bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Outcomes Following Hemodynamic Parameter or Intravascular Imaging-Guided Percutaneous Coronary Intervention in the Era of Drug-Eluting Stents: An Updated Systematic Review and Bayesian Network Meta-Analysis of 28 Randomized Trials and 11,860 Patients
Authors: Hu Meng-Jin , Tan Jiang-Shan , Yin Lu , Zhao Yan-Yan , Gao Xiao-Jin , Yang Jin-Gang , Yang Yue-Jin
Published: June 2022

Background

Coronary angiography (CAG) is the standard imaging modality for guiding percutaneous coronary interventions (PCI). Intracoronary imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), and hemodynamic parameter like fractional flow reserve (FFR) can overcome some limitations of CAG.

Objective

We sought to explore the clinical outcomes of different PCI guidance modalities in the era of drug-eluting stent (DES).

Methods

A network meta-analysis of 28 randomized trials and 11,860 patients undergoing different modalities-guided PCI in the era of DES was performed. Odds ratio (OR) with 95% credible interval (CrI) were calculated.

Results

In comparison with CAG, IVUS was associated with a significant reduction in major adverse cardiovascular events (MACE, OR: 0.60; 95% CrI: 0.46–0.79), cardiovascular death (OR: 0.46; 95% CrI: 0.20–0.94), target vessel/lesion revascularization (TVR/TLR, OR: 0.55; 95% CrI: 0.41–0.74), and a trend toward decreased risk of stent thrombosis (OR: 0.44; 95% CrI: 0.17 to 1.00). FFR/quantitative flow ratio (QFR) could significantly reduce stroke compared with CAG, IVUS, and OCT/optical frequency domain imaging (OFDI). However, myocardial infarction (MI), all-cause death, stent thrombosis, and any revascularization presented similar risks for different PCI guidance modalities.

Conclusion

In the era of DES, IVUS led to lower risks of MACE than CAG, which was mainly due to lower risks of cardiovascular death and TVR/TLR. A trend toward decreased risk of stent thrombosis was also observed with IVUS. Hemodynamic parameter (FFR/QFR)-guided PCI could significantly reduce the stroke risk compared with CAG, IVUS, and OCT/OFDI.

Systematic Review Registration

[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021291442].
Transcriptome Sequencing Data Reveal LncRNA-miRNA-mRNA Regulatory Network in Calcified Aortic Valve Disease
Authors: Huang Kai , Wu Lujia , Gao Yuan , Li Qin , Wu Hao , Liu Xiaohong , Han Lin
Published: June 2022

Background

Calcified aortic valve disease (CAVD) is one of the most common valvular heart diseases in the elderly population. However, no effective medical treatments have been found to interfere with the progression of CAVD, and specific molecular mechanisms of CAVD remain unclear.

Materials and Methods

Transcriptome sequencing data of GSE55492 and GSE148219 were downloaded from the European Nucleotide Archive, and the microarray dataset, GSE12644 was acquired from the Gene Expression Omnibus database. Software, including FastQC, HISAT2, samtools, and featureCounts was applied to generate the read count matrix. The “Limma” package in R was utilized to analyze differentially expressed genes (DEGs). Thereafter, weighted gene co-expression network analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the protein-protein interaction (PPI) network were used to identify hub genes associated with CAVD, which were further validated by receiver operating characteristic curve (ROC) analysis using GSE12644. The long non-coding RNA (LncRNA)-mediated regulatory network was established based on the differentially expressed LncRNAs and hub genes, which were detected using quantitative real-time PCR (qRT-PCR) in clinical samples and valve interstitial cells. Moreover, CIBERSORT was used to calculate the expression distribution of immune cell infiltration in CAVD.

Results

A total of 126 DEGs were included in the PPI network. PI3K-Akt signaling pathway, ECM-receptor interaction, hematopoietic cell lineage, cell adhesion molecules, and focal adhesion were the most enriched pathways revealed by KEGG. Four LncRNAs, including TRHDE-AS1, LINC00092, LINC01094, and LINC00702 were considered the differentially expressed LncRNA. SPP1, TREM1, GPM6A, CCL19, CR1, NCAM1, CNTN1, TLR8, SDC1, and COL6A6 were the 10 hub genes identified to be associated with CAVD. Moreover, the calcified aortic valve samples had a greater level of Tregs, naïve B cells, and M0 macrophages than the noncalcified ones, whereas CAVD samples had a lower M2 macrophage expression compared to the noncalcified valve tissues.

Conclusion

The current study identified SPP1, TREM1, TLR8, SDC1, GPM6A, and CNTN1 as hub genes that could potentially be associated with CAVD. The LINC00702–miR-181b-5p–SPP1 axis might participate in the development of CAVD. Additionally, M2 macrophages, Tregs, naïve B cells, and M0 macrophages might possibly play a role in the initiation of CAVD.
Cardioprotection of Repeated Remote Ischemic Conditioning in Patients With ST-Segment Elevation Myocardial Infarction
Authors: Chen Shaomin , Li Shijia , Feng Xinheng , Wang Guisong
Published: June 2022

Background

Repeated remote ischemic conditioning (RIC) after myocardial infarction (MI) has been shown to improve left ventricular (LV) remodeling in the experimental studies, but its cardioprotective effect in patients with ST-segment elevation myocardial infarction (STEMI) is still unknown.

Objective

To investigate whether repeated RIC started early after primary percutaneous coronary intervention (PCI) can improve LV function in patients with STEMI.

Methods

Patients with STEMI treated by primary PCI were included and randomized to the repeated RIC group (n = 30) or the control group (n = 30). RIC was started within 24 h after PCI and repeated daily for 1 week, using an Auto RIC device. 3D speckle-tracking echocardiography (STE) was used to assessed LV function. The primary study endpoint was the change in LV global longitudinal strain (GLS) from baseline to 1 month after PCI.

Results

The repeated RIC group and the control group were well-matched at baseline including mean GLS (−9.8 ± 2.6% vs. −10.1 ± 2.5%, P = 0.62). Despite there was no significant difference in mean GLS at 1 month between the two groups (−11.9 ± 2.1% vs. −10.9 ± 2.7%, P = 0.13), the mean change in GLS from baseline to 1 month was significantly higher in the treatment group than in the control group (−2.1 ± 2.5% vs. −0.8 ± 2.3%, P = 0.04). There were no significant differences in the changes in global circumferential strain (GCS), global area strain (GAS), global radial strain (GRS), LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) between the two groups. Peak creatine kinase isoenzyme-MB, peak high-sensitivity troponin T, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at 24 h after PCI did not differ significantly between the two groups, but NT-proBNP levels at 1 week were significantly lower in the treatment group than in the control group [357.5 (184.8–762.8) vs. 465.0 (305.8–1525.8) pg/ml, P = 0.04].

Conclusion

Daily repeated RIC started within 24 h after PCI can improve GLS and reduce plasma NT proBNP levels in patients with STEMI.
Case Report: Severe Peripartum Cardiac Disease in Myotonic Dystrophy Type 1
Authors: Besant Georgia , Bourque Pierre R. , Smith Ian C. , Chih Sharon , Lamacie Mariana M. , Breiner Ari , Zwicker Jocelyn , Lochmüller Hanns , Warman-Chardon Jodi
Published: June 2022

Background

Myotonic dystrophy type 1 (DM1) is a hereditary muscular dystrophy affecting ∼2.1–14.3/100,000 adults. Cardiac manifestations of DM1 include conduction disorders and rarely cardiomyopathies. DM1 increases the risk of obstetric complications, however, little is known about the relationship between pregnancy and cardiomyopathy in DM1 due to disease rarity.

Case

A 23-year-old with DM1 developed cardiomyopathy during pregnancy. Despite initial medical stabilization, she subsequently developed multiple spontaneous coronary artery dissections postpartum, worsening cardiomyopathy and multiorgan failure. She died 5 months postpartum.

Conclusion

Though cardiomyopathy and arterial dissection are both known complications of pregnancy, this case suggests individuals with myotonic dystrophy type 1 may be at heightened risk for cardiac disease during the peripartum period. Physicians caring for women with suspected or proven DM1 should offer counseling and be alerted to the risk of cardiac complications with pregnancy and in the peripartum period. Pregnant and peripartum women with DM1 are likely to benefit from more frequent assessments of cardiac function including echocardiograms and early institution of heart failure management protocols when symptoms of cardiomyopathy present.
The Association Between Subclinical Thyroid Dysfunction and Recurrence of Atrial Fibrillation After Catheter Ablation
Authors: Li Rui-bin , Yang Xiao-hong , Zhang Ji-dong , Wang Dong , Cui Xiao-ran , Bai Long , Zhao Lei , Cui Wei
Published: June 2022

Objective

The aim of this study was to evaluate the association between subclinical thyroid dysfunction and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA).

Methods

We examined the association between subclinical thyroid dysfunction and the recurrence of AF at a large university-affiliated cardiac arrhythmia center in China. Data were collected from consecutive patients who underwent RFCA for AF, excluding those with a history of hypothyroidism, hyperthyroidism, or ongoing medical treatment for hypothyroidism or hyperthyroidism, biochemically defined overt thyroid disease, and long-term use of amiodarone before admission. The primary end point was the recurrence of AF in a time-to-event analysis. We compared outcomes in patients who had subclinical hyperthyroidism or hypothyroidism with those who had euthyroid state, using a multivariable Cox model with inverse probability weighting and propensity score matching.

Results

In all, 93 patients were excluded from 435 consecutive patients who underwent RFCA for AF. Of the remaining 342 patients for the analysis, the prevalence of subclinical hyperthyroidism and subclinical hypothyroidism were 26 (7.6%) and 41 (12.0%), respectively; during a median follow-up of 489 days, 91 patients (26.6%) developed a primary end point event. In the main analysis of the multivariable Cox model, only subclinical hyperthyroidism [hazard ratio: 3.07, 95% confidence interval (CI): 1.54–6.14] was associated with an increased risk of end point event after adjusting for potential confounders. However, the association between subclinical hypothyroidism and the end point event was not significant (hazard ratio: 0.66, 95% CI: 0.31–1.43). Results were consistent either in multiple sensitivity analyses or across all subgroups of analysis. Compared with individuals with free triiodothyronine (fT3) in the lowest quintile, those with fT3 in the highest quintile had an HR of 2.23 (95% CI: 1.16–4.28) for recurrence of AF. With the increase of thyroid-stimulating hormone (TSH), a reduction in the risk of recurrence of AF was detected in the adjusted model, and the hazard ratio (HR) per standard deviation (SD) increase was 0.82 (95% CI: 0.68–0.98).

Conclusion

In this retrospective cohort study involving patients who underwent RFCA for AF, patients with subclinical hyperthyroidism were associated with a markedly higher prevalence of recurrence of AF, whereas patients with subclinical hypothyroidism had a similar recurrence rate of AF compared to those with the euthyroid state.
Enhance VR: A Multisensory Approach to Cognitive Training and Monitoring
Authors: Brugada-Ramentol Victòria , Bozorgzadeh Amir , Jalali Hossein
Published: June 2022

Cognitive training systems aim to improve specific domains or global cognition by engaging users in cognitively demanding tasks. While screen-based applications can improve performance in the trained cognitive abilities, they are often criticized for their poor transferability to activities of daily living. These systems, however, exclude the user's body and motor skills, which invariably serves to restrict the user experience. Immersive Virtual Reality (IVR) systems, in contrast, present the user with body-related information, such as proprioceptive and visuomotor information, allowing for an immersive and embodied experience of the environment. This feature renders VR a very appealing tool for cognitive training and neurorehabilitation applications. We present Enhance VR, an IVR-based cognitive training and monitoring application that offers short daily cognitive workouts. The games are designed to train and monitor specific cognitive domains such as memory, task flexibility, information processing, orientation, attention, problem-solving, and motor control. The aim is to test whether cognitively demanding tasks, presented in an IVR setting, provide a naturalistic system to train and monitor cognitive capabilities.
Immunomodulation—What to Modulate and Why? Potential Immune Targets
Authors: Quach Su Sheng , Zhu Alan , Lee Ryan S. B. , Seymour Gregory J.
Published: June 2022

Despite over 50 years of research into the immunology of periodontal disease, the precise mechanisms and the role of many cell types remains an enigma. Progress has been limited by the inability to determine disease activity clinically. Understanding the immunopathogenesis of periodontal disease, however, is fundamental if immunomodulation is to be used as a therapeutic strategy. It is important for the clinician to understand what could be modulated and why. In this context, potential targets include different immune cell populations and their subsets, as well as various cytokines. The aim of this review is to examine the role of the principal immune cell populations and their cytokines in the pathogenesis of periodontal disease and their potential as possible therapeutic targets.
The Controlling Factors of the Natural Gas Hydrate Accumulation in the Songnan Low Uplift, Qiongdongnan Basin, China
Authors: Wei Yang , Zenggui Kuang , Jinfeng Ren , Jinqiang Liang , Hong Lu , Zijie Ning , Chenlu Xu , Hongfei Lai , Rui Chen , Bin Zhao , Jing Chen , Xi Zhang , Lei Liu
Published: June 2022

Hydrocarbon charging stages and natural gas hydrate accumulation models were established in the Songnan Low Uplift, Qiongdongnan Basin (QDNB), China. Detailed geochemical analysis, paleotemperature and paleopressure analyses, seismic interpretation, and hydrocarbon charging characterization were conducted to investigate the controlling factors of natural gas hydrate accumulation. The Yacheng and Lingshui formations in the Lingshui Sag were identified as effective source rocks. The δ13C1 values of the gas hydrates vary from −35.97‰ to −59.50‰, following a direction from the Sag Center to the Low Uplift, indicating that δ13C1 values became relatively lighter during gas migration. Seismic data evidence revealed that large-scale faults, laterally distributed sandstones, and gas chimneys were comprehensive, however efficient hydrocarbon migration pathways. Systematic overpressure was developed in the Yacheng and Huangliu formations, which offer sufficient hydrocarbon migration impetus. Hydrocarbon-bearing aqueous inclusions and their coexisting aqueous inclusions were observed in the Huangliu Formation in the Lingshui Sag, indicating four stages of hydrocarbon charging in the QDNB. Based on the comprehensive analysis in this research, two gas hydrate accumulation models were proposed in the Songnan Low Uplift, QDNB, as follows: 1) a mixture of gas migrated by large-scale faults and a thermogenic-biogenic mixed gas model and 2) gas hydrates from laterally distributed sandstones sealed by MTDs.
Systematic Review of Learning Generic Skills in Higher Education—Enhancing and Impeding Factors
Authors: Tuononen Tarja , Hyytinen Heidi , Kleemola Katri , Hailikari Telle , Männikkö Iina , Toom Auli
Published: June 2022

The research field on generic skills in higher education has expanded rapidly. In addition, the importance of generic skills has been highlighted both in educational policy discourses and in practice of higher education. The present study reviews theoretical, methodological, and empirical viewpoints on learning generic skills and synthesizes the empirical evidence about the factors that enhance and impede student learning of generic skills. Altogether 116 articles were included in the analysis. The systematic analysis revealed remarkable variation in concepts, research methods, and operationalization of generic skills. These findings suggest that research in this field is still incoherent. According to the results, contextual factors that enhance or impede higher education students' learning of generic skills were investigated more often than individual factors. Furthermore, the articles included in this review emphasized learning of work-oriented professional skills over higher-order thinking skills. To ensure the development of research on generic skills, it is important to focus on more coherent theorization and operationalization of the various generic skills. More longitudinal studies with methods that genuinely capture actual skills and their development are also needed to advance the field. The results can be used for future discussions on theorization, empirical research, and practical development of student learning of generic skills.
What Kind of Students Attend Cyber Schools? Pandemic Enrollment as Evidence of Negative Selection
Authors: Kingsbury Ian , Beck Dennis , Bradley-Dorsey Martha
Published: June 2022

Fully online virtual schools have consistently underperformed academically compared to brick and mortar schools. Scholars debate the extent to which these differences are due school quality or the type of student that attends virtual schools. The large number of students who enrolled in virtual schools during the COVID-19 pandemic provides a unique opportunity to revisit this debate, as the phenomenon plausibly attenuates negative selection into virtual schools. Previous research concluded that a virtual school COVID cohort resembled prior groups demographically but reported greater success at their prior in-person schools and in cyber schools, however, it offered only limited insight into their academic performance at their virtual school. We use data from a large cyber charter network (“Countrywide Cyber”) to assess whether students who enrolled in full time virtual schools due to COVID-related concerns performed better on entry diagnostic assessments. Results indicate that students who enrolled due to COVID-19 were stronger academically, corroborating recent descriptive research. The implications of these results for practice and policy are discussed.
The Effect of Early Life Exposure to Triclosan on Thyroid Follicles and Hormone Levels in Zebrafish
Authors: Tang Ning , Fan Pianpian , Chen Li , Yu Xiaogang , Wang Wenjuan , Wang Weiye , Ouyang Fengxiu
Published: June 2022

Triclosan (TCS) is an antimicrobial chemical widely used in personal care products. Most of the TCS component is discharged and enters the aquatic ecosystem after usage. TCS has a similar structure as thyroid hormones that are synthesized by thyroid follicular epithelial cells, thus TCS has a potential endocrine disrupting effect. It is still not clear how the different levels of the environmental TCS would affect early development in vivo. This study examines the effects of TCS on thyroid hormone secretion and the early development of zebrafish. The fertilized zebrafish eggs were exposed to TCS at 0 (control), 3, 30, 100, 300, and 900 ng/mL, and the hatching rate and the larvae mortality were inspected within the first 14 days. The total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4) were measured at 7, 14, and 120 days post-fertilization (dpf). The histopathological examinations of thyroid follicles were conducted at 120 dpf. TCS exposure at 30-300 ng/mL reduced the hatching rate of larvae to 34.5% to 28.2 % in the first 48 hours and 93.8 .7 % to 86.8 % at 72 h. Extremely high TCS exposure (900 ng/mL) strongly inhibited the hatching rate, and all the larvae died within 1 day. Exposure to TCS from 3 to 300 ng/mL reduced the thyroid hormones production. The mean TT3 and FT3 levels of zebrafish decreased in 300 ng/mL TCS at 14 dpf (300 ng/mL TCS vs. control : TT3 , 0.19 ± 0.08 vs. 0.39 ± 0.06; FT3, 19.21 ± 3.13 vs. 28.53 ± 1.98 pg/mg), and the FT4 decreased at 120 dpf ( 0.09 ± 0.04 vs. 0.20 ± 0.14 pg/mg). At 120 dpf , in the 300 ng/mL TCS exposure group, the nuclear area and the height of thyroid follicular epithelial cells became greater, and the follicle cell layer got thicker. This happened along with follicle hyperplasia, nuclear hypertrophy, and angiogenesis in the thyroid. Our study demonstrated that early life exposure to high TCS levels reduces the rate and speed of embryos hatching, and induces the histopathological change of thyroid follicle, and decreases the TT3, FT3, and FT4 production in zebrafish.
Nationwide Trends of Pediatric Obesity and BMI z-Score From 2017-2021 in China: Comparable Findings From Real-World Mobile- and Hospital-Based Data
Authors: Yang Yan , Zhang Miao , Yu Jian , Pei Zhou , Sun Chengjun , He Jingwei , Qian Tian , Luo Feihong , Zhang Shaoyan , Xu Zhenran
Published: June 2022

Introduction

Lifestyle changes including COVID-19 lockdown cause weight gain and may change obesity trends; however, timely changes are largely unknown and monitoring measures are usually lack. This first large-scale study aimed to analyze the real-world national trends of obesity prevalence of Chinese children in the past five years, and the impact of COVID-19 pandemic on pediatric obesity development through both mobile- and hospital-based data.

Methods

This study included children aged 3 to 19 years old all over China from January 2017 to April 2021. Hospital-measured and parent-reported cases from XIGAO database were analyzed. Body mass index (BMI) z-score calculation and obesity status evaluation were made according to Chinese standards. We evaluated obesity/overweight prevalence over the past five years and the changes of BMI z-score during COVID-19 lockdown.

Results

A total of 656396 children from 31 provinces were involved, including 447481 hospital-measured cases and 208915 parent-reported cases. The obesity and overweight prevalence were 8.05% (95%CI 7.76%–8.39%) and 10.06% (95%CI 10.79%–11.55%), comparable to those of China National Nutrition Surveys during 2015–2019. Northern China had the highest obesity prevalence. Parent-reported data had higher obesity/overweight prevalence than hospital-measured data (18.3% [95%CI 17.7%–18.9%] vs. 21.7% [95%CI 20.7%–23.0%]). The trend of obesity prevalence remained stable with slight decrease, but COVID-19 lockdown caused a significant increase of 1.86% in 2020. Both mobile- and hospital-based data showed weight gain in the first half of 2020. High BMI z-score increase were found among primary and junior middle school children, and children in northeast area during lockdown.

Conclusion

Weight gain during COVID-19 among Chinese children had regional differences and mainly affect primary and junior middle school children, thus warrants targeted interventions. The mobile growth assessment based on parent-reported data was a feasible, efficient and timely way for obesity monitoring among Chinese children, especially during epidemic.
DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
Authors: Mangili Federica , Esposito Emanuela , Treppiedi Donatella , Catalano Rosa , Marra Giusy , Di Muro Genesio , Barbieri Anna Maria , Locatelli Marco , Lania Andrea G. , Mangone Alessandra , Spada Anna , Arosio Maura , Peverelli Erika , Mantovani Giovanna
Published: June 2022

The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
Association of Polycystic Ovary Syndrome Phenotypes With Adverse Pregnancy Outcomes After In-Vitro Fertilization/Intracytoplasmic Sperm Injection
Authors: Wang Qiumin , Wang Honghong , Li Ping , Li Xiufang , Wang Ze , Yan Lei , Shi Yuhua
Published: June 2022

Objective

This study aims to evaluate the association between polycystic ovary syndrome (PCOS) phenotypes and adverse perinatal outcomes, comparing the characteristics, ovarian response, and assisted reproductive outcomes in patients with various PCOS phenotypes after in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).

Methods

This study comprised 6,732 patients who underwent the first cycle of IVF/ICSI treatment in our outpatient department from January 2017 to July 2018. Propensity score matching (PSM) was used in PCOS and non-PCOS groups to balance the influence of intergroup confounding factors. After the PSM procedure, 1,186 patients were included in the two groups, and the PCOS patients were further divided into four PCOS phenotype groups based on the Rotterdam criteria.

Results

Patients with various PCOS phenotypes had similar rates of biochemical pregnancy, clinical pregnancy, and live birth (all P-values > 0.05). The overall incidence of adverse pregnancy outcomes (including ectopic pregnancy, miscarriage, preterm birth) was significantly higher in PCOS phenotype A and D groups than in the control group (44% and 46.4% vs. 28.7%, P = 0.027). The rates of hypertensive disorder of pregnancy (HDP) were significantly higher in PCOS phenotype A and C groups than in the control group (9.3% and 12.5% vs. 3.1%, P = 0.037). After adjustment for potential confounders, the differences in adverse pregnancy outcomes persisted (P = 0.025).

Conclusions

The overall incidence of adverse pregnancy outcomes is higher in women with PCOS phenotypes A and D than in women with non-PCOS.
The Regulation of Adipose Tissue Health by Estrogens
Authors: Steiner Benjamin M. , Berry Daniel C.
Published: June 2022

Obesity and its’ associated metabolic diseases such as type 2 diabetes and cardiometabolic disorders are significant health problems confronting many countries. A major driver for developing obesity and metabolic dysfunction is the uncontrolled expansion of white adipose tissue (WAT). Specifically, the pathophysiological expansion of visceral WAT is often associated with metabolic dysfunction due to changes in adipokine secretion profiles, reduced vascularization, increased fibrosis, and enrichment of pro-inflammatory immune cells. A critical determinate of body fat distribution and WAT health is the sex steroid estrogen. The bioavailability of estrogen appears to favor metabolically healthy subcutaneous fat over visceral fat growth while protecting against changes in metabolic dysfunction. Our review will focus on the role of estrogen on body fat partitioning, WAT homeostasis, adipogenesis, adipocyte progenitor cell (APC) function, and thermogenesis to control WAT health and systemic metabolism.
Modeling Emulsification Influence on Oil Properties and Fate to Inform Effective Spill Response
Authors: French-McCay Deborah P. , Frediani Matthew , Gloekler Melissa D.
Published: June 2022

Water-in-oil emulsification affects spilled oil fate and exposure, as well as the effectiveness of oil spill response options,viachanges in oil viscosity. While oil weathering processes such as evaporation, dissolution, photo-oxidation, and biodegradation increase oil viscosity about 10-fold, incorporation of water droplets into floating oil can increase viscosity by another order of magnitude. The objective of this study was to evaluate how changes in viscosity by oil type, with weathering, and with emulsification affect oil fate. Oil spill modeling analyses demonstrated that the increase in viscosity from emulsification prolonged floating oil exposure by preventing the oil from dispersing into the water column. Persistent emulsified oils are more likely to come ashore than low viscosity oils that readily disperse. Through a rapid increase in viscosity, emulsification restricted entrainment and slowed evaporation. Water column exposure to dissolved concentrations increased with lower viscosity oils. Thus, the ability to emulsify, and at what weathered state, are important predictors of oil fate. Oil viscosity is an important consideration for choosing response alternatives as it controls effectiveness of mechanical removal,in-situ-burning and surface-active chemicals. Therefore, understanding and quantification of oil emulsification are research priorities. The most influential model input determining emulsification and the emulsion’s viscosity is its maximum water content, as it controls the ultimate viscosity of the emulsion. Viscosities were also influenced by the volatile content and initial viscosity of the oil. Algorithms quantifying emulsion stability under field conditions have not been developed, so emulsions were assumed stable over the 30-day simulations. Changes in emulsion stability over time would affect oil properties and so floating oil and shoreline exposures, as well as response effectiveness. However, water column exposures to dissolved concentrations are determined within a few days of oil release, and as such would not be affected by differences in long-term stabilities of the emulsions.
The Potential Impacts of Invasive Quagga and Zebra Mussels on Macroinvertebrate Communities: An Artificial Stone Substrate Based Field Experiment Using Stable Isotopes
Authors: Zhang Hui , Yohannes Elizabeth , Rothhaupt Karl-Otto
Published: June 2022

Over the past decades, the zebra mussel (Dreissena polymorpha) and quagga mussel (D. rostriformis bugensis) invaded multiple freshwater systems and posed major threats to the overall ecosystem. In Lake Constance where zebra mussels invaded in the 1960s, the quagga mussel invasion progressed at a very high rate since 2016, providing an opportunity to study the ecological impact of both species at an early stage. We conducted a field experiment in the littoral region of the lake and monitored differences in macroinvertebrate community colonization. We used standardized stone substrates, which were blank, glued with empty shells of mussels, with living adult quagga mussels, and with living adult zebra mussels. Empty shells and the shells of both living adult quagga and zebra mussels created more colonization areas for newly settled macroinvertebrates. The abundance of newly settled quagga mussels was higher than zebra mussels, indicating the outcompeting behavior of quagga mussels. We used stable isotopes (δ13C and δ15N) of both dreissenids and their potential competitors, which include two snail species (New Zealand mud snail Potamopyrgus antipodarum and faucet snail Bithynia tentaculate) and additional invasive gammarid species (killer shrimp Dikerogammarus villosus), in order to investigate their feeding ecology and to evaluate their potential impacts on macroinvertebrate community. The δ13C and δ15N of neither the newly settled quagga mussels nor the well-established zebra mussels differed significantly among various treatments. Newly settled quagga mussels had higher δ13C values than newly settled zebra mussels and showed similar differences in all four stone setups. During the experimental period (with quagga and zebra mussels still coexisting in some regions), these two dreissenids exhibited clear dietary (isotopic) niche segregation. The rapid expansion of invasive quagga mussels coupled with the higher mortality rate of zebra mussels might have caused a dominance shift from zebra to quagga mussels. The study offers the first overview of the progressive invasion of quagga mussel and the reaction of zebra mussels and other newly settled macroinvertebrates, and compliments the hypothesis of facilitative associations between invasive dreissenids. Results provide an experimental benchmark by which future changes in trophic ecology and invasion dynamics can be measured across the ecosystem.
Genetic Diversity and Population Differentiation of Chinese Lizard Gudgeon (Saurogobio dabryi) in the Upper Yangtze River
Authors: Liu Hongyan , Xiong Fei , Zhai Dongdong , Duan Xinbin , Chen Daqing , Chen Yuanyuan , Wang Ying , Xia Ming
Published: June 2022

Dam construction on the upper Yangtze River has dramatically altered riverine ecosystems and caused habitat fragmentation of fishes, which might influence the genetic structure of fish populations. In this study, we examined the possible genetic effects of dam construction on Chinese lizard gudgeon (Saurogobio dabryi) populations in the upper Yangtze River, China. Seven populations were sampled, and genetic structure was analyzed using single nucleotide polymorphism (SNP) markers through the specific locus amplified fragment sequencing (SLAF-seq) method. The numbers of SNPs were lower in the upstream populations than in the downstream populations. Genetic similarity was increased from downstream to upstream. The upstream populations of S. dabryi might be more vulnerable to genetic drift than those downstream. Structure analysis indicated three distinct genetic groups of S. dabryi in the upper Yangtze River, among which the genetic differentiation values (Fst) were at a high level. The genetic differentiation of S. dabryi exhibited a close correlation with spatial distance. We did not detect a significant correlation between isolation time and genetic differentiation, suggesting that impacts of dams on the genetic structure of S. dabryi can be relatively minimal on a short time scale. The results quantify the genetic diversity and population structure patterns of S. dabryi after habitat fragmentation caused by dams, which will provide a reference for resource protection and management of this species in the upper Yangtze River.
Clonal Distribution and Intratumor Heterogeneity of the TCR Repertoire in Papillary Thyroid Cancer With or Without Coexistent Hashimoto’s Thyroiditis
Authors: Cui Likun , Zhang Chaoting , Ding Huirong , Feng Dongdong , Huang Hongying , Lu Zheming , Liu Baoguo
Published: June 2022

The intratumor heterogeneity (ITH) of the amount and TCR repertoires of tumor infiltrating lymphocytes (TILs) in PTC with and without coexistent Hashimoto’s thyroiditis (HT) are unclear. Here, we investigated the amount of T cells in tumor and corresponding normal tissues by immunohistochemical staining on 80 tumor samples and 40 normal samples from 40 patients. The immune repertoire of T cells was identified on 24 tumor samples and 12 normal samples from 12 patients using TCR high-throughput sequencing. The results demonstrated that the numbers of CD3+, CD4+ and CD8+ T cells in PTC without coexistent HT (PTC-WO) were significantly lower than those in PTC with existing HT (PTC-W). In PTC-W, the density of CD4+ TILs were generally higher when compared with CD8+ TILs. Furthermore, we found that the numbers of CD3+ T cells and their CD4+, CD8+ subtypes in tumor samples were generally higher than those in normal tissue in PTC-WO and moreover, the number of CD3+ T cells was negatively associated with TCR clonality in PTC-WO. In addition, although ITH of the TCR repertoire truly existed in PTC-W and PTC-WO, the TCR repertoires between distinct regions of the non-adjacent tumor foci were presented with a higher degree of similarity than those between tumor and matched normal tissue in PTC-WO, yet the similarity of intratumor repertoires was not significantly higher than those between tumor and corresponding normal samples in PTC-W. This research comprehensively delineated the quantity and TCR repertoire ITH of T cells in PTC-W and PTC-WO, suggesting that TILs might be reactive to tumor antigens in PTC-WO. Moreover, multiregion biopsies should be performed to precisely identify the immune background in PTC-W and PTC-WO.
SQLE, A Key Enzyme in Cholesterol Metabolism, Correlates With Tumor Immune Infiltration and Immunotherapy Outcome of Pancreatic Adenocarcinoma
Authors: You Weiqiang , Ke Jia , Chen Yufeng , Cai Zerong , Huang Ze-ping , Hu Peishan , Wu Xiaojian
Published: June 2022

Background

Pancreatic adenocarcinoma (PAAD) is a treatment-refractory cancer with poor prognosis. Accumulating evidence suggests that squalene epoxidase (SQLE) plays a pivotal role in the development and progression of several cancer types in humans. However, the function and underlying mechanism of SQLE in PAAD remain unclear.

Methods

SQLE expression data were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression database. SQLE alterations were demonstrated based on the cBioPortal database. The upstream miRNAs regulating SQLE expression were predicted using starBase. The function of miRNA was validated by Western blotting and cell proliferation assay. The relationship between SQLE expression and biomarkers of the tumor immune microenvironment (TME) was analyzed using the TIMER and TISIDB databases. The correlation between SQLE and immunotherapy outcomes was assessed using Tumor Immune Dysfunction and Exclusion. The log-rank test was performed to compare prognosis between the high and low SQLE groups.

Results

We demonstrated a potential oncogenic role of SQLE. SQLE expression was upregulated in PAAD, and it predicted poor disease-free survival (DFS) and overall survival (OS) in patients with PAAD. “Amplification” was the dominant type of SQLE alteration. In addition, this alteration was closely associated with the OS, disease-specific survival, DFS, and progression-free survival of patients with PAAD. Subsequently, hsa-miR-363-3p was recognized as a critical microRNA regulating SQLE expression and thereby influencing PAAD patient outcome. In vitro experiments suggested that miR-363-3p could knock down the expression of SQLE and inhibit the proliferation of PANC-1. SQLE was significantly associated with tumor immune cell infiltration, immune checkpoints (including PD-1 and CTLA-4), and biomarkers of the TME. KEGG and GO analyses indicated that cholesterol metabolism-associated RNA functions are implicated in the mechanisms of SQLE. SQLE was inversely associated with cytotoxic lymphocytes and predicted immunotherapy outcomes.

Conclusions

Collectively, our results indicate that cholesterol metabolism-related overexpression of SQLE is strongly correlated with tumor immune infiltration and immunotherapy outcomes in patients with PAAD.
Exhausted PD-1+ TOX+ CD8+ T Cells Arise Only in Long-Term Experimental Trypanosoma cruzi Infection
Authors: Gálvez Rosa Isela , Jacobs Thomas
Published: June 2022

Infection with Trypanosoma cruzi remains the most important neglected zoonosis in Latin America. This infection does not lead to specific symptoms in the acute phase, but chronic infection can result in Chagas disease (CD) with cardiac and/or gastrointestinal manifestations that can lead to death. CD8+ T cells are highly effective and essential to control this infection, but fail to eliminate all parasites. In this study, we show that the CD8+ T cells are modulated by the transient induction of co-inhibitory receptors during acute infection of C57BL/6 mice. Therapeutic intervention strategies with blocking antibodies only had a marginal effect on the elimination of parasite reservoirs. Only long-term chronic infection gave rise to dysfunctional CD8+ T cells, which were characterized by high expression of the inhibitory receptor PD-1 and the co-expression of the transcription factor TOX, which plays a crucial role in the maintenance of the exhausted phenotype. PD-1+ TOX+ CD8+ T cells isolated from the site of infection produced significantly less IFN-γ, TNF-α and Granzyme B than their PD-1- TOX- CD8+ T cell counterparts after T. cruzi-specific stimulation ex vivo. Taken together, we provide evidence that, in the context of experimental infection of mice, the magnitude of the CD8+ T cell response in the acute phase is sufficient for parasite control and cannot be further increased by targeting co-inhibitory receptors. In contrast, persistent long-term chronic infection leads to an increase of exhausted T cells within the tissues of persistence. To our knowledge, this is the first description of infection-induced CD8+ T cells with an exhausted phenotype and reduced cytokine production in muscles of T. cruzi-infected mice.
Pre-Clinical Autoimmunity in Lupus Relatives: Self-Reported Questionnaires and Immune Dysregulation Distinguish Relatives Who Develop Incomplete or Classified Lupus From Clinically Unaffected Relatives and Unaffected, Unrelated Individuals
Authors: Munroe Melissa E. , Young Kendra A. , Guthridge Joel M. , Kamen Diane L. , Gilkeson Gary S. , Weisman Michael H. , Ishimori Mariko L. , Wallace Daniel J. , Karp David R. , Harley John B. , Norris Jill M. , James Judith A.
Published: June 2022

Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting <4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort (p≤0.01). Increased levels of BLyS and decreased levels of IL-10 were associated with type 2 symptoms (p<0.05). SLE-CSQ scores, ACR scores, and accumulated AutoAb specificities correlated with levels of multiple inflammatory immune mediators (p<0.05), including BLyS, IL-2Rα, stem cell factor (SCF), soluble TNF receptors, and Th-1 type mediators and chemokines. Transition to SLE was associated with increased levels of SCF (p<0.05). ILE Rel also had increased levels of TNF-α and IFN-γ, offset by increased levels of regulatory IL-10 and TGF-β (p<0.05). Clinically unaffected Rel (vs. HC) had higher SLE-CSQ scores (p<0.001), increased serology (p<0.05), and increased inflammatory mediator levels, offset by increased IL-10 and TGF-β (p<0.01). These findings suggest that Rel at highest risk of transitioning to classified SLE have increased inflammation coupled with decreased regulatory mediators. In contrast, clinically unaffected Rel and Rel with ILE demonstrate increased inflammation offset with increased immune regulation, intimating a window of opportunity for early intervention and enrollment in prevention trials.
Modification of Extracellular Matrix by the Product of DHA Oxidation Switches Macrophage Adhesion Patterns and Promotes Retention of Macrophages During Chronic Inflammation
Authors: Casteel Jared L. , Keever Kasey R. , Ardell Christopher L. , Williams David L. , Gao Detao , Podrez Eugene A. , Byzova Tatiana V. , Yakubenko Valentin P.
Published: June 2022

Oxidation of polyunsaturated fatty acids contributes to different aspects of the inflammatory response due to the variety of products generated. Specifically, the oxidation of DHA produces the end-product, carboxyethylpyrrole (CEP), which forms a covalent adduct with proteinsviaan ϵ-amino group of lysines. Previously, we found that CEP formation is dramatically increased in inflamed tissue and CEP-modified albumin and fibrinogen became ligands for αDβ2(CD11d/CD18) and αMβ2(CD11b/CD18) integrins. In this study, we evaluated the effect of extracellular matrix (ECM) modification with CEP on the adhesive properties of M1-polarized macrophages, particularly during chronic inflammation. Using digested atherosclerotic lesions andin vitrooxidation assays, we demonstrated the ability of ECM proteins to form adducts with CEP, particularly, DHA oxidation leads to the formation of CEP adducts with collagen IV and laminin, but not with collagen I. Using integrin αDβ2-transfected HEK293 cells, WT andαD−/−mouse M1-polarized macrophages, we revealed that CEP-modified proteins support stronger cell adhesion and spreading when compared with natural ECM ligands such as collagen IV, laminin, and fibrinogen. Integrin αDβ2is critical for M1 macrophage adhesion to CEP. Based on biolayer interferometry results, the isolated αDI-domain demonstrates markedly higher binding affinity to CEP compared to the “natural” αDβ2ligand fibrinogen. Finally, the presence of CEP-modified proteins in a 3D fibrin matrix significantly increased M1 macrophage retention. Therefore, CEP modification converts ECM proteins to αDβ2-recognition ligands by changing a positively charged lysine to negatively charged CEP, which increases M1 macrophage adhesion to ECM and promotes macrophage retention during detrimental inflammation, autoimmunity, and chronic inflammation.