awareness about IUCD (OR = 3.86, 95% CI, 1.46–10.2) were positively associated with utilization of postpartum intrauterine contraception device.

Conclusions
Utilisation of post-partum intrauterine contraceptive device was significantly low. Scaling up women’s educational status and ANC use has paramount importance in increasing post-partum IUD use, which further improves maternal and child health in general. This finding may be useful in both reproductive health promotion at an individual level and policy-making regarding this issue.