bluuebunny/crossref_metadata_2025_split huggingface dataset:
I don't leave my people; They need me: Qualitative research of local health care professionals' working motivations in Syria
Authors: Kallström Agneta , Al-Abdulla Orwa , Parkki Jan , Häkkinen Mikko , Juusola Hannu , Kauhanen Jussi 
Published: January 2022

Abstract
Background
The Syrian conflict has endured for a decade, causing one of the most significant humanitarian crises since World War II. The conflict has inflicted massive damage to civil infrastructure, and not even the health care sector has been spared. On the contrary, health care has been targeted, and as a result, many health professionals have left the country. Despite the life-threatening condition, many health professionals continued to work inside Syria even in the middle of the acute crisis. This qualitative study aims to determine the factors that have motivated Syrian health professionals to work in a conflict-affected country.

Methods
The research is based on 20 semi-structured interviews of Syrian health care workers. Interviews were conducted in 2016–2017 in Gaziantep, Turkey. A thematic inductive content analysis examined the motivational factors Syrian health care workers expressed for their work in the conflict area.

Results
Motivating factors for health care workers were intrinsic and extrinsic. Intrinsic reasons included humanitarian principles and medical ethics. Also, different ideological reasons, patriotic, political and religious, were mentioned. Economic and professional reasons were named as extrinsic reasons for continuing work in the war-torn country.

Conclusions
The study adds information on the effects of the Syrian crisis on health care—from healthcare workers' perspective. It provides a unique insight on motivations why health care workers are continuing their work in Syria. This research underlines that the health care system would collapse totally without local professionals and leave the population without adequate health care.
RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner
Authors: Yu Dan , Pan Min , Li Yanshi , Lu Tao , Wang Zhihai , Liu Chuan , Hu Guohua 
Published: January 2022

Abstract
Background
Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined.

Methods
The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC.

Results
We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability.

Conclusions
Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.
Down-regulation of ZNF252P-AS1 alleviates ovarian cancer progression by binding miR-324-3p to downregulate LY6K
Authors: Geng Li , Wang Zhongqiu , Tian Yongju 
Published: January 2022

Abstract
Background
Ovarian cancer is a common gynecological malignant disease in women. Our work aimed to study the specific functions of ZNF252P antisense RNA 1 (ZNF252P-AS1) in ovarian cancer.

Methods
ZNF252P-AS1, miR-324-3p, and lymphocyte antigen 6 family member K (LY6K) expression were analyzed by bioinformatics tools in ovarian cancer tissues and was quantified by qRT-PCR in ovarian cancer cells. The effect of ZNF252P-AS1 knockdown, miR-324-3p suppression, and LY6K over-expression on apoptosis, cell viability, invasion, migration, and epithelial to mesenchymal transition (EMT) was determined in vitro by using colony formation and EdU assays, flow cytometry, transwell assay, and Western blot. The interactions between ZNF252P-AS1 and miR-324-3p and between miR-324-3p and LY6K were validated by luciferase assays. The effects of restraining ZNF252P-AS1 in vivo were studied using BALB/c male nude mice.

Results
ZNF252P-AS1 and LY6K levels were up-regulated, while miR-324-3p was declined in ovarian cancer tissues and cells. ZNF252P-AS1 knockdown reduced ovarian cancer cell proliferation, invasion, migration, and EMT, whereas promoted its apoptosis. Besides, ZNF252P-AS1 interacted with miR-324-3p and reversely regulated its level, and miR-324-3p was directly bound to LY6K and negatively regulated its expression. Moreover, ZNF252P-AS1 knockdown reversed the effect of miR-324-3p on cancer cell apoptosis, growth, migration, invasion, and EMT. Similar results were discovered in the rescue experiments between miR-324-3p and LY6K. Additionally, mouse models in vivo experiments further validated that ZNF252P-AS1 knockdown distinctly inhibited tumor growth.

Conclusion
ZNF252P-AS1 mediated miR-324-3p/LY6K signaling to facilitate progression of ovarian cancer.
Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial
Authors: Santamarina Mario G. , Beddings Ignacio , Lomakin Felipe Martinez , Boisier Riscal Dominique , Gutiérrez Claveria Mónica , Vidal Marambio Jaime , Retamal Báez Nicole , Pavez Novoa Cristian , Reyes Allende César , Ferreira Perey Paulina , Gutiérrez Torres Miguel , Villalobos Mazza Camila , Vergara Sagredo Constanza , Ahumada Bermejo Sebastian , Labarca Mellado Eduardo , Barthel Munchmeyer Elizabeth , Marchant Ramos Solange , Volpacchio Mariano , Vega Jorge 
Published: January 2022

Abstract
Background
SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation–perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA.

Methods
Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis.

Results
Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41–68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7–12 days vs. 12 IQR 9–21 days, p = 0.04).

Conclusions
No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results.
Trial Registration: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446.
Robust normalization and transformation techniques for constructing gene coexpression networks from RNA-seq data
Authors: Johnson Kayla A. , Krishnan Arjun 
Published: January 2022

AbstractBackgroundConstructing gene coexpression networks is a powerful approach for analyzing high-throughput gene expression data towards module identification, gene function prediction, and disease-gene prioritization. While optimal workflows for constructing coexpression networks, including good choices for data pre-processing, normalization, and network transformation, have been developed for microarray-based expression data, such well-tested choices do not exist for RNA-seq data. Almost all studies that compare data processing and normalization methods for RNA-seq focus on the end goal of determining differential gene expression.ResultsHere, we present a comprehensive benchmarking and analysis of 36 different workflows, each with a unique set of normalization and network transformation methods, for constructing coexpression networks from RNA-seq datasets. We test these workflows on both large, homogenous datasets and small, heterogeneous datasets from various labs. We analyze the workflows in terms of aggregate performance, individual method choices, and the impact of multiple dataset experimental factors. Our results demonstrate that between-sample normalization has the biggest impact, with counts adjusted by size factors producing networks that most accurately recapitulate known tissue-naive and tissue-aware gene functional relationships.ConclusionsBased on this work, we provide concrete recommendations on robust procedures for building an accurate coexpression network from an RNA-seq dataset. In addition, researchers can examine all the results in great detail athttps://krishnanlab.github.io/RNAseq_coexpressionto make appropriate choices for coexpression analysis based on the experimental factors of their RNA-seq dataset.
Assessing reproducibility of inherited variants detected with short-read whole genome sequencing
Authors: Pan Bohu , Ren Luyao , Onuchic Vitor , Guan Meijian , Kusko Rebecca , Bruinsma Steve , Trigg Len , Scherer Andreas , Ning Baitang , Zhang Chaoyang , Glidewell-Kenney Christine , Xiao Chunlin , Donaldson Eric , Sedlazeck Fritz J. , Schroth Gary , Yavas Gokhan , Grunenwald Haiying , Chen Haodong , Meinholz Heather , Meehan Joe , Wang Jing , Yang Jingcheng , Foox Jonathan , Shang Jun , Miclaus Kelci , Dong Lianhua , Shi Leming , Mohiyuddin Marghoob , Pirooznia Mehdi , Gong Ping , Golshani Rooz , Wolfinger Russ , Lababidi Samir , Sahraeian Sayed Mohammad Ebrahim , Sherry Steve , Han Tao , Chen Tao , Shi Tieliu , Hou Wanwan , Ge Weigong , Zou Wen , Guo Wenjing , Bao Wenjun , Xiao Wenzhong , Fan Xiaohui , Gondo Yoichi , Yu Ying , Zhao Yongmei , Su Zhenqiang , Liu Zhichao , Tong Weida , Xiao Wenming , Zook Justin M. , Zheng Yuanting , Hong Huixiao 
Published: January 2022

AbstractBackgroundReproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS.ResultsTo dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×.ConclusionsOur findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.
Low-dose corticosteroid therapy for cardiogenic shock in adults (COCCA): study protocol for a randomized controlled trial
Authors: Mekontso Dessap Armand , Bagate François , Delmas Clément , Morichau-Beauchant Tristan , Cholley Bernard , Cariou Alain , Lattuca Benoit , Moussa Mouhamed , Mongardon Nicolas , Fard Damien , Schmidt Matthieu , Bouglé Adrien , Kerneis Mathieu , Vivier Emmanuel , Roubille François , Duprey Matthieu , Decalf Véronique , Genet Thibaud , Merzoug Messaouda , Audureau Etienne , Squara Pierre 
Published: January 2022

Abstract
Background
Cardiogenic shock (CS) is a life-threatening condition characterized by circulatory insufficiency caused by an acute dysfunction of the heart pump. The pathophysiological approach to CS has recently been enriched by the tissue consequences of low flow, including inflammation, endothelial dysfunction, and alteration of the hypothalamic-pituitary-adrenal axis. The aim of the present trial is to evaluate the impact of early low-dose corticosteroid therapy on shock reversal in adults with CS.

Method/design
This is a multicentered randomized, double-blind, placebo-controlled trial with two parallel arms in adult patients with CS recruited from medical, cardiac, and polyvalent intensive care units (ICU) in France. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 380 patients (190 per group). For the treatment group, hydrocortisone (50 mg intravenous bolus every 6 h) and fludrocortisone (50 μg once a day enterally) will be administered for 7 days or until discharge from the ICU. The primary endpoint is catecholamine-free days at day 7. Secondary endpoints include morbidity and all-cause mortality at 28 and 90 days post-randomization. Pre-defined subgroups analyses are planned, including: postcardiotomy, myocardial infarction, etomidate use, vasopressor use, and adrenal profiles according the short corticotropin stimulation test. Each patient will be followed for 90 days. All analyses will be conducted on an intention-to-treat basis.

Discussion
This trial will provide valuable evidence about the effectiveness of low dose of corticosteroid therapy for CS. If effective, this therapy might improve outcome and become a therapeutic adjunct for patients with CS.

Trial registration
ClinicalTrials.gov, NCT03773822. Registered on 12 December 2018
Efficacy of Chinese herbal medicine Jiangniaosuan formula for treatment of hyperuricemia: study protocol for a double-blinded non-inferiority randomized controlled clinical trial
Authors: Guo Yafang , Lu Hong , Gan Jing , Li Dongdong , Gao Jiandong , Zhang Changming 
Published: January 2022

Abstract
Background
Jiangniaosuan formula (JNSF) is commonly used in China for treating hyperuricemia, but there is little research-based evidence to support its use. This randomized controlled trial aims to assess the efficacy and safety of JNSF.

Methods
A total of 72 patients with hyperuricemia will be selected and randomly assigned in a ratio of 1:2 to receive either Western medicine, i.e., febuxostat 40 mg (WG group; n = 24), or Chinese herbal medicine, i.e., Jiangniaosuan formula + febuxostat 20 mg (WJNSG group; n = 48). After 12 weeks, the WJNSG will be randomly divided into two groups of 24 patients each; one group (WJNSG; n = 24) still will receive febuxostat 20 mg + Jiangniaosuan formula, and the other group (JNSG; n = 24) will continue to receive Jiangniaosuan formula + placebo. Participants will be followed up at 4-week intervals. The primary outcome will be the change in serum uric acid level, and the secondary outcome will be the change in traditional Chinese medicine (TCM) syndrome scores. Serum creatinine, blood glucose, and insulin levels will also be measured.

Discussion
We hypothesize that patients with hyperuricemia will benefit from JNSF. This study will provide evidence-based recommendations for clinicians.

Dissemination
The results will be published in a peer-reviewed journal and disseminated by academic conferences. The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Trial registration
Chinese Clinical Trials Register ChiCTR2000041083. Registered on 3 May 2021. The protocol version number is V3.0, 20210301.
Nutritional support and prophylaxis of azithromycin for pregnant women to improve birth outcomes in peri-urban slums of Karachi, Pakistan—a protocol of multi-arm assessor-blinded randomized controlled trial (Mumta PW trial)
Authors: Muhammad Ameer , Fazal Zoha Zahid , Baloch Benazir , Nisar Imran , Jehan Fyezah , Shafiq Yasir 
Published: January 2022

Abstract
Background
Maternal undernutrition is critical in the etiology of poor perinatal outcomes and accounts for 20% of small-for-gestational-age (SGA) births. High levels of food insecurity, antenatal undernourishment, and childhood undernutrition necessitate the supplementation of fortified balanced energy protein (BEP) during pregnancy in low-income settings especially with scarce literature available in this subject. Hence, this paper extensively covers the protocol of such a trial conducted in an urban slum of Karachi, Pakistan.

Methods
The trial is community-based, open-labelled, four-arm, and randomized controlled that will include parallel group assignments with a 1:1:1:1 allocation ratio in low-income squatter settlements in urban Karachi, Pakistan. All pregnant women (PW), if identified between > 8 and < 19 weeks of gestation based on ultrasound, will be offered routine antenatal care (ANC) counseling and voluntary participation in the trial after written informed consent. A total number of 1836 PW will be enrolled with informed consent and randomly allocated to one of the four arms receiving: (1) ANC counseling only (control group), (2) ANC counseling plus BEP supplement (intervention arm 1), (3) ANC counseling plus BEP supplement plus 2 doses azithromycin (intervention arm 2), or (4) ANC counseling plus BEP supplement plus daily single dose of nicotinamide and choline (intervention arm 3).

Trial registration
ClinicalTrials.govNCT04012177. Registered on July 9, 2019.
Loss of Neuropilin2a/b or Sema3fa alters olfactory sensory axon dynamics and protoglomerular targeting
Authors: Cheng Ryan P. , Dang Puneet , Taku Alemji A. , Moon Yoon Ji , Pham Vi , Sun Xiaohe , Zhao Ethan , Raper Jonathan A. 
Published: January 2022

Abstract
Background
Olfactory Sensory Neuron (OSN) axons project from the zebrafish olfactory epithelium to reproducible intermediate target locations in the olfactory bulb called protoglomeruli at early stages in development. Two classes of OSNs expressing either OMP or TRPC2 exclusively target distinct, complementary protoglomeruli. Using RNAseq, we identified axon guidance receptors nrp2a and nrp2b, and their ligand sema3fa, as potential guidance factors that are differentially expressed between these two classes of OSNs.

Methods
To investigate their role in OSN axon guidance, we assessed the protoglomerular targeting fidelity of OSNs labeled by OMP:RFP and TRPC2:Venus transgenes in nrp2a, nrp2b, or sema3fa mutants. We used double mutant and genetic interaction experiments to interrogate the relationship between the three genes. We used live time-lapse imaging to compare the dynamic behaviors of OSN growth cones during protoglomerular targeting in heterozygous and mutant larvae.

Results
The fidelity of protoglomerular targeting of TRPC2-class OSNs is degraded in nrp2a, nrp2b, or sema3fa mutants, as axons misproject into OMP-specific protoglomeruli and other ectopic locations in the bulb. These misprojections are further enhanced in nrp2a;nrp2b double mutants suggesting that nrp2s work at least partially in parallel in the same guidance process. Results from genetic interaction experiments are consistent with sema3fa acting in the same biological pathway as both nrp2a and nrp2b. Live time-lapse imaging was used to examine the dynamic behavior of TRPC2-class growth cones in nrp2a mutants compared to heterozygous siblings. Some TRPC2-class growth cones ectopically enter the dorsal-medial region of the bulb in both groups, but in fully mutant embryos, they are less likely to correct the error through retraction. The same result was observed when TRPC2-class growth cone behavior was compared between sema3fa heterozygous and sema3fa mutant larvae.

Conclusions
Our results suggest that nrp2a and nrp2b expressed in TRPC2-class OSNs help prevent their mixing with axon projections in OMP-specific protoglomeruli, and further, that sema3fa helps to exclude TRPC2-class axons by repulsion from the dorsal-medial bulb.