bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence, characteristics, and costs of diagnosed homocystinuria, elevated homocysteine, and phenylketonuria in the United States: a retrospective claims-based comparison
Authors: Sellos-Moura Marcia , Glavin Frank , Lapidus David , Evans Kristin , Lew Carolyn R. , Irwin Debra E. 
Published: March 2020

Abstract
Background
Classical homocystinuria (HCU), an inborn error of homocysteine metabolism, has previously been estimated to affect approximately 1 in 100,000–200,000 people in the United States (US). HCU is poorly detected by newborn screening, resulting in underestimates of its prevalence. This study compared characteristics, healthcare use and costs, and projected prevalence between patients with diagnosed HCU, elevated total homocysteine (tHcy), and diagnosed phenylketonuria (PKU).

Methods
Patients in the MarketScan® Research Databases were identified with strictly-defined HCU (> 2 diagnoses, including 1 ICD-10), broadly-defined HCU (> 1 ICD-10), elevated tHcy (> 20 μmol/L) without an HCU diagnosis, or > 1 ICD-9/ICD-10 PKU diagnosis during 1/1/2010–12/31/2016 (first qualifying claim = index). Demographics and healthcare utilization and costs per patient per month (PPPM) were compared between all cohorts, frequencies of comorbidities and medications were compared between HCU and elevated tHcy patients, and healthcare provider types were assessed among HCU patients. The prevalence of patients meeting each cohort definition was projected to the United States (US) population.

Results
Patients with strictly-defined (N = 2450) and broadly-defined (N = 6613) HCU, and with elevated tHcy (N = 2017), were significantly older than PKU patients (N = 5120) (57 vs. 56 vs. 53 vs. 18 years; p < 0.05). Vitamin D deficiency, hyperlipidemia, folic acid/B vitamins, and lipid-lowering medications, among others, were more common among diagnosed HCU patients vs. those with elevated tHcy (all p < 0.05). Rates of healthcare utilization were generally higher among HCU and elevated tHcy patients, compared to PKU, though total healthcare costs were similar between groups. Most HCU patients (~ 38%) received their index diagnosis from a primary care physician; very few (~ 1%) had any claim from a geneticist during their enrollment. The age-adjusted national prevalence of HCU was projected at 31,162 (95% CI: 30,411 – 31,913; ~ 1 in 10,000 of the US population) using the broad definition.

Conclusions
The actual prevalence of HCU may be > 10 times prior estimates, at 1 in 10,000 in the US, and this study suggests that HCU is not being diagnosed until later in life. Improvements to newborn screening, detection in young children, and physician education regarding HCU among patients may be necessary to alleviate the burden of this genetic disease.
Approaches to overcome flow cytometry limitations in the analysis of cells from veterinary relevant species
Authors: Hunka Julia , Riley John T. , Debes Gudrun F. 
Published: March 2020

Abstract
Background
Flow cytometry is a powerful tool for the multiparameter analysis of leukocyte subsets on the single cell level. Recent advances have greatly increased the number of fluorochrome-labeled antibodies in flow cytometry. In particular, an increase in available fluorochromes with distinct excitation and emission spectra combined with novel multicolor flow cytometers with several lasers have enhanced the generation of multidimensional expression data for leukocytes and other cell types. However, these advances have mainly benefited the analysis of human or mouse cell samples given the lack of reagents for most animal species. The flow cytometric analysis of important veterinary, agricultural, wildlife, and other animal species is still hampered by several technical limitations, even though animal species other than the mouse can serve as more accurate models of specific human physiology and diseases.

Results
Here we present time-tested approaches that our laboratory regularly uses in the multiparameter flow cytometric analysis of ovine leukocytes. The discussed approaches will be applicable to the analysis of cells from most animal species and include direct modification of antibodies by covalent conjugation or Fc-directed labeling (Zenon™ technology), labeled secondary antibodies and other second step reagents, labeled receptor ligands, and antibodies with species cross-reactivity.

Conclusions
Using refined technical approaches, the number of parameters analyzed by flow cytometry per cell sample can be greatly increased, enabling multidimensional analysis of rare samples and giving critical insight into veterinary and other less commonly analyzed species. By maximizing information from each cell sample, multicolor flow cytometry can reduce the required number of animals used in a study.
A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report
Authors: Karolak Justyna A. , Gambin Tomasz , Honey Engela M. , Slavik Tomas , Popek Edwina , Stankiewicz Paweł 
Published: March 2020

AbstractBackgroundApplication of whole genome sequencing (WGS) enables identification of non-coding variants that play a phenotype-modifying role and are undetectable by exome sequencing. Recently, non-coding regulatory single nucleotide variants (SNVs) have been reported in patients with lethal lung developmental disorders (LLDDs) or congenital scoliosis with recurrent copy-number variant (CNV) deletions at 17q23.1q23.2 or 16p11.2, respectively.Case presentationHere, we report a deceased newborn with pulmonary hypertension and pulmonary interstitial emphysema with features suggestive of pulmonary hypoplasia, resulting in respiratory failure and neonatal death soon after birth. Using the array comparative genomic hybridization and WGS,two heterozygous recurrent CNV deletions: ~ 2.2 Mb on 17q23.1q23.2, involvingTBX4, and ~ 600 kb on 16p11.2, involvingTBX6,that both arose de novo on maternal chromosomes were identified. In the predicted lung-specific enhancer upstream toTBX4, we have detected seven novel putative regulatory non-coding SNVs that were absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies.ConclusionsOur findings further support a recently reported model of complex compound inheritance of LLDD in which both non-coding and coding heterozygousTBX4variants contribute to the lung phenotype. In addition, this is the first report of a patient with combined de novo heterozygous recurrent 17q23.1q23.2 and 16p11.2 CNV deletions.
Effect of average volume-assured pressure support treatment on health-related quality of life in COPD patients with chronic hypercapnic respiratory failure: a randomized trial
Authors: Magdy Doaa M. , Metwally Ahmed 
Published: March 2020

Abstract
The long-term effect of average volume-assured pressure support (AVAPS) on health-related quality of life (HRQOL) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure (CHRF) remains unclear.
The objective of this study is to identify the long-term effect of AVAPS in COPD patients with CHRF through assessment of HRQOL, exercise tolerance after six months duration.

Methods
In this randomized, controlled, parallel-group study, 40 stable hypercapnic COPD patients were randomized in a 1:1 ratio to receive either spontaneous timed AVAPS (ST/AVAPS) (intervention) or Bilevel positive airway pressure (ST/BiPAP) (control). HRQL was measured with the Short Form 12 Health Survey Questionnaire (SF-12). Exercise tolerance assessed by 6 min walking distance. Analyses were done between groups from baseline to the average of six months measurements.

Results
AVAPS led to significant 6 months improvements in several domains of (SF-12) compared to the control group, with the greatest improvement seen in general health [treatment effect of 8.2 points (95% confidence interval [95% CI 3.2 to 11.7; p = 0.001)], vitality (treatment effect 5.4 points [95% CI 1.4 to 9.3]; p = 0.001), physical functioning 5.5 points [95% CI 1.1 to 9.8]; p = 0.001) and bodily pain 5.1 points [95% CI 3.4 to 8.8]; p = 0.002). The physical health summary score improved by 3.7 points (95% CI 1.2 to 5.8; p = 0.001), but no significant improvement in the emotional or social role functioning, mental health subscale was noted.
AVAPS also resulted in improvement 6 min walking distance 9.2 points (95% CI − 1 to − 15];p = 0.001). A significant reduction in the daytime (PaCO2) was observed after 6 months in those treated with AVAPS.

Conclusions
In COPD patients with hypercapnic respiratory failure, AVAPS improved exercise tolerance and multiple domains of HRQOL over six months of follow-up, with the significant improvement observed in general health.
Production of ent-kaurene from lignocellulosic hydrolysate in Rhodosporidium toruloides
Authors: Geiselman Gina M. , Zhuang Xun , Kirby James , Tran-Gyamfi Mary B. , Prahl Jan-Philip , Sundstrom Eric R. , Gao Yuqian , Munoz Munoz Nathalie , Nicora Carrie D. , Clay Derek M. , Papa Gabriella , Burnum-Johnson Kristin E. , Magnuson Jon K. , Tanjore Deepti , Skerker Jeffrey M. , Gladden John M. 
Published: March 2020

Abstract
Background
Rhodosporidium toruloides has emerged as a promising host for the production of bioproducts from lignocellulose, in part due to its ability to grow on lignocellulosic feedstocks, tolerate growth inhibitors, and co-utilize sugars and lignin-derived monomers. Ent-kaurene derivatives have a diverse range of potential applications from therapeutics to novel resin-based materials.

Results
The Design, Build, Test, and Learn (DBTL) approach was employed to engineer production of the non-native diterpene ent-kaurene in R. toruloides. Following expression of kaurene synthase (KS) in R. toruloides in the first DBTL cycle, a key limitation appeared to be the availability of the diterpene precursor, geranylgeranyl diphosphate (GGPP). Further DBTL cycles were carried out to select an optimal GGPP synthase and to balance its expression with KS, requiring two of the strongest promoters in R. toruloides, ANT (adenine nucleotide translocase) and TEF1 (translational elongation factor 1) to drive expression of the KS from Gibberella fujikuroi and a mutant version of an FPP synthase from Gallus gallus that produces GGPP. Scale-up of cultivation in a 2 L bioreactor using a corn stover hydrolysate resulted in an ent-kaurene titer of 1.4 g/L.

Conclusion
This study builds upon previous work demonstrating the potential of R. toruloides as a robust and versatile host for the production of both mono- and sesquiterpenes, and is the first demonstration of the production of a non-native diterpene in this organism.
The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know
Authors: Zhou Wenjia , Chen Lu , Li Chao , Huang Rui , Guo Mian , Ning Shangwei , Ji Jingjing , Guo Xiaorong , Lou Ge , Jia Xinqi , Zhao Junjie , Luo Feng , Li Chunlong , Qu Zhaowei , Yu Shan , Tai Sheng 
Published: March 2020

AbstractPancreatic cancer (PC) is one of the leading causes of cancer-related deaths worldwide. Due to the shortage of effective biomarkers for predicting survival and diagnosing PC, the underlying mechanism is still intensively investigated but poorly understood. Long noncoding RNAs (lncRNAs) provide biological functional diversity and complexity in protein regulatory networks. Scientific studies have revealed the emerging functions and regulatory roles of lncRNAs in PC behaviors. It is worth noting that some in-depth studies have revealed that lncRNAs are significantly associated with the initiation and progression of PC. As lncRNAs have good properties for both diagnostic and prognostic prediction due to their translation potential, we herein address the current understanding of the multifaceted roles of lncRNAs as regulators in the molecular mechanism of PC. We also discuss the possibility of using lncRNAs as survival biomarkers and their contributions to the development of targeted therapies based on the literature. The present review, based on what we know about current research findings, may help us better understand the roles of lncRNAs in PC.
Skp2 modulates proliferation, senescence and tumorigenesis of glioma
Authors: Wu Juan , Su Hong-kai , Yu Zhi-hui , Xi Shao-yan , Guo Cheng-cheng , Hu Zhe-yu , Qu Yue , Cai Hai-ping , Zhao Yi-ying , Zhao Hua-fu , Chen Fu-rong , Huang Yu-fan , To Shing-shun Tony , Feng Bing-hong , Sai Ke , Chen Zhong-ping , Wang Jing 
Published: March 2020

AbstractBackgroundGliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma.MethodsTo investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model.ResultsSkp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo.ConclusionOur data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.
Circ_0032821 acts as an oncogene in cell proliferation, metastasis and autophagy in human gastric cancer cells in vitro and in vivo through activating MEK1/ERK1/2 signaling pathway
Authors: Jiang Yuanyuan , Zhang Yan , Chu Feifei , Xu Lidong , Wu Huili 
Published: March 2020

Abstract
Background
Circular RNA (circRNA) is increasingly attracting attention in gastric cancer (GC). Hsa_circ_0032821 (circ_0032821) has been declared to be upregulated in human GC tissues. However, the biological role of circ_0032821 remains undisclosed in GC cells.

Methods
Expression of circ_0032821 was measured by real-time quantitative PCR. Cell proliferation, autophagy, Epithelial-mesenchymal transition (EMT), migration, and invasion were evaluated by Cell counting kit-8 assay, western blotting or transwell assays. Expression of proliferating cell nuclear antigen (PCNA), Matrix metalloproteinase 2 (MMP2), MMP9, Light chain 3 (LC3), p62, total and phosphorylated Extracellular signal-regulated kinase 1/2 (ERK1/2) and Mitogen-activated protein kinase’s kinase 1 (MEK1) was evaluated by western blotting. Xenograft tumor model was established to measure tumor growth in vivo.

Results
Circ_0032821 was significantly upregulated in human GC tumors and cells. Moreover, circ_0032821 might be a biomarker for the advanced Tumor node metastasis (TNM) stage, lymphoid node metastasis and poor prognosis in gastric cancer. Knockdown of circ_0032821 by transfection induced decrease of cell proliferation, EMT, migration and invasion, but increase of autophagy of AGS and HGC-27 cells in vitro, as well as induced tumor growth inhibition in vivo. Besides, overexpression of circ_0032821 by transfection functioned the opposite effects in human GC cells. Mechanically, the MEK1/ERK1/2 signaling pathway was activated when circ_0032821 upregulation, whereas inhibited when circ_0032821 silencing.

Conclusion
Circ_0032821 expression induced cell proliferation, EMT, migration, invasion, and autophagy inhibition in human GC cells in vitro and in vivo through activating MEK1/ERK1/2 signaling pathway, suggesting circ_0032821 as an oncogenic role in GC.
Clarifying workforce flexibility from a division of labor perspective: a mixed methods study of an emergency department team
Authors: Wise Sarah , Duffield Christine , Fry Margaret , Roche Michael 
Published: March 2020

AbstractBackgroundThe need for greater flexibility is often used to justify reforms that redistribute tasks through the workforce. However, “flexibility” is never defined or empirically examined. This study explores the nature of flexibility in a team of emergency doctors, nurse practitioners (NPs), and registered nurses (RNs), with the aim of clarifying the concept of workforce flexibility. Taking a holistic perspective on the team’s division of labor, it measures task distribution to establish the extent of multiskilling and role overlap, and explores the behaviors and organizational conditions that drive flexibly.MethodsThe explanatory sequential mixed methods study was set in the Fast Track area of a metropolitan emergency department (ED) in Sydney, Australia. In phase 1, an observational time study measured the tasks undertaken by each role (151 h), compared as a proportion of time (Kruskal Wallis, Mann-WhitneyU), and frequency (Pearson chi-square). The time study was augmented with qualitative field notes. In phase 2, 19 semi-structured interviews sought to explain the phase 1 observations and were analyzed thematically.ResultsThe roles were occupationally specialized: “Assessment and Diagnosis” tasks consumed the largest proportion of doctors’ (51.1%) and NPs’ (38.1%) time, and “Organization of Care” tasks for RNs (27.6%). However, all three roles were also multiskilled, which created an overlap in the tasks they performed. The team used this role overlap to work flexibly in response to patients’ needs and adapt to changing demands. Flexibility was driven by the urgent and unpredictable workload in the ED and enabled by the stability provided by a core group of experienced doctors and nurses.ConclusionNot every healthcare team requires the type of flexibility found in this study since that was shaped by patient needs and the specific organizational conditions of the ED. The roles, tasks, and teamwork that a team requires to “be flexible” (i.e., responsive and adaptable) are highly context dependent. Workforce flexibility therefore cannot be defined as a particular type of reform or role; rather, it should be understood as the capacity of a team to respond and adapt to patients’ needs within its organizational context. The study’s findings suggest that solutions for a more flexible workforce may lay in the organization of healthcare work.
SNP rs12982687 affects binding capacity of lncRNA UCA1 with miR-873-5p: involvement in smoking-triggered colorectal cancer progression
Authors: Fu Yang , Zhang Yizheng , Cui Jinyuan , Yang Ge , Peng Sanfei , Mi Wunan , Yin Xiangya , Yu Yang , Jiang Jianwu , Liu Qi , Qin Yiyu , Xu Wen 
Published: March 2020

Abstract
Background
This investigation was arranged to elucidate whether single nucleotide polymorphisms (SNPs) of lncRNA UCA1 was implicated in elevating colorectal cancer (CRC) risk by interacting with environmental exposures.

Methods
LncRNASNP database was firstly adopted to predict SNPs that possibly affected binding of UCA1 with miRNAs and then the interactive effect of SNPs and environmental exposure on CRC risk was evaluated by recurring to type 2 gene-environment interactions (GEI) model. Besides, MTT assay, colony formation assay, transwell assay and wound healing assay were performed to assess the activity of CRC cell lines which carried distinct genotypes of specific SNPs. The impact of nicotine on activity of CRC cells was also appraised.

Results
SNP rs12982687 of UCA1 intervened in the binding capacity of UCA1 with several miRNAs, especially miR-873-5p. MiRNAs regulated by UCA1, as predicted by mirPath software, shared genes that were enriched in HIF1 signaling pathway. Moreover, homozygote TT of rs12982687 reduced CRC risk among smokers, and CRC cells that carried rs12982687 (CC) displayed strong migration and invasion. By contrast, miR-873-5p mimic, which reduced UCA1 expression, delayed metastasis of CRC cells (all P < 0.05). Additionally, nicotine not merely elevated UCA1 and HIF-1α expressions in CRC cells, but also facilitated proliferation and metastasis of CRC cells (P < 0.05).

Conclusions
SNP rs12982687 was involved in smoking-triggered CRC progression, given its influence on UCA1's binding with miR-873-5p and HIF-1 signaling.
Adaptive conjunctive cognitive training (ACCT) in virtual reality for chronic stroke patients: a randomized controlled pilot trial
Authors: Maier Martina , Ballester Belén Rubio , Leiva Bañuelos Nuria , Duarte Oller Esther , Verschure Paul F. M. J. 
Published: March 2020

AbstractBackgroundCurrent evidence for the effectiveness of post-stroke cognitive rehabilitation is weak, possibly due to two reasons. First, patients typically express cognitive deficits in several domains. Therapies focusing on specific cognitive deficits might not address their interrelated neurological nature. Second, co-occurring psychological problems are often neglected or not diagnosed, although post-stroke depression is common and related to cognitive deficits. This pilot trial aims to test a rehabilitation program in virtual reality that trains various cognitive domains in conjunction, by adapting to the patient’s disability and while investigating the influence of comorbidities.MethodsThirty community-dwelling stroke patients at the chronic stage and suffering from cognitive impairment performed 30 min of daily training for 6 weeks. The experimental group followed, so called, adaptive conjunctive cognitive training (ACCT) using RGS, whereas the control group solved standard cognitive tasks at home for an equivalent amount of time. A comprehensive test battery covering executive function, spatial awareness, attention, and memory as well as independence, depression, and motor impairment was applied at baseline, at 6 weeks and 18-weeks follow-up.ResultsAt baseline, 75% of our sample had an impairment in more than one cognitive domain. The experimental group showed improvements in attention ($$ {\chi}_F^2 $$χF2(2) = 9.57,p < .01), spatial awareness ($$ {\chi}_F^2 $$χF2(2) = 11.23,p < .01) and generalized cognitive functioning ($$ {\chi}_F^2 $$χF2(2) = 15.5,p < .001). No significant change was seen in the executive function and memory domain. For the control group, no significant change over time was found. Further, they worsened in their depression level after treatment (T = 45,r = .72,p < .01) but returned to baseline at follow-up. The experimental group displayed a lower level of depression than the control group after treatment (Ws = 81.5, z = − 2.76,r = − .60,p < .01) and (Ws = 92, z = − 2.03,r = − .44,p < .05).ConclusionsACCT positively influences attention and spatial awareness, as well as depressive mood in chronic stroke patients.Trial registrationThe trial was registered prospectively at ClinicalTrials.gov (NCT02816008) on June 21, 2016.