bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial
Authors: Maltais F. , Naya I. P. , Vogelmeier C. F. , Boucot I. H. , Jones P. W. , Bjermer L. , Tombs L. , Compton C. , Lipson D. A. , Kerwin E. M. 
Published: October 2020

Abstract
Background
Short-acting β2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD.

Methods
The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 μg, once-daily umeclidinium 62.5 μg or twice-daily salmeterol 50 μg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates.

Results
At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59–74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: − 0.56 [p < 0.001]; low: − 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day.

Conclusions
In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome.

Funding
GlaxoSmithKline (study number 201749 [NCT03034915]).
Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients
Authors: Wang Jun , Zhang Hongliang , Sun Xin , Wang Xiaofang , Ren Tingting , Huang Yi , Zhang Ranxin , Zheng Bingxin , Guo Wei 
Published: October 2020

Abstract
Background
Recent studies indicated that exosomal programmed death-ligand 1 (PD-L1) derived from cancers could induce immunosuppression and tumor pathogenesis. However, it is unclear how exosomes influence osteosarcoma (OS) progression and whether PD-L1 also exists in serum exosomes (Sr-exosomes) of patients with osteosarcoma. We examined serum exosomes from 70 OS patients, 9 patients with benign tumors and 22 healthy donors. OS-derived exosomes were functionally evaluated in vivo and in vitro.

Results
The characteristics of exosomes derived from OS patient serum and OS cell lines were confirmed by several methods. We found OS patients had a higher level of exosomal PD-L1 compared to healthy donors. Meanwhile, OS patients with pulmonary metastasis also showed a relatively higher level of exosomal PD-L1 than patients without metastasis. Next, bioinformatic analysis demonstrated that Sr-exosomes isolated from OS patients may involve in the important process of immune function and cancer pathogenesis for OS patients. Co-expression network centered with PD-L1 among Sr-exosomal differently expressed mRNA demonstrated exosomal N-cadherin had a close relationship with exosomal PD-L1 expression. Then, we confirmed higher level of Sr-exosomal N-cadherin in OS patients with pulmonary metastasis compared to ones without metastasis. Furthermore, we elucidated osteosarcoma-derived exosomes and exosomal-PD-L1 promoted the pulmonary metastasis in metastatic models. ROC (Receiver Operating Characteristic Curve) analysis showed AUC (Area Under Curve) of 0.823 for exosomal PD-L1, 0.806 for exosomal N-cadherin and 0.817 for exosomal N-cadherin/E-cadherin to distinguish OS patients with pulmonary metastasis from ones without metastasis.

Conclusions
Osteosarcoma stimulates pulmonary metastasis by releasing exosomes, that carry PD-L1 and N-cadherin. Detection of exosomal PD-L1 and N-cadherin from serum of OS patients may predict pulmonary metastasis progression for OS patients.
Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) in mainland China: an investigation of reliability, validity, and responsiveness
Authors: Zhou Feifei , Li Shuyang , Zhang Yilong , Zhao Yanbin , Ju Kevin L. , Zhang Fengshan , Pan Shengfa , Sun Yu 
Published: October 2020

Abstract
Background
The aim of this study is to investigate the reliability, validity, and responsiveness of JOACMEQ for CSM patients in mainland China.

Methods
A retrospective review was performed on 91 patients with CSM in our hospital from March 2015 to June 2015. Patients completed the JOACMEQ, the mJOA and the SF-36 questionnaires during the process. Cronbach's α was used to evaluate the internal consistency reliability, and test–retest reliability was checked. An exploratory factor analysis was used to determine the correlations among the JOACMEQ questions and the construct validity. The concurrent validity was assessed by Spearman correlation coefficient. The internal responsiveness was determined by effect sizes and standardized response means. External responsiveness was determined by the area under the receiver operating characteristic curve on the basis of the Youden Index.

Results
The mean age of patients was 57.61 years old. The mean follow-up was 24 months. JOACMEQ showed a good internal consistency (Cronbach's α, 0.897). Test–retest reliability showing good result (Pearson's correlation, 0.695–0.905). Our data were amenable to factor analysis (KMO = 0.816, Bartlett's test, χ2(45) = 1199.99, p < 0.001), and five factors above 1 were strongly loaded and clustered for each of the five factors. Comparing the scales preoperative to those 2 years postoperative, the average scores of the subscales all increased, and both the ES and SRM showing satisfied responsiveness. In external responsiveness analysis, the recovery rate a appeared to be most responsive to post-operative improvement.

Conclusions
The Simplified Chinese version of JOACMEQ was well-developed with great reliability and sensitive responsiveness. Our study demonstrated that JOACMEQ has content psychometric properties to identify postoperative improvements in CSM patients.
Italian observational study on HPV infection, E6, and p16 expression in men with penile cancer
Authors: Muresu Narcisa , Sotgiu Giovanni , Saderi Laura , Sechi Illari , Cossu Antonio , Marras Vincenzo , Meloni Marta , Martinelli Marianna , Cocuzza Clementina , Tanda Francesco , Piana Andrea 
Published: October 2020

Abstract
Background
Human Papillomavirus (HPV) infection is one of the most important causes of cancer. It can play a role in cervical and extra-cervical cancers. Penile cancer is rare, even if an increasing trend was recently reported. Aim of the present study was to assess the prevalence and distribution of HPV genotypes in cases of penile cancer diagnosed in Sardinia, Italy. Surrogate markers of HPV infection (i.e., E6 and p16 genes) were also evaluated in all cases.

Methods
An observational, retrospective study which recruited all cases of penile cancer diagnosed between 2002 and 2019 at a tertiary care hospital in Sardinia, Italy, was carried out. HPV-DNA detection and genotyping were performed by Real-time PCR. Specimens were tested for oncogene E6 mRNA and for p16(INK4a) expression.

Results
HPV prevalence was 28.1% (9/32); HPV-16 was the most prevalent genotype (7/9, 77.8%). p16INK4a positivity was found in 66.7% of the samples with a statistically significant difference between HPV-positive and -negative groups. E6-transcript was detected in 71% of the HPV-16 positive samples. The overall survival was not statistically different between HPV-positives and -negatives.

Discussion
The present study confirms the etiologic role of HPV in penile cancer and supports the adoption of vaccination strategies in men and women. Further studies should clarify the diagnostic and prognostic role of E6 and p16 proteins.

Conclusion
HPV infection can favor the occurrence of penile cancer, whose diagnosis and prognosis could be improved with the implementation of validated molecular techniques.
Ethnobotanical survey of wild edible plants used by Baka people in southeastern Cameroon
Authors: Billong Fils Pascal Eric , Afiong Nana Natacha , Betti Jean Lagarde , Farick Njimbam Oumar , Tientcheu Womeni Stéphanie , Ávila Martin Eva , Ros Brull Guillermo , Okale Robert , Fa Julia E. , Funk Stephan M. 
Published: October 2020

Abstract
Background
Forest inhabitants worldwide, and indigenous people especially, have depended for generations on plants and animals harvested in these ecosystems. A number of Baka hunter-gatherer populations in south-eastern Cameroon became sedentarised in the 1950s, but still rely on hunting and gathering to meet their basic needs. The use of wild edible plants (WEP) by these communities remains largely undocumented. In this study, we record the diversity of WEP used by Baka people in dense rainforests in the Mintom region. The area still contains relatively undisturbed forest expanses, just south of the Dja Biosphere Reserve, one of the most important protected areas in the Congo Basin.

Methods
We conducted two ethnobotanical surveys in 2019 in four villages on the Mintom road. In the first survey, we interviewed a total of 73 individuals to determine WEP usage. In our second survey, we specifically quantified WEP harvested and consumed daily in a number of households over a 2-week period during the major rainy season, when use of forest products is highest. Specimens of all recorded plants were collected and identified at the National Herbarium of Cameroon.

Results
We documented 88 plant species and 119 unique species/plant organ/recipes in 1519 different citations. A total of 61 genera and 43 families were noted. Excluding 14 unidentified wild yam species, 17 WEP species had not been reported in previous ethnobotanical surveys of the Baka. Our results showed that cultivated starchy plant foods make up a significant proportion of our study population’s daily nutritional intake.

Conclusions
A high diversity of WEP is consumed by the studied Baka communities. The study area is likely to be significant in terms of WEP diversity since 18 out of the 30 “key” non-timber forest products, NTFP, in Cameroon were mentioned. Documentation of the use of WEP by indigenous communities is vital to ensure the continuity of traditional knowledge and future food security.
An in-depth exploration of the post-test informational needs of BRCA1 and BRCA2 pathogenic variant carriers in Asia
Authors: Yuen Jeanette , Fung Si Ming , Sia Chin Leong , Venkatramani Mallika , Shaw Tarryn , Courtney Eliza , Li Shao-Tzu , Chiang Jianbang , Tan Veronique Kiak-Mien , Tan Benita Kiat-Tee , Ngeow Joanne 
Published: October 2020

Abstract
Introduction
Identification of one’s status as a BRCA1/2 pathogenic variant carrier often marks the start of navigating challenging decisions related to cancer risk management and result disclosure. Carriers report unmet informational needs, but studies have yet to explore the specific aspects of and how best to fulfill these needs. This study aims to explore the informational needs of BRCA1/2 pathogenic variant carriers in Asia to inform for the design of educational materials to support risk management decision-making.

Methods
Semi-structured in-depth interviews were conducted with two male and 22 female English-speaking BRCA1/2 pathogenic variant carriers, aged 29–66 years, identified through the Cancer Genetics Service at the National Cancer Centre Singapore. A grounded theory approach with thematic analysis was undertaken to extract dominant themes.

Results
Four themes were identified: (i) proactive online information seeking behaviors (ii) personalized informational needs; (iii) challenges in sharing the results; and (iv) lack of genetic awareness.

Discussion
Participants highlight challenges with sharing their result arising from significant post-result informational needs, which have manifested into proactive online information-seeking behaviors. They desire for an online source of information, where content is personalized, reliable and local. Participants foresee the potential of an online resource to raise genetic awareness. This suggests the use of a culturally tailored online-based genetics resource, to promote result disclosure, empower risk-management decisions and raise genetic literacy rates.
Recommendations for hemodynamic monitoring for critically ill children—expert consensus statement issued by the cardiovascular dynamics section of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC)
Authors: Singh Yogen , Villaescusa Javier Urbano , da Cruz Eduardo M. , Tibby Shane M. , Bottari Gabriella , Saxena Rohit , Guillén Marga , Herce Jesus Lopez , Di Nardo Matteo , Cecchetti Corrado , Brierley Joe , de Boode Willem , Lemson Joris 
Published: October 2020

Abstract
Background
Cardiovascular instability is common in critically ill children. There is a scarcity of published high-quality studies to develop meaningful evidence-based hemodynamic monitoring guidelines and hence, with the exception of management of shock, currently there are no published guidelines for hemodynamic monitoring in children. The European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Cardiovascular Dynamics section aimed to provide expert consensus recommendations on hemodynamic monitoring in critically ill children.

Methods
Creation of a panel of experts in cardiovascular hemodynamic assessment and hemodynamic monitoring and review of relevant literature—a literature search was performed, and recommendations were developed through discussions managed following a Quaker-based consensus technique and evaluating appropriateness using a modified blind RAND/UCLA voting method. The AGREE statement was followed to prepare this document.

Results
Of 100 suggested recommendations across 12 subgroups concerning hemodynamic monitoring in critically ill children, 72 reached “strong agreement,” 20 “weak agreement,” and 2 had “no agreement.” Six statements were considered as redundant after rephrasing of statements following the first round of voting. The agreed 72 recommendations were then coalesced into 36 detailing four key areas of hemodynamic monitoring in the main manuscript. Due to a lack of published evidence to develop evidence-based guidelines, most of the recommendations are based upon expert consensus.

Conclusions
These expert consensus-based recommendations may be used to guide clinical practice for hemodynamic monitoring in critically ill children, and they may serve as a basis for highlighting gaps in the knowledge base to guide further research in hemodynamic monitoring.
Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits
Authors: Maas Silvana C. E. , Mens Michelle M. J. , Kühnel Brigitte , van Meurs Joyce B. J. , Uitterlinden André G. , Peters Annette , Prokisch Holger , Herder Christian , Grallert Harald , Kunze Sonja , Waldenberger Melanie , Kavousi Maryam , Kayser Manfred , Ghanbari Mohsen 
Published: October 2020

Abstract
Background
Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits.

Results
We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression.

Conclusions
Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.
Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure
Authors: Kong Defu , Xu Huiming , Chen Mo , Yu Yeping , Qian Yongbing , Qin Tian , Tong Ying , Xia Qiang , Hang Hualian 
Published: October 2020

Abstract
Background
Acute liver failure (ALF) is a complicated condition that is characterized by global hepatocyte death and often requires immediate liver transplantation. However, this therapy is limited by shortage of donor organs. Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies to treat ALF. The combined transplantation of hepatocytes and MSCs is considered to be more effective for the treatment of ALF than single-cell transplantation. We have previously demonstrated that HNF4α-overexpressing human umbilical cord MSCs (HNF4α-UMSCs) promoted the expression of hepatic-specific genes. In addition, microencapsulation allows exchange of nutrients, forming a protective barrier to the transplanted cells. Moreover, encapsulation of hepatocytes improves the viability and synthetic ability of hepatocytes and circumvents immune rejection. This study aimed to investigate the therapeutic effect of microencapsulation of hepatocytes and HNF4α-UMSCs in ALF mice.

Methods
Human hepatocytes and UMSCs were obtained separately from liver and umbilical cord, followed by co-encapsulation and transplantation into mice by intraperitoneal injection. LPS/D-gal was used to induce ALF by intraperitoneal injection 24 h after transplantation. In addition, Raw 264.7 cells (a macrophage cell line) were used to elucidate the effect of HNF4α-UMSCs-hepatocyte microcapsules on polarization of macrophages. The protein chip was used to define the important paracrine factors in the conditioned mediums (CMs) of UMSCs and HNF4α-UMSCs and investigate the possible mechanism of HNF4α-UMSCs for the treatment of ALF in mice.

Results
HNF4α-UMSCs can enhance the function of primary hepatocytes in alginate–poly-L-lysine–alginate (APA) microcapsules. The co-encapsulation of both HNF4α-UMSCs and hepatocytes achieved better therapeutic effects in ALF mice by promoting M2 macrophage polarization and reducing inflammatory response mainly mediated by the paracrine factor HB-EGF secreted by HNF4α-UMSCs.

Conclusions
The present study confirms that the co-encapsulation of HNF4α-UMSC and hepatocytes could exert therapeutic effect on ALF mainly by HB-EGF secreted by HNF4α-UMSCs and provides a novel strategy for the treatment of ALF.
HSPB7 regulates osteogenic differentiation of human adipose derived stem cells via ERK signaling pathway
Authors: Jin Chanyuan , Shuai Ting , Tang Zhihui 
Published: October 2020

Abstract
Background
Heat shock protein B7 (HSPB7), which belongs to small heat shock protein family, has been reported to be involved in diverse biological processes and diseases. However, whether HSPB7 regulates osteogenic differentiation of human adipose derived stem cells (hASCs) remains unexplored.

Methods
The expression level of HSPB7 during the osteogenesis of hASCs was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. Lentivirus transfection was used to knock down or overexpress HSPB7, which enabled us to investigate the effect of HSPB7 on osteogenic differentiation of hASCs. U0126 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) siRNA were used to identify the mechanism of the HSPB7/ERK1/2 axis in regulating osteogenic differentiation of hASCs. Moreover, ectopic bone formation in nude mice and osteoporosis mice model was used to investigate the effect of HSPB7 on osteogenesis in vivo.

Results
In this study, we found the expression of HSPB7 was significantly downregulated during the osteogenic differentiation of hASCs. HSPB7 knockdown remarkably promoted osteogenic differentiation of hASCs, while HSPB7 overexpression suppressed osteogenic differentiation of hASCs both in vitro and in vivo. Moreover, we discovered that the enhancing effect of HSPB7 knockdown on osteogenic differentiation was related to the activation of extracellular signal-regulated protein kinase (ERK) signaling pathway. Inhibition of ERK signaling pathway with U0126 or silencing ERK1/2 effectively blocked the stimulation of osteogenic differentiation induced by HSPB7 knockdown. Additionally, we found that HSPB7 expression was markedly increased in mouse bone marrow mesenchymal stem cells (mBMSCs) from the osteoporotic mice which suggested that HSPB7 might be utilized as a potential target in the development of effective therapeutic strategies to treat osteoporosis and other bone diseases.

Conclusion
Taken together, these findings uncover a previously unrecognized function of HSPB7 in regulating osteogenic differentiation of hASCs, partly via the ERK signaling pathway.