bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring new uses for existing drugs: innovative mechanisms to fund independent clinical research
Authors: Verbaanderd Ciska , Rooman Ilse , Huys Isabelle 
Published: May 2021

Abstract
Background
Finding new therapeutic uses for existing medicines could lead to safe, affordable and timely new treatment options for patients with high medical needs. However, due to a lack of economic incentives, pharmaceutical developers are rarely interested to invest in research with approved medicines, especially when they are out of basic patent or regulatory protection. Consequently, potential new uses for these medicines are mainly studied in independent clinical trials initiated and led by researchers from academia, research institutes, or collaborative groups. Yet, additional financial support is needed to conduct expensive phase III clinical trials to confirm the results from exploratory research.

Methods
In this study, scientific and grey literature was searched to identify and evaluate new mechanisms for funding clinical trials with repurposed medicines. Semi-structured interviews were conducted with 16 European stakeholders with expertise in clinical research, funding mechanisms and/or drug repurposing between November 2018 and February 2019 to consider the future perspectives of applying new funding mechanisms.

Results
Traditional grant funding awarded by government and philanthropic organisations or companies is well known and widely implemented in all research fields. In contrast, only little research has focused on the application potential of newer mechanisms to fund independent clinical research, such as social impact bonds, crowdfunding or public-private partnerships. Interviewees stated that there is a substantial need for additional financial support in health research, especially in areas where there is limited commercial interest. However, the implementation of new funding mechanisms is facing several practical and financial challenges, such as a lack of expertise and guidelines, high transaction costs and difficulties to measure health outcomes. Furthermore, interviewees highlighted the need for increased collaboration and centralisation at a European and international level to make clinical research more efficient and reduce the need for additional funding.

Conclusions
New funding mechanisms to support clinical research may become more important in the future but the unresolved issues identified in the current study warrant further exploration.
Development of a prognostic risk model for clear cell renal cell carcinoma by systematic evaluation of DNA methylation markers
Authors: Joosten S. C. , Odeh S. N. O. , Koch A. , Buekers N. , Aarts M. J. B. , Baldewijns M. M. L. L. , Van Neste L. , van Kuijk S. , Schouten L. J. , van den Brandt P. A. , Tjan-Heijnen V. C. , van Engeland M. , Smits K. M. 
Published: May 2021

Abstract
Background
Current risk models for renal cell carcinoma (RCC) based on clinicopathological factors are sub-optimal in accurately identifying high-risk patients. Here, we perform a head-to-head comparison of previously published DNA methylation markers and propose a potential prognostic model for clear cell RCC (ccRCC).

Patients and methods
Promoter methylation of PCDH8, BNC1, SCUBE3, GREM1, LAD1, NEFH, RASSF1A, GATA5, SFRP1, CDO1, and NEURL was determined by nested methylation-specific PCR. To identify clinically relevant methylated regions, The Cancer Genome Atlas (TCGA) was used to guide primer design. Formalin-fixed paraffin-embedded (FFPE) tissue samples from 336 non-metastatic ccRCC patients from the prospective Netherlands Cohort Study (NLCS) were used to develop a Cox proportional hazards model using stepwise backward elimination and bootstrapping to correct for optimism. For validation purposes, FFPE ccRCC tissue of 64 patients from the University Hospitals Leuven and a series of 232 cases from The Cancer Genome Atlas (TCGA) were used.

Results
Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade. Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region. A prognostic biomarker model containing GREM1, GATA5, LAD1, NEFH and NEURL methylation in combination with clinicopathological characteristics, performed better compared to the model with clinicopathological characteristics only (clinical model), in both the NLCS and the validation population with a c-statistic of 0.71 versus 0.65 and a c-statistic of 0.95 versus 0.86 consecutively. However, the biomarker model had limited added prognostic value in the TCGA series with a c-statistic of 0.76 versus 0.75 for the clinical model.

Conclusion
In this study we performed a head-to-head comparison of potential prognostic methylation markers for ccRCC using a novel approach to guide primers design which utilizes the optimal location for measuring DNA methylation. Using this approach, we identified five methylation markers that potentially show prognostic value in addition to currently known clinicopathological factors.
Nonlinear $(m,\infty )$-isometries and $(m,\infty )$-expansive (contractive) mappings on normed spaces
Authors: Ayed Al-Ahmadi Aydah Mohammed 
Published: May 2021

AbstractLet S be a self-mapping on a normed space ${\mathcal{X}}$
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Improved permeate flux and rejection of ultrafiltration membranes prepared from polyethylene terephthalate (PET) bottle waste
Authors: Kusumocahyo Samuel P. , Ambani Syarifa K. , Marceline Shelly 
Published: May 2021

AbstractThe vast amount of not-recycled polyethylene terephthalate (PET) bottle waste is a serious threat to the environment. In order to utilize the waste, PET ultrafiltration membranes were prepared using PET bottle waste as the raw material by using the phase inversion technique. Low molecular weight polyethylene glycol (PEG 400) was used as the additive for the membranes. PET resin was also used as the membrane material to compare the properties of the membrane from PET bottle waste and those from the PET resin. The membrane prepared from PET bottle waste and that prepared from PET resin showed similar membrane characteristics such as IR spectra, morphology, hydrophilicity and porosity, indicating that instead of using PET resin, PET bottle waste can be utilized as a source of the polymer material to fabricate low-cost membranes. The morphology, hydrophilicity and porosity of the membranes were strongly affected by the PEG 400 concentration. The analysis of the membrane morphology using Scanning Electron Microscopy showed that the membranes had an asymmetric structure that consisted of a macroporous cross section and a smooth active layer. Increasing the PEG 400 concentration resulted in a smaller pore size, however the hydrophilicity and the porosity of the membranes increased. As a result, the membranes showed an increase in both permeate flux and rejection with increasing concentration of PEG 400 as observed from the results of the ultrafiltration experiments. Using Bovine Serum Albumin as a solute model in the feed, high values of rejection of up to 94% were achieved. Thus, ultrafiltration membranes with improved permeate flux and rejection could be prepared from PET bottle waste by the addition of PEG 400 as the additive.
Mid-term results and survival rates following a single-design rotating hinge knee arthroplasty in non-tumor conditions in a Pakistani population
Authors: Memon Nouman , Iqbal Faizan , Noor Syed Shahid , Najjad Kazim Rahim , Sozera Muhammad Farhan , Abro Arsalan , Khan Noman 
Published: May 2021

Abstract
Background
Information regarding the use of hinged implants in non-oncological conditions is limited in our region due to a lack of adequate data collection and follow-up. The purpose of this study is to evaluate mid-term results and risk factors affecting the survivorship of third-generation rotating hinge knee (RHK) patients in non-oncological conditions.

Methods
We retrospectively reviewed 41 single, third-generation, rotating hinge prostheses in three complex primary knee procedures and 38 revision knee surgeries in between 2007 to 2014. Implant survival was assessed using the Kaplan-Meier method. Factors influencing implant survival were identified using the log-rank test. During the study period, clinical results along with complications were assessed. Clinical outcomes were assessed by using the Knee Society Score (KSS).

Results
RHK arthroplasty was used in 41 patients. Out of 41 patients, a RHK was used in three patients with a complex primary deformed knee whereas in 38 patients, a RHK was used in revision arthroplasty surgery. The cumulative implant survival rate with re-revision due to any cause was found to be 87.8% (95% CI 69.2–90.1) at 5–7 years. Prosthetic joint infection, peri-prosthetic fracture and extensor mechanism complications were the commonest mode of failure. The P value was found to be significant when comparing KSS pre-operatively and post-operatively.

Conclusion
The cumulative implant survival rate was found to be 87.8%. Prosthetic joint infection was the commonest mode of failure in patients who underwent third-generation RHK surgery for variable indications. Being a patient with a high Charlson comorbidity index is the main risk factor associated with failure of the rotating hinge implant.
HLA-A gene knockout using CRISPR/Cas9 system toward overcoming transplantation concerns
Authors: Amiri Farshid , Ranjbar Maryam , Pirouzfar Mohammad , Nourigorji Marjan , Dianatpour Mehdi 
Published: May 2021

Abstract
Background
The treatment of many cancers and genetic diseases relies on novel engraftment approaches such as cell therapy and hematopoietic stem cell transplantation (HSCT). However, these methods are hindered by the alloreactive immune responses triggered by incompatible human leukocyte antigen (HLA) molecules. A successful HSCT procedure requires the eradication of donor and recipient HLA alloimmunization. Eliminating HLA-A gene expression using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9) could be a great approach to increase the possibility of a successful HSCT through extending pool of unrelated donors.

Results
Our dual gRNA approach introduced a large deletion in the HLA-A gene. Among 22 single-cloned cells, two clones (9.09%) and 11 clones (50%) received homozygous and heterozygous large deletions, respectively. Finally, the real-time PCR results also revealed that HLA-A gene expression was diminished significantly.

Conclusion
The results suggested that CRISPR/Cas9 could be used as an efficient technique to introduce HLA-A gene knockout; thus, it can considerably lessen the burden of finding a fully matched donor by lowering the alleles required for a successful HSCT.
Genome wide association study for the identification of genes associated with tail fat deposition in Chinese sheep breeds
Authors: Zhu Caiye , Li Na , Cheng Heping , Ma Youji 
Published: May 2021

ABSTRACT
Chinese indigenous sheep can be classified into three types based on tail morphology: fat-tailed, fat-rumped, and thin-tailed sheep, of which the typical breeds are large-tailed Han sheep, Altay sheep, and Tibetan sheep, respectively. To unravel the molecular genetic basis underlying the phenotypic differences among Chinese indigenous sheep with these three different tail types, we used ovine high-density 600K single nucleotide polymorphism (SNP) arrays to detect genome-wide associations, and performed general linear model analysis to identify candidate genes, using genotyping technology to validate the candidate genes. Tail type is an important economic trait in sheep. However, the candidate genes associated with tail type are not known. The objective of this study was to identify SNP markers, genes, and chromosomal regions related to tail traits. We performed a genome-wide association study (GWAS) using data from 40 large-tailed Han sheep, 40 Altay sheep (cases) and 40 Tibetan sheep (controls). A total of 31 significant (P&lt;0.05) SNPs associated with tail-type traits were detected. For significant SNPs' loci, we determined their physical location and performed a screening of candidate genes within each region. By combining information from previously reported and annotated biological functional genes, we identified SPAG17, Tbx15, VRTN, NPC2, BMP2 and PDGFD as the most promising candidate genes for tail-type traits. Based on the above identified candidate genes for tail-type traits, BMP2 and PDGFD genes were selected to investigate the relationship between SNPs within the tails in the Altay and Tibetan populations. rs119 T&gt;C in exon1 of the BMP2 gene and one SNP in exon4 (rs69 C&gt;A) of the PDGFD gene were detected. rs119 was of the TT genotype in Altay sheep, while it was of the CC genotype in Tibetan sheep. On rs69 of the PDGFD gene, Altay sheep presented with the CC genotype; however, Tibetan sheep presented with the AA genotype.
Determinants of exclusive breastfeeding and overall duration of breastfeeding among mothers in Plateau, Nigeria
Authors: Emmanuel Andy , Clow Sheila E 
Published: May 2021

Background It is recommended that infants should be fed exclusively with breast milk for the first 6 months, and up to 2 years after birth. This has the potential to improve child survival in limited resource settings. The aim of this study was to identify determinants of exclusive breastfeeding and overall duration of breastfeeding among pregnant mothers in Plateau, Nigeria. Method This was a cross-sectional study involving 763 pregnant mothers attending antenatal clinics in the three senatorial districts of Plateau state, who completed a validated questionnaire. Informed consent was obtained, and all women participated voluntarily. Data were coded and analysed using Chi-square tests and logistic regression, with P<0.05 considered significant. Results Overall, 84.4% of mothers were exclusively breastfeeding at discharge or 48 hours after birth. Exclusive breastfeeding for 6 months was practiced by 36.2% of respondents. Exclusive breastfeeding rates showed a decline as infant age increased. Women with fewer than five children were 2.3 times more likely to feed their baby other foods within the first 6 months than those with five or more children (P=0.001). The average overall duration of breastfeeding was 15 (standard deviation±4) months. Women less than 30 years old were 2.4 times more likely to breastfeed for a shorter period of time, compared to women who were 30 years or older (P<0.001). Chi-square analysis suggested a significant relationship between place of delivery, type of delivery, parity and infant feeding practices. Conclusions Exclusive breastfeeding was not common among the women who participated in this study and declined with increased infant age. The overall duration of breastfeeding was 15 months, which is less than the recommended 2 years. Maternal age, place of delivery, type of delivery and parity were found to influence exclusive breastfeeding and overall breastfeeding. Understanding current practices and factors that influence breastfeeding is important to implement strategies that will empower mothers to breastfeed exclusively. Identifying the cultural practices that act as barriers to early breastfeeding is necessary for the drafting of future interventions to promote breastfeeding.
Risk factors for a radiolucent line around the acetabular component with an interface bioactive bone cement technique after primary cemented total hip arthroplasty
Authors: Miyamoto Shuichi , Iida Satoshi , Suzuki Chiho , Nakatani Takushi , Kawarai Yuya , Nakamura Junichi , Orita Sumihisa , Ohtori Seiji 
Published: May 2021

AimsThe main aims were to identify risk factors predictive of a radiolucent line (RLL) around the acetabular component with an interface bioactive bone cement (IBBC) technique in the first year after THA, and evaluate whether these risk factors influence the development of RLLs at five and ten years after THA.MethodsA retrospective review was undertaken of 980 primary cemented THAs in 876 patients using cemented acetabular components with the IBBC technique. The outcome variable was any RLLs that could be observed around the acetabular component at the first year after THA. Univariate analyses with univariate logistic regression and multivariate analyses with exact logistic regression were performed to identify risk factors for any RLLs based on radiological classification of hip osteoarthritis.ResultsRLLs were detected in 27.2% of patients one year postoperatively. In multivariate regression analysis controlling for confounders, atrophic osteoarthritis (odds ratio (OR) 2.17 (95% confidence interval (CI), 1.04 to 4.49); p = 0.038) and 26 mm (OR 3.23 (95% CI 1.85 to 5.66); p < 0.001) or 28 mm head diameter (OR 3.64 (95% CI 2.07 to 6.41); p < 0.001) had a significantly greater risk for any RLLs one year after surgery. Structural bone graft (OR 0.19 (95% CI 0.13 to 0.29) p < 0.001) and location of the hip centre within the true acetabular region (OR 0.15 (95% CI 0.09 to 0.24); p < 0.001) were significantly less prognostic. Improvement of the cement-bone interface including complete disappearance and poorly defined RLLs was identified in 15.1% of patients. Kaplan-Meier survival analysis for the acetabular component at ten years with revision of the acetabular component for aseptic loosening as the end point was 100.0% with a RLL and 99.1% without a RLL (95% CI 97.9 to 100). With revision of the acetabular component for any reason as the end point, the survival rate was 99.2% with a RLL (95% CI 97.6 to 100) and 96.5% without a RLL (95% CI 93.4 to 99.7).ConclusionThis study demonstrates that acetabular bone quality, head diameter, structural bone graft, and hip centre position may influence the presence of the any RLL. Cite this article: Bone Joint Open 2021;2(5):278–292.
Can High-Resolution Satellite Multispectral Imagery Be Used to Phenotype Canopy Traits and Yield Potential in Field Conditions?
Authors: Sankaran Sindhuja , Marzougui Afef , Hurst J. Preston , Zhang Chongyuan , Schnable James C. , Shi Yeyin 
Published: May 2021

HighlightsVegetation indices (NDVI, GNDVI, and SAVI) extracted from high-resolution satellite imagery were significantly associated with vegetation indices extracted from UAV imagery.High-resolution satellite data can be used to predict maize yield at breeding plot scale.Breeding plot sizes and the variability between maize genotypes may be associated with prediction accuracies.Abstract. The recent availability of high spatial and temporal resolution satellite imagery has widened its applications in agriculture. Plant breeding and genetics programs are currently adopting unmanned aerial vehicle (UAV) based imagery data as a complement to ground data collection. With breeding trials across multiple geographic locations, UAV imaging is not always convenient. Hence, we anticipate that, similar to UAV imaging, phenotyping of individual test plots from high-resolution satellite imagery may also provide value to plant genetics and breeding programs. In this study, high spatial resolution satellite imagery (~38 to 48 cm pixel-1) was compared to imagery acquired using a UAV for its ability to phenotype maize grown in two-row and six-row breeding plots. Statistics (mean, median, sum) of color (red, green, blue), near-infrared, and vegetation indices such as normalized difference vegetation index (NDVI), green normalized difference vegetation index (GNDVI), and soil adjusted vegetation index (SAVI) were extracted from imagery from both sources (UAV and satellite) for comparison at three time points. In general, a strong correlation between satellite and UAV imagery extracted NDVI, GNDVI, and SAVI features (especially with mean and median statistics, p &lt; 0.001) was observed at different time points. The correlation of both UAV and satellite image features with yield potential was maximum (p &lt; 0.001) at the third time point (milk/dough growth stages). For example, Pearson’s correlation coefficients between mean NDVI, GNDVI, and SAVI features with yield potential were 0.52, 0.54, and 0.51 for data derived from UAV imagery, and 0.34, 0.41, and 0.40 for data derived from satellite imagery, respectively. Machine learning algorithms, including least absolute shrinkage and selection operator (Lasso) regression, were evaluated for yield prediction using vegetation index features that were significantly correlated with observed yield. The relationship between satellite imagery with crop performance can be a function of plot size in addition to crop variability. Nevertheless, with the ongoing improvement of satellite technologies, there is a possibility for the integration of satellite data into breeding programs, thus improving phenotyping efficiencies. Keywords: Image processing, Machine learning, Plant breeding, Statistical analysis, Unmanned aerial vehicles.