bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry
Authors: Sánchez-Martínez Rosario , Iriarte Adriana , Mora-Luján José María , Patier José Luis , López-Wolf Daniel , Ojeda Ana , Torralba Miguel Angel , Juyol María Coloma , Gil Ricardo , Añón Sol , Salazar-Mendiguchía Joel , Riera-Mestre Antoni ,   for the RiHHTa Investigators of the Rare Diseases Working Group from the Spanish Society of Internal Medicine, Alonso-Cotoner C. , Añón S. , Beneyto M. , Bermejo-Olano M. M. , Cerdà P. , Cruellas F. , De Los Santos A. , Díez L. , Fernández A. , García-Morillo J. S. , Gil R. , Gómez-Cerezo J. F. , Gómez del Olmo V. , González-García A. , Iriarte A. , Iglesias P. , Juyol M. C. , López-Osle N. , López M. , López-Wolf D. , Mora-Luján J. M. , Moreno M. , Ojeda A. , Patier J. L. , Pérez de León J. A. , Perez M. L. , Riera-Mestre A. , Rivera S. , Rodríguez S. , Sánchez-Martínez R. , Torralba M. A. , Zarrabeitia R. 
Published: June 2020

Abstract
Background
Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis.

Methods
We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain.

Results
By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients.

Conclusions
ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.
Recommendations for fluid management of adults with sepsis in sub-Saharan Africa: a systematic review of guidelines
Authors: Silberberg Benjamin , Aston Stephen , Boztepe Selda , Jacob Shevin , Rylance Jamie 
Published: June 2020

Abstract
Background
Sepsis guidelines are widely used in high-income countries and intravenous fluids are an important supportive treatment modality. However, fluids have been harmful in intervention trials in low-income countries, most notably in sub-Saharan Africa. We assessed the relevance, quality and applicability of available guidelines for the fluid management of adult patients with sepsis in this region.

Methods
We identified sepsis guidelines by systematic review with broad search terms, duplicate screening and data extraction. We included peer-reviewed publications with explicit relevance to sepsis and fluid therapy. We excluded those designed exclusively for specific aetiologies of sepsis, for limited geographic locations, or for non-adult populations. We used the AGREE II tool to assess the quality of guideline development, performed a narrative synthesis and used theoretical case scenarios to assess practical applicability to everyday clinical practice in resource-constrained settings.

Results
Published sepsis guidelines are heterogeneous in sepsis definition and in quality: 8/10 guidelines had significant deficits in applicability, particularly with reference to resource considerations in low-income settings. Indications for intravenous fluid were hypotension (8/10), clinical markers of hypoperfusion (6/10) and lactataemia (3/10). Crystalloids were overwhelmingly recommended (9/10). Suggested volumes varied; 5/10 explicitly recommended “fluid challenges” with reassessment, totalling between 1 L and 4 L during initial resuscitation. Fluid balance, including later de-escalation of therapy, was not specifically described in any. Norepinephrine was the preferred initial vasopressor (5/10), specifically targeted to MAP > 65 mmHg (3/10), with higher values suggested in pre-existing hypertension (1/10). Recommendations for guidelines were almost universally derived from evidence in high-income countries. None of the guidelines suggested any refinement for patients with malnutrition.

Conclusions
Widely used international guidelines contain disparate recommendations on intravenous fluid use, lack specificity and are largely unattainable in low-income countries given available resources. A relative lack of high-quality evidence from sub-Saharan Africa increases reliance on recommendations which may not be relevant or implementable.
Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients
Authors: Ma Aijia , Cheng Jiangli , Yang Jing , Dong Meiling , Liao Xuelian , Kang Yan 
Published: June 2020

Trial registrationChiCTR, ChiCTR2000029758. Registered 12 February 2020 - Retrospectively registered
Procedural volume and outcomes in patients undergoing VA-ECMO support
Authors: Becher Peter Moritz , Goßling Alina , Schrage Benedikt , Twerenbold Raphael , Fluschnik Nina , Seiffert Moritz , Bernhardt Alexander M. , Reichenspurner Hermann , Blankenberg Stefan , Westermann Dirk 
Published: June 2020

Abstract
Background
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used in patients with critical cardiopulmonary failure. To investigate the association between hospital VA-ECMO procedure volume and outcomes in a large, nationwide registry.

Methods
By using administrative data from the German Federal Health Monitoring System, we analyzed all VA-ECMO procedures performed in Germany from 2013 to 2016 regarding the association of procedural volumes with outcomes and complications.

Results
During the study period, 10,207 VA-ECMO procedures were performed; mean age was 61 years, 43.4% had prior CPR, and 71.2% were male patients. Acute coronary syndrome was the primary diagnosis for VA-ECMO implantation (n = 6202, 60.8%). The majority of implantations (n = 5421) were performed at hospitals in the lowest volume category (≤ 50 implantations per year).
There was a significant association between annualized volume of VA-ECMO procedures and 30-day in-hospital mortality for centers with lower vs. higher volume per year. Multivariable logistic regression showed an increased 30-day in-hospital mortality at hospitals with the lowest volume category (adjusted odds ratio 1.13, 95% confidence interval [CI] 1.01–1.27, p = 0.034).
Similarly, higher likelihood for complications was observed at hospitals with lower vs. higher annual VA-ECMO volume (adjusted odds ratio 1.46, 95% CI 1.29–1.66, p = 0.001).

Conclusions
In this analysis of more than 10,000 VA-ECMO procedures for cardiogenic shock, the majority of implantations were performed at hospitals with the lowest annual volume. Thirty-day in-hospital mortality and likelihood for complications were higher at hospitals with the lowest annual VA-ECMO volume.
Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer
Authors: Humphries Brock A. , Cutter Alyssa C. , Buschhaus Johanna M. , Chen Yu-Chih , Qyli Tonela , Palagama Dilrukshika S. W. , Eckley Samantha , Robison Tanner H. , Bevoor Avinash , Chiang Benjamin , Haley Henry R. , Sahoo Saswat , Spinosa Phillip C. , Neale Dylan B. , Boppisetti Jagadish , Sahoo Debashis , Ghosh Pradipta , Lahann Joerg , Ross Brian D. , Yoon Eusik , Luker Kathryn E. , Luker Gary D. 
Published: June 2020

AbstractBackgroundMitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC).MethodsWe enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer.ResultsEnforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer.ConclusionsIn TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer.
Efficacy and safety of YinQiSanHuang-antiviral decoction in chronic hepatitis B: study protocol for a randomized, placebo-controlled, double-blinded trial
Authors: Wu Qing-Juan , Lv Wen-Liang , Li Juan-Mei , Zhang Ting-Ting , Zhou Wen-hui , Zhang Qiang , Wang Jiu-Chong , Wang Qing-Nan , Zhang Ruo-Xuan , Zhao Xin , Chen Si-Tong , Liu Shuang , Li Gao-Hui , Cao Zheng-Min , Xu Lei , Chen Jing 
Published: June 2020

Abstract
Introduction
Chronic hepatitis B (CHB) is a global public health problem. Antiviral therapy is the primary treatment. Studies have shown that a combined therapy of traditional Chinese medicine (TCM) and conventional antiviral drugs has better efficacy than conventional antiviral for treatment of CHB. YinQiSanHuang-antiviral decoction (YQSH) is a TCM compound preparation that has shown an effect on anti-hepatitis B virus and on slowing progression of hepatitis B-related liver diseases. To evaluate the efficacy and safety of YQSH combined with entecavir and its preventive effect on hepatitis B cirrhosis, we designed this randomized, double-blind and placebo-controlled trial. The objective is that the combination of YinQiSanHuang-antiviral decoction with entecavir will reduce the annual incidence of liver fibrosis/cirrhosis to 1%.

Methods
This is a multicenter, randomized, placebo-controlled, double-blinded trial involving five hospitals. A total of 802 patients are randomly allocated to two groups: the YQSH group (n = 401) or the placebo group (n = 401). The YQSH group receives YQSH with entecavir; the placebo group receives granules of placebo with entecavir. Patients receive treatment for 52 weeks and then are followed up for 52 ± 2 weeks. The primary outcome measure is the annual incidence of cirrhosis. The secondary outcome measures are hepatitis B virus DNA negative rate, hepatitis B surface antigen negative rate, hepatitis B e antigen seroconversion rate, liver function (alanine aminotransferase, aspartate aminotransferase , gamma-glutamyl transferase , alkaline phosphatase , serum albumin, and total bilirubin), spleen thickness, evaluation scores of patients’ clinical symptoms, and safety assessment. Outcomes will be assessed at baseline and after treatment.

Discussion
Combination therapy could become a trend for treatment of CHB, and this trial expects to provide credible clinical evidence for the future combination of TCM and conventional antiviral drugs for the treatment of CHB.

Trial registration
Chinese Clinical Trial Registry: ChiCTR1900021521. Registered on 25 February 2019.
Developing a national atlas to support the progressive control of tsetse-transmitted animal trypanosomosis in Kenya
Authors: Ngari Nancy N. , Gamba Daniel O. , Olet Pamela A. , Zhao Weining , Paone Massimo , Cecchi Giuliano 
Published: June 2020

Abstract
Background
African animal trypanosomosis (AAT) is a major livestock disease in Kenya. Even though, over the years various organizations have collected a vast amount of field data on tsetse and AAT in different parts of the country, recent national-level maps are lacking. To address this gap, a national atlas of tsetse and AAT distribution is being developed by the Kenya Tsetse and Trypanosomosis Eradication Council (KENTTEC) and partners.

Methods
All data collected by KENTTEC from 2006 to 2019 were systematically assembled, georeferenced and harmonized. A comprehensive data repository and a spatially-explicit database were created. Input data were collected mainly in the context of control activities, and include both baseline surveys (i.e. pre-intervention) and the subsequent monitoring during and after interventions. Surveys were carried out in four regions (i.e. Western, Rift Valley, Central and Coast), and in 21 of the 47 counties in Kenya. Various devices were used for entomological data collection (i.e. biconical, NGU and H traps, and sticky panels), while the buffy-coat technique was the method used to detect AAT.

Results
Tsetse trapping was carried out in approximately 5000 locations, and flies (> 71,000) were caught in all four investigated regions. Six species of Glossina were detected: G. pallidipes (87% of the catches); G. brevipalpis (8%); G. fuscipes fuscipes (4%); G. longipennis (< 1%); G. austeni (< 1%); and G. swynnertoni (< 1%). A total of 49,785 animals (98% of which cattle) were tested for AAT in approximately 500 locations. Of these, 914 animals were found to be infected. AAT was confirmed in all study regions, in particular caused by Trypanosoma vivax (48% of infections) and T. congolense (42%). Fewer cases of T. brucei were found.

Conclusions
The development and regular update of a comprehensive national database of tsetse and AAT is crucial to guide decision making for the progressive control of the disease. This first version of the atlas based on KENTTEC data has achieved a remarkable level of geographical coverage, but temporal and spatial gaps still exist. Other stakeholders at the national and international level will contribute to the initiative, thus improving the completeness of the atlas.
Initiator and executioner caspases in salivary gland apoptosis of Rhipicephalus haemaphysaloides
Authors: Wang Yanan , Hu Shanming , Tuerdi Mayinuer , Yu Xinmao , Zhang Houshuang , Zhou Yongzhi , Cao Jie , da Silva Vaz Itabajara , Zhou Jinlin 
Published: June 2020

Abstract
Background
Apoptosis is fundamental in maintaining cell balance in multicellular organisms, and caspases play a crucial role in apoptosis pathways. It is reported that apoptosis plays an important role in tick salivary gland degeneration. Several different caspases have been found in ticks, but the interactions between them are currently unknown. Here, we report three new caspases, isolated from the salivary glands of the tick Rhipicephalus haemaphysaloides.

Methods
The full-length cDNA of the RhCaspases 7, 8 and 9 genes were obtained by transcriptome, and RhCaspases 7, 8 and 9 were expressed in E. coli; after protein purification and immunization in mice, specific polyclonal antibodies (PcAb) were created in response to the recombinant protein. Reverse-transcription quantitative PCR (RT-qPCR) and western blot were used to detect the existence of RhCaspases 7, 8 and 9 in ticks. TUNEL assays were used to determine the apoptosis level in salivary glands at different feeding times after gene silencing. The interaction between RhCaspases 7, 8 and 9 were identified by co-transfection assays.

Results
The transcription of apoptosis-related genes in R. haemaphysaloides salivary glands increased significantly after tick engorgement. Three caspase-like molecules containing conserved caspase domains were identified and named RhCaspases 7, 8 and 9. RhCaspase8 and RhCaspase9 contain a long pro-domain at their N-terminals. An RT-qPCR assay demonstrated that the transcription of these three caspase genes increased significantly during the engorged periods of the tick developmental stages (engorged larval, nymph, and adult female ticks). Transcriptional levels of RhCaspases 7, 8 and 9 in salivary glands increased more significantly than other tissues post-engorgement. RhCaspase9-RNAi treatment significantly inhibited tick feeding. In contrast, knockdown of RhCaspase7 and RhCaspase8 had no influence on tick feeding. Compared to the control group, apoptosis levels were significantly reduced after interfering with RhCaspase 7, 8 and 9 expressions. Co-transfection assays showed RhCaspase7 was cleaved by RhCaspases 8 and 9, demonstrating that RhCaspases 8 and 9 are initiator caspases and RhCaspase7 is an executioner caspase.

Conclusions
To the best of our knowledge, this is the first study to identify initiator and executioner caspases in ticks, confirm the interaction among them, and associate caspase activation with tick salivary gland degeneration.
Epigenome-wide association study in healthy individuals identifies significant associations with DNA methylation and PBMC extract VEGF-A concentration
Authors: Gorenjak Vesna , Vance Dwaine R. , Dade Sébastien , Stathopoulou Maria G. , Doherty Lauren , Xie Ting , Murray Helena , Masson Christine , Lamont John , Fitzgerald Peter , Visvikis-Siest Sophie 
Published: June 2020

AbstractIntroductionVascular endothelial growth factor A (VEGF-A) is a chemokine that induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It is known for its high heritability (> 60%) and involvement in most common morbidities, which makes it a potentially interesting biomarker. Large GWAS studies have already assessed polymorphisms related to VEGF-A. However, no previous research has provided epigenome-wide insight in regulation of VEGF-A.MethodsVEGF-A concentrations of healthy participants from the STANISLAS Family Study (n= 201) were comprehensively assessed for association with DNA methylation. Genome-wide DNA methylation profiles were determined in whole blood DNA using the 450K Infinium BeadChip Array (Illumina). VEGF-A concentration in PBMC extracts was detected using a high-sensitivity multiplex Cytokine Array (Randox Laboratories, UK).ResultsEpigenome-wide association analysis identified 41 methylation sites significantly associated with VEGF-A concentrations derived from PBMC extracts. Twenty CpG sites within 13 chromosomes reached Holm-Bonferroni significance. Significant values ranged fromP= 1.08 × 10−7toP= 5.64 × 10−15.ConclusionThis study exposed twenty significant CpG sites linking DNA methylation to VEGF-A concentration. Methylation detected in promoter regions, such as TPX2 and HAS-1, could explain previously reported associations with theVEGFAgene. Methylation may also help in the understanding of the regulatory mechanisms of other genes located in the vicinity of detected CpG sites.
Intra-carotid arterial transfusion of circulatory-derived autologous endothelial progenitor cells in rodent after ischemic stroke—evaluating the impact of therapeutic time points on prognostic outcomes
Authors: Lin Kun-Chen , Chai Han-Tan , Chen Kuan-Hung , Sung Pei-Hsun , Chiang John Y. , Shao Pei-Lin , Huang Chi-Ruei , Li Yi-Chen , Ko Sheung-Fat , Yip Hon-Kan 
Published: June 2020

AbstractBackgroundThis study tested the optimal time point for left intra-carotid arterial (LICA) administration of circulatory-derived autologous endothelial progenitor cells (EPCs) for improving the outcome in rat after acute ischemic stroke (IS).Methods and resultsAdult male SD rats (n = 70) were equally categorized into group 1 (sham-operated control), group 2 (IS), group 3 (IS+EPCs/1.2 × 106cells/by LICA administration 3 h after IS), group 4 (IS+EPCs/LICA administration post-day-3 IS), group 5 (IS+EPCs/LICA administration post-day-7 IS), group 6 (IS+EPCs/LICA administration post-day-14 IS), and group 7 (IS+EPCs/LICA administration post-day-28 IS). The brain infarct volume (BIV) (at day 60/MRI) was lowest in group 1, highest in group 2, and significantly progressively increased from groups 3 to 7, whereas among the IS animals, the neurological function was significantly preserved in groups 3 to 6 than in groups 2 and 7 post-day-60 IS (allP < 0.0001). By day 60, the endothelial cell markers at protein and cellular levels and number of small vessels exhibited an opposite pattern of BIV among the groups (allP < 0.0001). The protein and cellular levels of inflammation, and protein levels of oxidative stress, autophagy, and apoptosis were highest in group 2, lowest in group 1, and progressively increased from groups 3 to 7 (allP < 0.0001). The angiogenesis biomarkers at protein and cellular levels were significantly progressively increased from groups 1 to 3, then significantly progressively decreased from groups 4 to 7 (allP < 0.0001).ConclusionEarly EPC administration provided better benefits on improving functional/image/molecular-cellular outcomes after acute IS in rat.