bluuebunny/crossref_metadata_2025_split huggingface dataset:
The challenges in data integration – heterogeneity and complexity in clinical trials and patient registries of Systemic Lupus Erythematosus
Authors: Le Sueur Helen , Bruce Ian N. , Geifman Nophar ,   on behalf of the MASTERPLANS Consortium
Published: June 2020

Abstract
Background
Individual clinical trials and cohort studies are a useful source of data, often under-utilised once a study has ended. Pooling data from multiple sources could increase sample sizes and allow for further investigation of treatment effects; even if the original trial did not meet its primary goals. Through the MASTERPLANS (MAximizing Sle ThERapeutic PotentiaL by Application of Novel and Stratified approaches) national consortium, focused on Systemic Lupus Erythematosus (SLE), we have gained valuable real-world experiences in aligning, harmonising and combining data from multiple studies and trials, specifically where standards for data capture, representation and documentation, were not used or were unavailable. This was not without challenges arising both from the inherent complexity of the disease and from differences in the way data were captured and represented across different studies.

Main body
Data were, unavoidably, aligned by hand, matching up equivalent or similar patient variables across the different studies. Heterogeneity-related issues were tackled and data were cleaned, organised and combined, resulting in a single large dataset ready for analysis. Overcoming these hurdles, often seen in large-scale data harmonization and integration endeavours of legacy datasets, was made possible within a realistic timescale and limited resource by focusing on specific research questions driven by the aims of MASTERPLANS. Here we describe our experiences tackling the complexities in the integration of large, diverse datasets, and the lessons learned.

Conclusions
Harmonising data across studies can be complex, and time and resource consuming. The work carried out here highlights the importance of using standards for data capture, recording, and representation, to facilitate both the integration of large datasets and comparison between studies. Where standards are not implemented at the source harmonisation is still possible by taking a flexible approach, with systematic preparation, and a focus on specific research questions.
Organised and opportunistic prevention in primary health care: estimation of missed opportunities by population based health interview surveys in Hungary
Authors: Sándor János , Tokaji Ildikó , Harsha Nouh , Papp Magor , Ádány Róza , Czifra Árpád 
Published: June 2020

Abstract
Background
Improvement of preventive services for adults can be achieved by opportunistic or organised methods in primary care. The unexploited opportunities of these approaches were estimated by our investigation.

Methods
Data from the Hungarian implementation of European Health Interview Surveys in 2009 (N = 4709) and 2014 (N = 5352) were analysed. Proportion of subjects used interventions in target group (screening for hypertension and diabetes mellitus, and influenza vaccination) within a year were calculated. Taking into consideration recommendations for the frequency of intervention, numbers of missed interventions among patients visited a general practitioner in a year and among patients did not visit a general practitioner in a year were calculated in order to describe missed opportunities that could be utilised by opportunistic or organised approaches. Numbers of missed interventions were estimated for the entire population of the country and for an average-sized general medical practice.

Results
Implementation ratio were 66.8% for blood pressure measurement among subjects above 40 years and free of diagnosed hypertension; 63.5% for checking blood glucose among adults above 45 and overweighed and free of diagnosed diabetes mellitus; and 19.1% for vaccination against seasonal influenza. There were 4.1 million interventions implemented a year in Hungary, most of the (3.8 million) among adults visited general practitioner in a year. The number of missed interventions was 4.5 million a year; mostly (3.4 million) among persons visited general practitioner in a year. For Hungary, the opportunistic and organised missed opportunities were estimated to be 561,098, and 1,150,321 for hypertension screening; 363,270, and 227,543 for diabetes mellitus screening; 2,784,072, and 380,033 for influenza vaccination among the < 60 years old high risk subjects, and 3,029,700 and 494,150 for influenza vaccination among more than 60 years old adults, respectively. By implementing all missed services, the workload in an average-sized general medical practice would be increased by 12–13 opportunistic and 4–5 organised interventions a week.

Conclusions
The studied interventions are much less used than recommended. The opportunistic missed opportunities is prevailing for influenza vaccination, and the organised one is for hypertension screening. The two approaches have similar significance for diabetes mellitus screening.
Self-reported generalised pruritus among community-dwelling older adults in Malaysia
Authors: Yong Shin Shen , Kwan Zhenli , Ch’ng Chin Chwen , Yong Adrian Sze Wai , Tan Leng Leng , Han Winn Hui , Kamaruzzaman Shahrul Bahyah , Chin Ai-Vyrn , Tan Maw Pin 
Published: June 2020

AbstractBackgroundThe ageing skin is more susceptible to pruritic dermatoses, which are associated with adverse psychosocial effects and reduced quality of life among older adults. This cross-sectional study aimed to identify the burden of pruritus and factors associated with its presence and severity among older adults recruited to the Malaysian Elders Longitudinal Research study.MethodsSeven hundred seventy individuals aged 55 years (lower age limit) and above were interviewed as to whether they experienced pruritus during the preceding week and the locations involved if present. The association between generalised pruritus, sleep quality, and major systemic risk factors were explored.Results5.97% of respondents reported generalised pruritus. Generalised pruritus was associated with poorer sleep quality, with Pittsburgh Sleep Quality Index score above 6. Mean haemoglobin level was lower in subjects with generalised pruritus (13.14 g/dL) but there was no significant difference in the frequency of generalised pruritus and severe generalized pruritus between subjects with clinically defined anaemia. Also, there were no significant associations between other major systemic risk factors and generalised pruritus in this population-based study. There was no association between generalised pruritus with depression, anxiety or stress.ConclusionThe negative effect of pruritus on sleep quality suggests a possible deleterious effect of pruritus on health and quality of life. Further prospective research on the longer-term effects of pruritus on health status is now warranted.(222 words)
Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations
Authors: Chande Aroon T. , Rishishwar Lavanya , Conley Andrew B. , Valderrama-Aguirre Augusto , Medina-Rivas Miguel A. , Jordan I. King 
Published: June 2020

Abstract
Background
Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations.

Methods
Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here.

Results
T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences.

Conclusions
T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.
Oxytocin receptor gene, childhood maltreatment and borderline personality disorder features among male inmates in China
Authors: Zhang Min , Liu Na , Chen Haocheng , Zhang Ning 
Published: June 2020

Abstract
Background
Borderline personality disorder (BPD) is caused by a variety of biological and environmental factors. Accumulating evidence suggests that childhood maltreatment is a risk environmental factor in the development of BPD, but research on the genetic pathology of BPD is still in its early stages, and very little is known about the oxytocin receptor (OXTR) gene. The purpose of this study is to further explore the interactive effects between OXTR gene polymorphisms and childhood maltreatment on BPD risk.

Methods
Among the 1804 Chinese Han male inmates, 765 inmates who had BPD or antisocial personality disorder (ASPD) or highly impulsive or violent crime were considered as high-risk inmates and included in this study. Childhood maltreatment, BPD, antisocial personality disorder (ASPD) and impulsivity were measured by self-reported questionnaires. Peripheral venous blood was collected for the genotype test.

Results
Analyses revealed that the BP group (inmates with BPD features) had higher rs53576 AA genotype frequency and rs237987 AA genotype frequency than the non-BP group, while the statistical significances were lost after Bonferroni correction. Total childhood maltreatment score, emotional abuse and neglect could positively predict BPD risk. Among the high-risk samples, rs53576 GG genotype carriers had higher BPD scores at higher levels of physical abuse and sexual abuse and had lower BPD scores at lower levels of physical abuse and sexual abuse.

Conclusions
The findings suggest that the interaction between OXTR gene variations and childhood maltreatment is an important mechanism for the development of BPD. The moderating role of the OXTR gene provides evidence for gene plasticity.
Evaluation of serum amino acids and non-enzymatic antioxidants in drug-naïve first-episode major depressive disorder
Authors: Islam Md. Rabiul , Ali Samia , Karmoker James Regun , Kadir Mohammad Fahim , Ahmed Maizbha Uddin , Nahar Zabun , Islam Sardar Mohammad Ashraful , Islam Mohammad Safiqul , Hasnat Abul , Islam Md. Saiful 
Published: June 2020

AbstractBackgroundThe alterations of biological markers are thought to be effective tools to understand the pathophysiology and management of major depressive disorder (MDD). A lot of researches has implied many markers for depression, but any of them fully discovered the association between the markers and depression. The present study investigated the serum levels of amino acids and non-enzymatic antioxidants in major depression, and also explained their association with depression.MethodsThis study examined 247 MDD patients and 248 healthy controls (HCs) matched by age and sex. The Hamilton Depression Rating Scale (Ham-D) was used to all the participants to measure the severity of depression. Quantification of serum amino acids, vitamin A and E were carried out using the HPLC system whereas vitamin C levels were measured by UV-spectrophotometer. All the statistical analysis was performed by SPSS statistical software (version 23.0). The independent sample t-test, the Mann-Whitney U test, and the Fisher’s exact test were applied to detect the group differences where a Bonferroni correction applied to thepvalue.ResultsIt was observed that serum levels of four amino acids (methionine, phenylalanine, tryptophan, and tyrosine) along with three non-enzymatic antioxidants (vitamin A, E, and C) were significantly dropped in MDD patients compared to HCs (Cohen’s d (d): − 0.45, − 0.50, − 0.68, − 0.21, − 0.27, − 0.65, and − 0.24, respectively). Furthermore, Ham-D scores of cases were negatively correlated with serum levels of methionine (r = − 0.155,p = 0.015) and tyrosine (r = − 0.172,p = 0.007).ConclusionThe present study suggests that lowered serum methionine, phenylalanine, tryptophan, tyrosine, and non-enzymatic antioxidants are associated with depression. The reduction of these parameters in MDD patients may be the consequence, and not the cause, of major depression.
GUIP1: a R package for dose escalation strategies in phase I cancer clinical trials
Authors: Dinart D. , Fraisse J. , Tosi D. , Mauguen A. , Touraine C. , Gourgou S. , Le Deley M. C. , Bellera C. , Mollevi C. 
Published: June 2020

AbstractBackgroundThe main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. The main ones are: the continual reassessment method (CRM), the escalation with overdose control (EWOC) method and, for late-onset and cumulative toxicities, the time-to-event continual reassessment method (TITE-CRM) and the time-to-event escalation with overdose control (TITE-EWOC) methods. The objective of this work was to perform a user-friendly R package that combines the latter model-guided adaptive designs.ResultsGUIP1 is an R Graphical User Interface for dose escalation strategies in Phase 1 cancer clinical trials. It implements the CRM (based on Bayesian or maximum likelihood estimation), EWOC and TITE-CRM methods using the dfcrm and bcrm R packages, while the TITE-EWOC method has been specifically developed. The program is built using the TCL/TK programming language, which can be compiled via R software libraries (tcltk, tkrplot, tcltk2). GUIP1 offers the possibility of simulating and/or conducting and managing phase I clinical trials in real-time using file management options with automatic backup of study and/or simulation results.ConclusionsGUIP1 is implemented using the software R, which is widely used by statisticians in oncology. This package simplifies the use of the main model-based dose escalation methods and is designed to be fairly simple for beginners in R. Furthermore, it offers multiple possibilities such as a full traceability of the study. By including multiple innovative adaptive methods in a free and user-friendly program, we hope that GUIP1 will promote and facilitate their use in designing future phase I cancer clinical trials.
Use of the theoretical domains framework and behaviour change wheel to develop a novel intervention to improve the quality of multidisciplinary cancer conference decision-making
Authors: Fahim Christine , Acai Anita , McConnell Meghan M. , Wright Frances C. , Sonnadara Ranil R. , Simunovic Marko 
Published: June 2020

Abstract
Background
Multidisciplinary Cancer Conferences (MCCs) are prospective meetings involving cancer specialists to discuss treatment plans for patients with cancer. Despite reported gaps in MCC quality, there have been few efforts to improve its functioning. The purpose of this study was to use theoretically-rooted knowledge translation (KT) theories and frameworks to inform the development of a strategy to improve MCC decision-making quality.

Methods
A multi-phased approach was used to design an intervention titled the KT-MCC Strategy. First, key informant interviews framed using the Theoretical Domains Framework (TDF) were conducted with MCC participants to identify barriers and facilitators to optimal MCC decision-making. Second, identified TDF domains were mapped to corresponding strategies using the COM-B Behavior Change Wheel to develop the KT-MCC Strategy. Finally, focus groups with MCC participants were held to confirm acceptability of the proposed KT-MCC Strategy.

Results
Data saturation was reached at n = 21 interviews. Twenty-seven barrier themes and 13 facilitator themes were ascribed to 11 and 10 TDF domains, respectively. Differences in reported barriers by physician specialty were observed. The resulting KT-MCC Strategy included workshops, chair training, team training, standardized intake forms and a synoptic discussion checklist, and, audit and feedback. Focus groups (n = 3, participants 18) confirmed the acceptability of the identified interventions.

Conclusion
Myriad factors were found to influence MCC decision making. We present a novel application of the TDF and COM-B to the context of MCCs. We comprehensively describe the barriers and facilitators that impact MCC decision making and propose strategies that may positively impact the quality of MCC decision making.
New targeted approaches for epigenetic age predictions
Authors: Han Yang , Franzen Julia , Stiehl Thomas , Gobs Michael , Kuo Chao-Chung , Nikolić Miloš , Hapala Jan , Koop Barbara Elisabeth , Strathmann Klaus , Ritz-Timme Stefanie , Wagner Wolfgang 
Published: June 2020

Abstract
Background
Age-associated DNA methylation changes provide a promising biomarker for the aging process. While genome-wide DNA methylation profiles enable robust age-predictors by integration of many age-associated CG dinucleotides (CpGs), there are various alternative approaches for targeted measurements at specific CpGs that better support standardized and cost-effective high-throughput analysis.

Results
In this study, we utilized 4647 Illumina BeadChip profiles of blood to select CpG sites that facilitate reliable age-predictions based on pyrosequencing. We demonstrate that the precision of DNA methylation measurements can be further increased with droplet digital PCR (ddPCR). In comparison, bisulfite barcoded amplicon sequencing (BBA-seq) gave slightly lower correlation between chronological age and DNA methylation at individual CpGs, while the age-predictions were overall relatively accurate. Furthermore, BBA-seq data revealed that the correlation of methylation levels with age at neighboring CpG sites follows a bell-shaped curve, often associated with a CTCF binding site. We demonstrate that within individual BBA-seq reads the DNA methylation at neighboring CpGs is not coherently modified, but reveals a stochastic pattern. Based on this, we have developed a new approach for epigenetic age predictions based on the binary sequel of methylated and non-methylated sites in individual reads, which reflects heterogeneity in epigenetic aging within a sample.

Conclusion
Targeted DNA methylation analysis at few age-associated CpGs by pyrosequencing, BBA-seq, and particularly ddPCR enables high precision of epigenetic age-predictions. Furthermore, we demonstrate that the stochastic evolution of age-associated DNA methylation patterns in BBA-seq data enables epigenetic clocks for individual DNA strands.
Knockdown of ALPK2 inhibits the development and progression of Ovarian Cancer
Authors: Zhu Xiaogang , Yan Siqi , Xiao Songshu , Xue Min 
Published: June 2020

Abstract
Background
Alpha protein kinase 2 (ALPK2) was known to play a vital role in cancer by regulating cell cycle and DNA repair. Ovarian cancer (OC) is one of the most lethal malignancies in the female reproductive system. The emphasis of this study is to explore the role of ALPK2 in OC.

Methods
Firstly, tumor and normal tissues were collected for detecting expression of ALPK2 in OC. Lentivirus-mediated shRNA knockdown of ALPK2 was used to construct OC cell model, which was verified by qRT-PCR and Western blot. The cell proliferation was detected by MTT, cell cycle and apoptosis were measured through flow cytometry. Wound-healing assay was conducted to detect the migration of OC cells.

Results
It was proved that the expression of ALPK2 in OC tissues was significantly higher than that in normal ovarian tissues. Moreover, knockdown of ALPK2 could inhibit proliferation, migration and promote apoptosis, arrested cell cycle of OC cells. It was also found that ALPK2 knockdown inhibited tumor growth in xenograft mice in vivo. Furthermore, ALPK2 was involved in OC cells via regulating EMT-related proteins (N-cadherin, Vimentin and Snail), inhibiting apoptosis-related proteins (Bcl-2, Bcl-w, HSP27, HSP60, IGF-I, IGF-1sR, Survivin and XIAP), as well as the regulation of downstream pathways (Akt, p-Akt, Cyclin D1, CDK6 and PIK3CA).

Conclusions
In conclusion, ALPK2 might serve as an optional target for prognosis and therapeutic of OC patients.
Untargeted LC–MS/MS analysis reveals metabolomics feature of osteosarcoma stem cell response to methotrexate
Authors: Wang Feng , Zhang Zhiyu , Li Qin , Yu Tao , Ma Chengbin 
Published: June 2020

Abstract
Background
Cancer stem cell (CSC) is identified in osteosarcoma (OS) and considered resistant to chemotherapeutic agents. However, the mechanism of osteosarcoma stem cell (OSC) resistant to chemotherapy remains debatable and vague, and the metabolomics feature of OSC is not clarified.

Materials and methods
OSC was isolated by using sphere forming assay and identified. Untargeted LC–MS/MS analysis was performed to reveal the metabolomics feature of OSC and underlying mechanisms of OSC resistant to methotrexate (MTX).

Results
OSC was efficiently isolated and identified from human OS 143B and MG63 cell lines with enhanced chemo-resistance to MTX. The untargeted LC–MS analysis revealed that OSC showed differential metabolites and perturbed signaling pathways, mainly involved in metabolisms of fatty acid, amino acid, carbohydrate metabolism and nucleic acid. After treated with MTX, metabolomics feature of OSC was mainly involved metabolisms of amino acid, fatty acid, energy and nucleic acid. Moreover, compared with their parental OS cells response to MTX, the differential metabolites and perturbed signaling pathways were mainly involved in metabolism of amino acid, fatty acid and nucleic acid. What’s more, Rap1 signaling pathway and Ras signaling pathway were involved in OS cells and their SCs response to MTX.

Conclusion
Sphere-forming assay was able to efficiently isolate OSC from human OS cell lines and the untargeted LC–MS/MS analysis was suggested a sufficient methodology to investigate metabolomics features of OS cells and OSCs. Moreover, the metabolomics features of OSCs response to MTX might reveal a further understanding of chemotherapeutic resistance in OS.