bluuebunny/crossref_metadata_2025 huggingface dataset:
Population segments as a tool for health care performance reporting: an exploratory study in the Canadian province of British Columbia
Authors: Langton Julia M. , Wong Sabrina T. , Burge Fred , Choi Alexandra , Ghaseminejad-Tafreshi Niloufar , Johnston Sharon , Katz Alan , Lavergne Ruth , Mooney Dawn , Peterson Sandra , McGrail Kimberlyn
Published: May 2020

Background

Primary care serves all age groups and individuals with health states ranging from those with no chronic conditions to those who are medically complex, or frail and approaching the end of life. For information to be actionable and guide planning, there must be some population disaggregation based on differences in expected needs for care. Promising approaches to segmentation in primary care reflect both the breadth and severity of health states, the types and amounts of health care utilization that are expected, and the roles of the primary care provider. The purpose of this study was to assess population segmentation as a tool to create distinct patient groups for use in primary care performance reporting.

Methods

This cross-sectional study used administrative data (patient characteristics, physician and hospital billings, prescription medicines data, emergency department visits) to classify the population of British Columbia (BC), Canada into one of four population segments: low need, multiple morbidities, medically complex, and frail. Each segment was further classified using socioeconomic status (SES) as a proxy for patient vulnerability. Regression analyses were used to examine predictors of health care use, costs and selected measures of primary care attributes (access, continuity, coordination) by segment.

Results

Average annual health care costs increased from the low need ($ 1460) to frail segment ($10,798). Differences in primary care cost by segment only emerged when attributes of primary care were included in regression models: accessing primary care outside business hours and discontinuous primary care (≥5 different GP’s in a given year) were associated with higher health care costs across all segments and higher continuity of care was associated with lower costs in the frail segment (cost ratio = 0.61). Additionally, low SES was associated with higher costs across all segments, but the difference was largest in the medically complex group (cost ratio = 1.11).

Conclusions

Population segments based on expected need for care can support primary care measurement and reporting by identifying nuances which may be lost when all patients are grouped together. Our findings demonstrate that variables such as SES and use of regression analyses can further enhance the usefulness of segments for performance measurement and reporting.
Anti-inflammatory effect of Salsola komarovii extract with dissociated glucocorticoid activity
Authors: Seo Ji Hyun , Jin Mu Hyun , Chang Yun Hee
Published: June 2020

Background

Glucocorticoids (GCs) are anti-inflammatory drugs widely used to treat acute and chronic inflammatory diseases. However, despite their excellent efficacy, the long-term use of GCs is relatively limited owing to their adverse effects. Recent studies have sought to reduce these adverse effects by developing dissociated GCs that bind to GC receptors (GRs) to induce potent anti-inflammatory effects without the transcription of GC response element (GRE)-promoted genes. Some species of the genus Salsola are used in traditional Chinese medicine to treat cancer, hypertension, and inflammation. In this study, we investigated the potential dissociated GC activities and underlying mechanisms of Salsola komarovii (SK), which is native to Korea.

Methods

To determine whether SK ethanol extract (SEE) directly interacts with the GR, an in vitro fluorescence polarization based-GR competitor assay was performed. The effect of SEE on the transcriptional activity of nuclear factor (NF)-κB and GRE was confirmed in HepG2 cells using the Cignal reporter assay. The anti-inflammatory effect of SK was determined by assessing lipopolysaccharide (LPS)-induced interleukin (IL)-6 production. To confirm whether SEE induces GRE-driven gene expression, preadipocyte differentiation followed by lipid deposition was performed in the presence of SEE.

Results

SEE exhibited GR binding activity in the fluorescence polarization competitive binding assay and induced GR nuclear translocation. It also interfered with the nuclear translocation of NF-κB and the NF-κB-dependent transcriptional activity based on the immunofluorescence analysis and reporter assay, respectively. SEE exerted anti-inflammatory effects by reducing LPS-induced IL-6 production as effectively as hydrocortisone (positive control). SK did not induce GRE-driven gene expression and preadipocyte differentiation, which is one of the major adverse effects of GCs.

Conclusions

Collectively, these results suggest that SK could be a novel and safe anti-inflammatory agent with dissociated GC properties and, therefore, it has great potential for use in treating inflammatory disorders.
Serum metabolite profiles are associated with the presence of advanced liver fibrosis in Chinese patients with chronic hepatitis B viral infection
Authors: Xie Guoxiang , Wang Xiaoning , Wei Runmin , Wang Jingye , Zhao Aihua , Chen Tianlu , Wang Yixing , Zhang Hua , Xiao Zhun , Liu Xinzhu , Deng Youping , Wong Linda , Rajani Cynthia , Kwee Sandi , Bian Hua , Gao Xin , Liu Ping , Jia Wei
Published: June 2020

Background

Accurate and noninvasive diagnosis and staging of liver fibrosis are essential for effective clinical management of chronic liver disease (CLD). We aimed to identify serum metabolite markers that reliably predict the stage of fibrosis in CLD patients.

Methods

We quantitatively profiled serum metabolites of participants in 2 independent cohorts. Based on the metabolomics data from cohort 1 (504 HBV associated liver fibrosis patients and 502 normal controls, NC), we selected a panel of 4 predictive metabolite markers. Consequently, we constructed 3 machine learning models with the 4 metabolite markers using random forest (RF), to differentiate CLD patients from normal controls (NC), to differentiate cirrhosis patients from fibrosis patients, and to differentiate advanced fibrosis from early fibrosis, respectively.

Results

The panel of 4 metabolite markers consisted of taurocholate, tyrosine, valine, and linoelaidic acid. The RF models of the metabolite panel demonstrated the strongest stratification ability in cohort 1 to diagnose CLD patients from NC (area under the receiver operating characteristic curve (AUROC) = 0.997 and the precision-recall curve (AUPR) = 0.994), to differentiate fibrosis from cirrhosis (0.941, 0.870), and to stage liver fibrosis (0.918, 0.892). The diagnostic accuracy of the models was further validated in an independent cohort 2 consisting of 300 CLD patients with chronic HBV infection and 90 NC. The AUCs of the models were consistently higher than APRI, FIB-4, and AST/ALT ratio, with both greater sensitivity and specificity.

Conclusions

Our study showed that this 4-metabolite panel has potential usefulness in clinical assessments of CLD progression in patients with chronic hepatitis B virus infection.
Perception of farmers about endometritis prevention and control measures for zero-grazed dairy cows on smallholder farms in Rwanda
Authors: Nyabinwa Pascal , Kashongwe Olivier Basole , Hirwa Claire d’Andre , Bebe Bockline Omedo
Published: June 2020

Background

Endometritis is a prevalent uterine disease in postpartum cows. The disease reduces fertility performance and milk yield, and subsequently, productivity and profitability of dairy farms. The reduction in performance is associated with considerable economic losses on dairy farms. Smallholder farmers are likely to incur considerable economic losses from the disease where they lack knowledge of effective prevention and control measures for the disease. This study used farmer’s perspectives to determine the effectiveness of different management interventions (MIs) for endometritis prevention and control on smallholder farms in Rwanda practicing dairy zero-grazing. The best-worst scaling (BWS) choice method was applied that relied on past 1 year recall data obtained from 154 farmers. These farmers were identified through snowball sampling in a cross-sectional study.

Results

Of the 20 MIs evaluated, 12 scored highly for effectiveness. The top four most effective are: avoiding sharing equipment with neighbouring farms (45.5%), consulting animal health service provider about disease treatment (31.8%), keeping cows in a clean and dry shed (26.7%), and selecting sires based on calving ease (26.6%). The MIs considered least effective were: maintaining clean transition cow housing (35.1%), removal of fetal membrane immediately after passing (33.1%), disinfecting the equipment used in calving assistance before and after use (32.5%), and selecting sires with low percent stillbirths (29.2%).

Conclusion

This study has demonstrated the application of BWS object case method in understanding the MIs that farmers consider are most effective in the prevention and control of endometritis disease in the dairy herds. The MIs are on-farm biosecurity and hygiene, seeking veterinary services for disease treatment and selecting sires for ease of calving. These MIs should be considered for prioritization in extension services and research to continuously improve and enhance their practical application on smallholder dairy farms.
LncRNA FLVCR1-AS1 promotes proliferation, migration and activates Wnt/β-catenin pathway through miR-381-3p/CTNNB1 axis in breast cancer
Authors: Pan Zhiyu , Ding Junbin , Yang Zhen , Li Huaqing , Ding Hongjian , Chen Qian
Published: June 2020

Background

Understanding the molecular mechanism of long non-coding RNAs (lncRNAs) in carcinogenesis is conducive for providing potential target for cancers. The role of FLVCR1-AS1 in breast cancer (BC) has not been probed yet.

Materials and methods

qRT-PCR and western blot assays were used to estimate relevant expressions of mRNAs and proteins. CCK8, MTT and EdU were implemented to assess cell proliferation ability. TUNEL was performed to investigate cell apoptosis, whereas transwell assay was performed to test cell migration and invasion capacities. TOP/FOP Flash assay was conducted to determine the activity of Wnt/β-catenin pathway. Luciferase reporter, RNA pull down and RIP assays were performed to verify interaction between genes.

Results

FLVCR1-AS1 was abnormally up-regulated in BC cells. Silencing FLVCR1-AS1 inhibited cell proliferation, migration, invasion, yet accelerating apoptosis. Inhibition of miR-381-3p reversed the tumor restraining impacts of FLVCR1-AS1 depletion on BC progression. Additionally, CTNNB1 was recognized to be targeted by miR-381-3p. FLVCR1-AS1 aggravated BC malignant progression via up-regulation CTNNB1 through sponging miR-381-3p.

Conclusion

FLVCR1-AS1 regulates BC malignant behavior via sequestering miR-381-3p and then freeing CTNNB1, implying a promising target for BC therapy.
Assessing health outcomes in the aftermath of the great recession: a comparison of Spain and the Netherlands
Authors: Thompson Kristina , Wagemakers Annemarie , van Ophem Johan
Published: June 2020

Background

Across time and space, financial security has been shown to impact health outcomes, with the acute loss of financial security being particularly detrimental. We compare financial security’s association with health in Spain and the Netherlands. These countries respectively exemplify low and high levels of financial security, general trends that have been exacerbated by the Great Recession of the 2010s.

Methods

We exploit the Spanish (n = 1001) and Dutch (n = 1010) editions of the European Social Survey 7, conducted in 2014, and condense relevant financial security- and health-related survey questions into latent variables using factor analyses. Using the component loadings as quasi-weightings, we generate one financial security variable and three health variables (mental, physical and social). Then, we run ordinary least squares regressions interacting financial security and nationality, for each of the three health outcomes.

Results

In unadjusted models, we find that financial security (p < 0.01) is positively associated with the three health outcomes, while being Spanish relative to being Dutch (p < 0.01) is associated with worse health outcomes. However, the results of the interaction term show that being Spanish relative to being Dutch weakens the relationship between physical health and social health, although not mental health.

Conclusions

We find evidence that financial security’s influence on health outcomes may vary in different contexts. This may be an important aspect of determining the Great Recession’s influence on health outcomes. Our study is a first step in understanding how the relationships between financial security and health may differ in countries with different experiences of the Great Recession.
Extent of and trends in inequalities in child stunting in Sierra-Leone from 2005 to 2013: evidence from demographic and health surveys and multiple indicator cluster surveys
Authors: Shibre Gebretsadik , Zegeye Betregiorigis , Haidar Jemal
Published: June 2020

Background

Comprehensive assessment of stunting disparity in Sierra-Leone has not been done so far. We aimed to document extent and over time dynamics of inequality in stunting in Sierra-Leone using approaches that facilitate implementation of interventions aim to eliminate non-justified stunting disparity in the country.

Methods

The data for the study were derived from two rounds of the Sierra Leone Demographic and Health Survey conducted in 2008 and 2013, and two rounds of the Sierra Leone Multiple Indicator Cluster Survey done in 2005 and 2010. We used the 2019 update WHO Health Equity Assessment Toolkit (HEAT) to do the analysis. The toolkit makes use of data stored in the WHO Health Equity Monitor database. We analyzed stunting inequality using summary measures: Population Attributable Risk, Population Attributable Fraction, Difference and Ratio. The summary measures were computed for five equity stratifers: wealth, education, child’s sex, place of residence and subnational region. We computed 95% Confidence Interval (CI) for each point estimate to show whether or not observed stunting inequalities are statistically significant, and whether or not the disparity changed over time statistically significantly.

Results

The findings demonstrated stark inequalities in stunting in all the studied dimensions of inequality. While residence and subnational regional related inequalities remain unchanged over time, wealth and educational inequality had seen slight improvement during the same time period. Large sex related stunting inequality remained during the first three surveys time points, but it disappeared in 2013.

Conclusions

Huge stunting disparities occurred in Sierra Leone, and the disparity disproportionately affects disadvantaged subpopulations and male children. Nutrition interventions that specifically target the subgroups which suffer more from the burden of stunting are required.
Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology
Authors: Hu Wei , Liu Cong , Bi Zhuo-Yue , Zhou Qun , Zhang Han , Li Lin-Lin , Zhang Jian , Zhu Wei , Song Yang-Yi-Yan , Zhang Feng , Yang Hui-Min , Bi Yong-Yi , He Qi-Qiang , Tan Gong-Jun , Sun Cheng-Cao , Li De-Jia
Published: June 2020

Extracellular vesicles (EVs), a class of heterogeneous membrane vesicles, are generally divided into exosomes and microvesicles on basis of their origination from the endosomal membrane or the plasma membrane, respectively. EV-mediated bidirectional communication among various cell types supports cancer cell growth and metastasis. EVs derived from different cell types and status have been shown to have distinct RNA profiles, comprising messenger RNAs and non-coding RNAs (ncRNAs). Recently, ncRNAs have attracted great interests in the field of EV-RNA research, and growing numbers of ncRNAs ranging from microRNAs to long ncRNAs have been investigated to reveal their specific functions and underlying mechanisms in the tumor microenvironment and premetastatic niches. Emerging evidence has indicated that EV-RNAs are essential functional cargoes in modulating hallmarks of cancers and in reciprocal crosstalk within tumor cells and between tumor and stromal cells over short and long distance, thereby regulating the initiation, development and progression of cancers. In this review, we discuss current findings regarding EV biogenesis, release and interaction with target cells as well as EV-RNA sorting, and highlight biological roles and molecular mechanisms of EV-ncRNAs in cancer biology.
Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis
Authors: Liu Shou-Sheng , Ma Xue-Feng , Zhao Jie , Du Shui-Xian , Zhang Jie , Dong Meng-Zhen , Xin Yong-Ning
Published: May 2020

Background

NAFLD is tightly associated with various diseases such as diabetes, cardiovascular disease, kidney disease, and cancer. Previous studies had investigated the association between NAFLD and various extrahepatic cancers, but the available data to date is not conclusive. The aim of this study was to investigate the association between NAFLD and various extrahepatic cancers comprehensively.

Methods

Searches were conducted of various electronic databases (PubMed, EMBASE, Medline, and the Cochrane Library) to identify observational studies published between 1996 and January 2020 which investigated the association between NAFLD and extrahepatic cancers. The pooled OR/HR/IRR of the association between NAFLD and various extrahepatic cancers were analyzed.

Results

A total of 26 studies were included to investigate the association between NAFLD and various extrahepatic cancers. As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40–2.11) and 1.37 (95%CI: 1.29–1.46), respectively. The pooled OR values of the risk of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in patients with NAFLD were 2.46 (95%CI: 1.77–3.44) and 2.24 (95%CI: 1.58–3.17), respectively. The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44–1.99). In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer.

Conclusions

NAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer. NAFLD could be considered as one of the influencing factors during the clinical diagnosis and treatment for the extrahepatic cancers.
MiR-9-5p promotes rabbit preadipocyte differentiation by suppressing leptin gene expression
Authors: Luo Gang , Hu Shenqiang , Lai Tianfu , Wang Jie , Wang Li , Lai Songjia
Published: June 2020

Background

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which participate in the regulation of cell differentiation. Previous studies have demonstrated that miR-9-5p plays a key role in cancer cell development, but the mechanisms by which miR-9-5p regulates adipogenesis remain poorly understood. The present study intended to investigate its significance in producing rabbits with high-quality meat by observing the regulatory effect of miR-9-5p in preadipocytes and finding the related targets.

Methods

In this study, a dual-luciferase reporter assay was employed to validate the targeting relationship between miR-9-5p and leptin gene. We also utilized quantitative reverse transcription PCR (qRT-PCR), western blot, oil red-O staining assay, and determination of triglyceride content to analyze the regulation of miR-9-5p and leptin gene during adipocyte differentiation.

Results

The analysis demonstrated that during preadipocyte differentiation, miR-9-5p was up-regulated and the fat formation related biomarkers, i.e., fatty acid-binding protein 4 (FABP4), CCAAT-enhancer binding protein α (C/EBPα), and peroxisome proliferator activated receptor γ (PPARγ) were also up-regulated. Meanwhile, the oil red-O staining assay revealed that the accumulation of lipid droplets increased. We also explored the expression pattern and role of miR-9-5p in adipogenesis using white pre-adipocytes. The results showed that miR-9-5p was up-regulated during preadipocyte differentiation, and overexpression of miR-9-5p enhanced lipid accumulation. Furthermore, we found that the overexpression of miR-9-5p significantly up- regulated the expression of marker genes, PPARγ, C/EBPα and FABP4, and increased the protein levels of PPARγ and triglyceride content. The results suggest that miR-9-5p might be involved in the regulation of rabbit preadipocyte differentiation. We predicted that leptin is the target gene of miR-9-5p, by using bioinformatics tools and the conclusion was validated by a luciferase reporter assay. Finally, we verified that the knock-down of leptin by si-leptin promoted preadipocyte differentiation in rabbits.

Conclusion

The results of the present study indicate that miR-9-5p regulates white preadipocyte differentiation in rabbits by targeting the leptin gene.
808 nm-activable core@multishell upconverting nanoparticles with enhanced stability for efficient photodynamic therapy
Authors: Martínez Raquel , Polo Ester , Barbosa Silvia , Taboada Pablo , del Pino Pablo , Pelaz Beatriz
Published: June 2020

Background

The unique upconversion properties of rare-earth-doped nanoparticles offers exciting opportunities for biomedical applications, in which near-IR remote activation of biological processes is desired, including in vivo bioimaging, optogenetics, and light-based therapies. Tuning of upconversion in purposely designed core–shell nanoparticles gives access to biological windows in biological tissue. In recent years there have been several reports on NIR-excitable upconverting nanoparticles capable of working in biological mixtures and cellular settings. Unfortunately, most of these nanosystems are based on ytterbium’s upconversion at 980 nm, concurrent with water’s absorption within the first biological window. Thus, methods to produce robust upconverting nanoplatforms that can be efficiently excited with other than 980 nm NIR sources, such as 808 nm and 1064 nm, are required for biomedical applications.

Results

Herein, we report a synthetic method to produce aqueous stable upconverting nanoparticles that can be activated with 808 nm excitation sources, thus avoiding unwanted heating processes due to water absorbance at 980 nm. Importantly, these nanoparticles, once transferred to an aqueous environment using an amphiphilic polymer, remain colloidally stable for long periods of time in relevant biological media, while keeping their photoluminescence properties. The selected polymer was covalently modified by click chemistry with two FDA-approved photosensitizers (Rose Bengal and Chlorin e6), which can be efficiently and simultaneously excited by the light emission of our upconverting nanoparticles. Thus, our polymer-functionalization strategy allows producing an 808 nm-activable photodynamic nanoplatform. These upconverting nanocomposites are preferentially stored in acidic lysosomal compartments, which does not negatively affect their performance as photodynamic agents. Upon 808 nm excitation, the production of reactive oxidative species (ROS) and their effect in mitochondrial integrity were demonstrated.

Conclusions

In summary, we have demonstrated the feasibility of using photosensitizer-polymer-modified upconverting nanoplatforms that can be activated by 808 nm light excitation sources for application in photodynamic therapy. Our nanoplatforms remain photoactive after internalization by living cells, allowing for 808 nm-activated ROS generation. The versatility of our polymer-stabilization strategy promises a straightforward access to other derivatizations (for instance, by integrating other photosensitizers or homing ligands), which could synergistically operate as multifunctional photodynamic platforms nanoreactors for in vivo applications.
Development and use of health outcome descriptors: a guideline development case study
Authors: Baldeh Tejan , Saz-Parkinson Zuleika , Muti Paola , Santesso Nancy , Morgano Gian Paolo , Wiercioch Wojtek , Nieuwlaat Robby , Gräwingholt Axel , Broeders Mireille , Duffy Stephen , Hofvind Solveig , Nystrom Lennarth , Ioannidou-Mouzaka Lydia , Warman Sue , McGarrigle Helen , Knox Susan , Fitzpatrick Patricia , Rossi Paolo Giorgi , Quinn Cecily , Borisch Bettina , Lebeau Annette , de Wolf Chris , Langendam Miranda , Piggott Thomas , Giordano Livia , van Landsveld-Verhoeven Cary , Bernier Jacques , Rabe Peter , Schünemann Holger J.
Published: June 2020

Background

During healthcare guideline development, panel members often have implicit, different definitions of health outcomes that can lead to misunderstandings about how important these outcomes are and how to balance benefits and harms. McMaster GRADE Centre researchers developed ‘health outcome descriptors’ for standardizing descriptions of health outcomes and overcoming these problems to support the European Commission Initiative on Breast Cancer (ECIBC) Guideline Development Group (GDG). We aimed to determine which aspects of the development, content, and use of health outcome descriptors were valuable to guideline developers.

Methods

We developed 24 health outcome descriptors related to breast cancer screening and diagnosis for the European Commission Breast Guideline Development Group (GDG). Eighteen GDG members provided feedback in written format or in interviews. We then evaluated the process and conducted two health utility rating surveys.

Results

Feedback from GDG members revealed that health outcome descriptors are probably useful for developing recommendations and improving transparency of guideline methods. Time commitment, methodology training, and need for multidisciplinary expertise throughout development were considered important determinants of the process. Comparison of the two health utility surveys showed a decrease in standard deviation in the second survey across 21 (88%) of the outcomes.

Conclusions

Health outcome descriptors are feasible and should be developed prior to the outcome prioritization step in the guideline development process. Guideline developers should involve a subgroup of multidisciplinary experts in all stages of development and ensure all guideline panel members are trained in guideline methodology that includes understanding the importance of defining and understanding the outcomes of interest.
Health-related quality of life in Norwegian adolescents living with chronic fatigue syndrome
Authors: Similä Wenche Ann , Halsteinli Vidar , Helland Ingrid B. , Suvatne Christer , Elmi Hanna , Rø Torstein Baade
Published: June 2020

Purpose

The primary aim was to measure health related quality of life (HRQoL) in a Norwegian cohort of adolescents with Chronic Fatigue Syndrome (CFS/ME). A secondary aim was to identify factors before diagnosis, at time of diagnosis and after diagnosis that were associated with HRQoL.

Methods

In this cross-sectional population-based study, HRQoL was measured by Pediatric Quality of Life Inventory™ Generic Core scale version 4.0 (PedsQL4.0) in 63 adolescents with CFS/ME. In addition, fatigue was measured by PedsQL Multidimensional Fatigue scale (PedsQL-MFS), depressive symptoms were measured by the Short Mood and Feelings Questionnaire (SMFQ), and disruption in school activities was measured by The De Paul Pediatric Health Questionnaire (DPHQ-N). Data were also collected from medical records and patient interviews.

Results

Age at diagnosis was 15 (2) years (mean (SD)), and four out of five participants were female. Time from diagnosis to reply was 39 (22) months. Adolescents with CFS/ME reported PedsQL4.0 score 50 (17), and boys reported a better score than girls (64 vs 47, 95% Confidence Interval (CI) for difference (− 27; − 6)). There were positive associations between overall HRQoL and support from a schoolteacher, school attendance or participation in leisure activities. There were negative associations between overall HRQoL and delayed school progression, having been to rehabilitation stay and depressive symptoms.

Conclusion

HRQoL in adolescents diagnosed with CFS/ME was low. The associations between reported HRQoL, healthcare previously provided, support from a schoolteacher, school attendance and participation in leisure activity may provide information of value when developing refined strategies for healthcare among adolescents with CFS/ME. Possible causal relationships must however be explored in future studies.
MACC1 driven alterations in cellular biomechanics facilitate cell motility in glioblastoma
Authors: Hohmann Tim , Hohmann Urszula , Kolbe Marc R. , Dahlmann Mathias , Kobelt Dennis , Stein Ulrike , Dehghani Faramarz
Published: June 2020

Background

Metastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). Nevertheless, the mechanism underlying the increased migratory capacity in GBM is not comprehensively explored.

Methods

We performed live cell and atomic force microscopy measurements to assess cell migration and mechanical properties ofMACC1overexpressing GBM cells. We quantifiedMACC1dependent dynamics of 3D aggregate formation. For mechanistic studies we measured the expression of key adhesion molecules using qRT-PCR, and MACC1 dependent changes in short term adhesion to fibronectin and laminin. We then determined changes in sub-cellular distribution of integrins and actin in dependence ofMACC1, but also in microtubule and intermediate filament organization.

Results

MACC1increased the migratory speed and elastic modulus of GBM cells, but decreased cell-cell adhesion and inhibited the formation of 3D aggregates. These effects were not associated with altered mRNA expression of several key adhesion molecules or altered short-term affinity to laminin and fibronectin.MACC1did neither change the organization of the microtubule nor intermediate filament cytoskeleton, but resulted in increased amounts of protrusive actin on laminin.

Conclusion

MACC1overexpression increases elastic modulus and migration and reduces adhesion of GBM cells thereby impeding 3D aggregate formation. The underlying molecular mechanism is independent on the organization of microtubules, intermediate filaments and several key adhesion molecules, but depends on adhesion to laminin. Thus, targeting re-organization of the cytoskeleton and cell motility via MACC1 may offer a treatment option to impede GBM spreading.
A prognostic nomogram integrating novel biomarkers identified by machine learning for cervical squamous cell carcinoma
Authors: Li Yimin , Lu Shun , Lan Mei , Peng Xinhao , Zhang Zijian , Lang Jinyi
Published: June 2020

Background

Cervical cancer (CC) represents the fourth most frequently diagnosed malignancy affecting women all over the world. However, effective prognostic biomarkers are still limited for accurately identifying high-risk patients. Here, we provided a combination machine learning algorithm-based signature to predict the prognosis of cervical squamous cell carcinoma (CSCC).

Methods and materials

After utilizing RNA sequencing (RNA-seq) data from 36 formalin-fixed and paraffin-embedded (FFPE) samples, the most significant modules were highlighted by the weighted gene co-expression network analysis (WGCNA). A candidate genes-based prognostic classifier was constructed by the least absolute shrinkage and selection operator (LASSO) and then validated in an independent validation set. Finally, based on the multivariate analysis, a nomogram including the FIGO stage, therapy outcome, and risk score level was built to predict progression-free survival (PFS) probability.

Results

A mRNA-based signature was developed to classify patients into high- and low-risk groups with significantly different PFS and overall survival (OS) rate (training set: p < 0.001 for PFS, p = 0.016 for OS; validation set: p = 0.002 for PFS, p = 0.028 for OS). The prognostic classifier was an independent and powerful prognostic biomarker for PFS in both cohorts (training set: hazard ratio [HR] = 0.13, 95% CI 0.05–0.33, p < 0.001; validation set: HR = 0.02, 95% CI 0.01–0.04, p < 0.001). A nomogram that integrated the independent prognostic factors was constructed for clinical application. The calibration curve showed that the nomogram was able to predict 1-, 3-, and 5-year PFS accurately, and it performed well in the external validation cohorts (concordance index: 0.828 and 0.864, respectively).

Conclusion

The mRNA-based biomarker is a powerful and independent prognostic factor. Furthermore, the nomogram comprising our prognostic classifier is a promising predictor in identifying the progression risk of CSCC patients.
Big data from small tissues: extraction of high-quality RNA for RNA-sequencing from different oilseed Brassica seed tissues during seed development
Authors: Siles Laura , Eastmond Peter , Kurup Smita
Published: June 2020

Background

Obtaining high-quality RNA for gene expression analyses from different seed tissues is challenging due to the presence of various contaminants, such as polyphenols, polysaccharides and lipids which interfere with RNA extraction methods. At present, the available protocols for extracting RNA from seeds require high amounts of tissue and are mainly focused on extracting RNA from whole seeds. However, extracting RNA at the tissue level enables more detailed studies regarding tissue specific transcriptomes during seed development.

Results

Seeds from heart stage embryo to mature developmental stages of Brassica napus and B. oleracea were sampled for isolation of the embryo, endosperm and seed coat tissues. Ovules and ovary wall tissue were also collected from pre-fertilized buds. Subsequent to testing several RNA extraction methods, modifications applied to E.Z.N.A. Plant RNA and Picopure RNA Isolation kit extraction methods resulted in RNA with high yield and quality. Furthermore, the use of polyvinylpolypyrrolidone for seed coats and endosperm at green stages resulted in high-quality RNA. As a result of the introduced modifications to established RNA extraction methods, the RNA from all the above-mentioned tissues presented clear 28S and 18S bands and high RIN values, ranging from 7.0 to 10.0. The protocols reported in this study are not only suitable for different and challenging seed tissue types, but also enable the extraction of high-quality RNA using only 2 to 3 mg of starting tissue.

Conclusions

Here, we present efficient, reproducible and reliable high-quality RNA extraction methods for diverse oilseed Brassica spp reproductive tissue types including pre-fertilization and developing seed tissues for diploid and polyploid species. The high-quality RNA obtained is suitable for RNA-Sequencing and subsequent gene expression analysis.
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

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

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 registration

ChiCTR, 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

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

Background

Mitochondrial 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).

Methods

We 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.

Results

Enforcing 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.

Conclusions

In 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

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.