bluuebunny/crossref_metadata_2025_split huggingface dataset:
OASIS +: leveraging machine learning to improve the prognostic accuracy of OASIS severity score for predicting in-hospital mortality
Authors: EL-Manzalawy Yasser , Abbas Mostafa , Hoaglund Ian , Cerna Alvaro Ulloa , Morland Thomas B. , Haggerty Christopher M. , Hall Eric S. , Fornwalt Brandon K. 
Published: May 2021

Abstract
Background
Severity scores assess the acuity of critical illness by penalizing for the deviation of physiologic measurements from normal and aggregating these penalties (also called “weights” or “subscores”) into a final score (or probability) for quantifying the severity of critical illness (or the likelihood of in-hospital mortality). Although these simple additive models are human readable and interpretable, their predictive performance needs to be further improved.

Methods
We present OASIS +, a variant of the Oxford Acute Severity of Illness Score (OASIS) in which an ensemble of 200 decision trees is used to predict in-hospital mortality based on the 10 same clinical variables in OASIS.

Results
Using a test set of 9566 admissions extracted from the MIMIC-III database, we show that OASIS + outperforms nine previously developed severity scoring methods (including OASIS) in predicting in-hospital mortality. Furthermore, our results show that the supervised learning algorithms considered in our experiments demonstrated higher predictive performance when trained using the observed clinical variables as opposed to OASIS subscores.

Conclusions
Our results suggest that there is room for improving the prognostic accuracy of the OASIS severity scores by replacing the simple linear additive scoring function with more sophisticated non-linear machine learning models such as RF and XGB.
Applied techniques for putting pre-visit planning in clinical practice to empower patient-centered care in the pandemic era: a systematic review and framework suggestion
Authors: Gholamzadeh Marsa , Abtahi Hamidreza , Ghazisaeeidi Marjan 
Published: May 2021

AbstractBackgroundOne of the main elements of patient-centered care is an enhancement of patient preparedness. Thus, pre-visit planning assessment tools was emerged to prepare and involve patients in their treatment process.ObjectiveThe main objective of this article was to review the applied tools and techniques for consideration of putting pre-visit planning into practice.MethodsWeb of Science, Scopus, IEEE, and PubMed databases were searched using keywords from January 2001 to November 2020. The review was completed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Then, qualitative analysis was done to suggest an appropriate framework by mapping the main concepts.ResultsOut of 385 citations were retrieved in initial database searches, 49 studies from ten countries were included. Applied pre-visit techniques can be classified into eight categories. Our results showed that almost 81% of studies were related to procedures that were done between each visit, while 42% of articles were related to before visits. Accordingly, the main approach of included articles was patient preparedness. While 38 studies reported this approach is effective, three studies reported the effectiveness of such tools as moderate, only two articles believed it had a low effect on improving patient-centered care.ConclusionThis survey summarized the characteristics of published studies on pre-visit planning in the proposed framework. This approach could enhance the quality of patient care alongside enhancement patient-provider communication. However, such an approach can also be helpful to control pandemic diseases by reducing unnecessary referrals.
Trends and equity in the use of health services in Spain and Germany around austerity in Europe
Authors: Moreno Almudena , Lostao Lourdes , Beller Johannes , Sperlich Stefanie , Ronda Elena , Geyer Siegfried , Pulido José , Regidor Enrique 
Published: May 2021

Abstract
Background
Following the 2008 economic crisis many countries implemented austerity policies, including reducing public spending on health services. This paper evaluates the trends and equity in the use of health services during and after that period in Spain – a country with austerity policies – and in Germany – a country without restriction on healthcare spending.

Methods
Data from several National Surveys in Spain and several waves of the Socio-Economic Panel in Germany, carried out between 2009 and 2017, were used. The dependent variables were number of doctor’s consultations and whether or not a hospital admission occurred. The measure of socioeconomic position was education. In each year, the estimates were made for people with and without pre-existing health problems. First, the average number of doctor’s consultations and the percentage of respondents who had had been hospitalized were calculated. Second, the relationship between education and use of those health services was estimated by calculating the difference in consultations using covariance analysis – in the case of number of consultations – and by calculating the percentage ratio using binomial regression – in the case of hospitalization.

Results
The annual mean number of consultations went down in both countries. In Spain the average was 14.2 in 2009 and 10.4 in 2017 for patients with chronic conditions; 16.6 and 13.5 for those with a mental illness; and 6.4 and 5.9 for those without a defined illness. In Germany, the averages were 13.8 (2009) and 12.9 (2017) for the chronic group; 21.1 and 17.0 for mental illness; and 8.7 and 7.5 with no defined illness. The hospitalization frequency also decreased in both countries. The majority of the analyses presented no significant differences in relation to education.

Conclusion
In both Spain and Germany, service use decreased between 2009 and 2017. In the first few years, this reduction coincided with a period of austerity in Spain. In general, we did not find socioeconomic differences in health service use.
Rapid sequence induction: where did the consensus go?
Authors: Avery Pascale , Morton Sarah , Raitt James , Lossius Hans Morten , Lockey David 
Published: May 2021

Abstract
Background
Rapid Sequence Induction (RSI) was introduced to minimise the risk of aspiration of gastric contents during emergency tracheal intubation. It consisted of induction with the use of thiopentone and suxamethonium with the application of cricoid pressure.
This narrative review describes how traditional RSI has been modified in the UK and elsewhere, aiming to deliver safe and effective emergency anaesthesia outside the operating room environment. Most of the key aspects of traditional RSI – training, technique, drugs and equipment have been challenged and often significantly changed since the procedure was first described. Alterations have been made to improve the safety and quality of the intervention while retaining the principles of rapidly securing a definitive airway and avoiding gastric aspiration. RSI is no longer achieved by an anaesthetist alone and can be delivered safely in a variety of settings, including in the pre-hospital environment.

Conclusion
The conduct of RSI in current emergency practice is far removed from the original descriptions of the procedure. Despite this, the principles – rapid delivery of a definitive airway and avoiding aspiration, are still highly relevant and the indications for RSI remain relatively unchanged.
Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways
Authors: Ho Won Jin , Erbe Rossin , Danilova Ludmila , Phyo Zaw , Bigelow Emma , Stein-O’Brien Genevieve , Thomas Dwayne L. , Charmsaz Soren , Gross Nicole , Woolman Skylar , Cruz Kayla , Munday Rebecca M. , Zaidi Neeha , Armstrong Todd D. , Sztein Marcelo B. , Yarchoan Mark , Thompson Elizabeth D. , Jaffee Elizabeth M. , Fertig Elana J. 
Published: May 2021

AbstractBackgroundThe majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed at the metastatic stage, and standard therapies have limited activity with a dismal 5-year survival rate of only 8%. The liver and lung are the most common sites of PDAC metastasis, and each have been differentially associated with prognoses and responses to systemic therapies. A deeper understanding of the molecular and cellular landscape within the tumor microenvironment (TME) metastasis at these different sites is critical to informing future therapeutic strategies against metastatic PDAC.ResultsBy leveraging combined mass cytometry, immunohistochemistry, and RNA sequencing, we identify key regulatory pathways that distinguish the liver and lung TMEs in a preclinical mouse model of metastatic PDAC. We demonstrate that the lung TME generally exhibits higher levels of immune infiltration, immune activation, and pro-immune signaling pathways, whereas multiple immune-suppressive pathways are emphasized in the liver TME. We then perform further validation of these preclinical findings in paired human lung and liver metastatic samples using immunohistochemistry from PDAC rapid autopsy specimens. Finally, in silico validation with transfer learning between our mouse model and TCGA datasets further demonstrates that many of the site-associated features are detectable even in the context of different primary tumors.ConclusionsDetermining the distinctive immune-suppressive features in multiple liver and lung TME datasets provides further insight into the tissue specificity of molecular and cellular pathways, suggesting a potential mechanism underlying the discordant clinical responses that are often observed in metastatic diseases.
Association of TNF-α -308G > A polymorphism with susceptibility to tendinopathy in athletes: a case–control study
Authors: Lopes Lucas Rafael , de Miranda Vitor Almeida Ribeiro , Guimarães João Antonio Matheus , de Araujo Souza Gabriel Garcez , Wainchtock Victor Soares , Grangeiro Neto João Alves , de Araújo Goes Rodrigo , Perini Jamila Alessandra 
Published: May 2021

Abstract
Background
High levels of the tumor necrosis factor alpha (TNF-α) induce apoptosis and pro-inflammatory effects for primary degeneration of tendon and development of tendinopathy. The aim of this study was to investigate the association between the TNF-α polymorphisms and tendinopathy in athletes.

Methods
Two hundred and seventy athletes (135 tendinopathy cases and 135 controls) were included and genotyped (TNF-α -1031T > C; -857 C > T; -308G > A) using TaqMan validated assays. The association of the polymorphisms with tendinopathy was evaluated by a multivariate logistic regression model, using odds ratios (OR) and 95 % confidence intervals (CI).

Results
The variant allele − 308 A was significantly associated with patellar (OR: 1.9; 95 % CI: 1.01–3.6) or Achilles tendinopathies (OR: 2.7; 95 % CI: 1.1–6.7). No significant differences were found in allele or genotype distributions of the − 1031T > C and − 857 C > T polymorphisms between cases and controls. TNF-α TCA haplotype was associated with increased tendinopathies risk, either considering all cases (OR: 2.6, 95 % CI: 1.3–5.3), patellar (OR: 3.3, 95 % CI: 1.5–7.3), rotator cuff (OR: 3.1, 95 % CI: 1.4–7.2) or Achilles tendinopathies (OR: 3.8, 95 % CI: 1.1–12.7).

Conclusions
These results suggest that the TNF-α polymorphisms could influence the susceptibility to developing tendinopathy among athletes. Knowledge of the TNF-α polymorphisms associated to tendinopathy in athletes can further understanding of the inflammatory role in the early stages of the disease and contribute for sports injury surveillance programmes, in which athletes with TNF-α TCA haplotype could be early subjected to cryotherapy after training and competition to avoid tendinopathy development.
Bayonet-shaped language development in autism with regression: a retrospective study
Authors: Gagnon David , Zeribi Abderrahim , Douard Élise , Courchesne Valérie , Rodríguez-Herreros Borja , Huguet Guillaume , Jacquemont Sébastien , Loum Mor Absa , Mottron Laurent 
Published: May 2021

Abstract
Background
Language delay is one of the major referral criteria for an autism evaluation. Once an autism spectrum diagnosis is established, the language prognosis is among the main parental concerns. Early language regression (ELR) is observed by 10–50% of parents but its relevance to late language level and socio-communicative ability is uncertain. This study aimed to establish the predictive value of ELR on the progression of language development and socio-communicative outcomes to guide clinicians in addressing parents’ concerns at the time of diagnosis.

Methods
We used socio-communicative, language, and cognitive data of 2,047 autism spectrum participants from the Simons Simplex Collection, aged 4–18 years (mean = 9 years; SD = 3.6). Cox proportional hazard and logistic regression models were used to evaluate the effect of ELR on language milestones and the probability of using complex and flexible language, as defined by the choice of ADOS module at enrollment. Linear models were then used to evaluate the relationship of ELR and non-verbal IQ with socio-communicative and language levels.

Results
ELR is associated with earlier language milestones but delayed attainment of fluent, complex, and flexible language. However, this language outcome can be expected for almost all autistic children without intellectual disability at 18 years of age. It is mostly influenced by non-verbal IQ, not ELR. The language and socio-communicative level of participants with flexible language, as measured by the Vineland and ADOS socio-communicative subscales, was not affected by ELR.

Limitations
This study is based on a relatively coarse measure of ultimate language level and relies on retrospective reporting of early language milestones and ELR. It does not prospectively document the age at which language catches up, the relationship between ELR and other behavioral areas of regression, nor the effects of intervention.

Conclusions
For autistic individuals with ELR and a normal level of non-verbal intelligence, language development follows a “bayonet shape” trajectory: early first words followed by regression, a plateau with limited progress, and then language catch up.
Vitamin D3 suppresses intestinal epithelial stemness via ER stress induction in intestinal organoids
Authors: Sittipo Panida , Kim Hyun Kyu , Han Jaeseok , Lee Man Ryul , Lee Yun Kyung 
Published: May 2021

Abstract
Background
Vitamin D3 is important for normal function of the intestinal epithelial cells (IECs). In this study, we aimed to investigate the effects of vitamin D3 on the differentiation, stemness, and viability of healthy IECs in intestinal organoids.

Methods
Intestinal organoids derived from mouse small intestine were treated with vitamin D3, and the effects on intestinal stemness and differentiation were evaluated using real-time PCR and immunofluorescence staining of the distinct lineage markers. Cell viability was analyzed using viability and apoptosis assays.

Results
Vitamin D3 enhanced IEC differentiation into the distinct lineages of specialized IECs, including Paneth, goblet, and enteroendocrine cells and absorptive enterocytes. Decreased expression levels of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) and the presence of several LGR5-green fluorescent protein (GFP)-positive cells were observed in vitamin D3-treated organoids derived from LGR5-GFP mice. The formation of the crypt-villus structure was also inhibited by vitamin D3, suggesting that vitamin D3 suppresses intestinal cell stemness. Furthermore, the expression levels of unfolded protein response genes, C/EBP homologous protein (CHOP), and activating transcription factor 6 (ATF6) were upregulated in vitamin D3-treated organoids. Moreover, vitamin D3 promoted apoptotic cell death in intestinal cells, which may be associated with the decrease in intestinal stemness. LGR5 gene expression, ISC number, and apoptotic cell death were partially recovered in the presence of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), suggesting that intestinal stemness suppression and intestinal apoptosis occurred via ER stress activation.

Conclusions
Our study provides important insights into the effects of vitamin D3 on the induction of IEC differentiation and apoptotic cell death, and inhibition of intestinal stemness accompanied by ER stress augmentation.
Development, characterization, and hematopoietic differentiation of Griscelli syndrome type 2 induced pluripotent stem cells
Authors: Güney-Esken Gülen , Erol Özgür Doğuş , Pervin Burcu , Gürhan Sevinç Gülben , Önder Tamer , Bilgiç Elif , Korkusuz Petek , Günel-Özcan Ayşen , Uçkan-Çetinkaya Duygu , Aerts-Kaya Fatima 
Published: May 2021

Abstract
Background
Griscelli syndrome type 2 (GS-2) is a rare, autosomal recessive immune deficiency syndrome caused by a mutation in the RAB27A gene, which results in the absence of a protein involved in vesicle trafficking and consequent loss of function of in particular cytotoxic T and NK cells. Induced pluripotent stem cells (iPSC) express genes associated with pluripotency, have the capacity for infinite expansion, and can differentiate into cells from all three germ layers. They can be induced using integrative or non-integrative systems for transfer of the Oct4, Sox2, Klf4, and cMyc (OSKM) transcription factors. To better understand the pathophysiology of GS-2 and to test novel treatment options, there is a need for an in vitro model of GS-2.

Methods
Here, we generated iPSCs from 3 different GS-2 patients using lentiviral vectors. The iPSCs were characterized using flow cytometry and RT-PCR and tested for the expression of pluripotency markers. In vivo differentiation to cells from all three germlines was tested using a teratoma assay. In vitro differentiation of GS-2 iPSCs into hematopoietic stem and progenitor cells was done using Op9 feeder layers and specified media.

Results
All GS-2 iPSC clones displayed a normal karyotype (46XX or 46XY) and were shown to express the same RAB27A gene mutation that was present in the original somatic donor cells. GS-2 iPSCs expressed SSEA1, SSEA4, TRA-1-60, TRA-1-81, and OCT4 proteins, and SOX2, NANOG, and OCT4 expression were confirmed by RT-PCR. Differentiation capacity into cells from all three germ layers was confirmed using the teratoma assay. GS-2 iPSCs showed the capacity to differentiate into cells of the hematopoietic lineage.

Conclusions
Using the lentiviral transfer of OSKM, we were able to generate different iPSC clones from 3 GS-2 patients. These cells can be used in future studies for the development of novel treatment options and to study the pathophysiology of GS-2 disease.
Adrenomedullin 2 improves bone regeneration in type 1 diabetic rats by restoring imbalanced macrophage polarization and impaired osteogenesis
Authors: Wang Feng , Kong Lingchi , Wang Wenbo , Shi Li , Wang Mengwei , Chai Yimin , Xu Jia , Kang Qinglin 
Published: May 2021

Abstract
Background
Both advanced glycation end products (AGEs) and AGE-mediated M1 macrophage polarization contribute to bone marrow mesenchymal stem cell (BMSC) dysfunction, leading to impaired bone regeneration in type 1 diabetes mellitus (T1DM). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and reduction of insulin resistance. However, the effects and underlying mechanisms of ADM2 in AGE-induced macrophage M1 polarization, BMSC dysfunction, and impaired bone regeneration remain poorly understood.

Methods
The polarization of bone marrow-derived macrophages was verified using flow cytometry analysis. Alkaline phosphatase (ALP) staining, ALP activity detection, and alizarin red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence staining were used to assess polarization markers, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and osteogenic markers. In vivo, a distraction osteogenesis (DO) rat model with T1DM was established, and tibia samples were collected at different time points for radiological, biomechanical, and histological analyses, to verify the effects of ADM2 on bone regeneration and M2 polarization under diabetic conditions.

Results
ADM2 treatment reversed AGE-induced M1 macrophage polarization towards the M2 phenotype, which was partially achieved by the peroxisome proliferator-activated receptor γ (PPARγ)-mediated inhibition of NF-κB signaling. The PPARγ inhibitor GW9662 significantly attenuated the effects of ADM2. Besides, ADM2 treatment improved the AGE-impaired osteogenic potential of BMSCs in vitro. Furthermore, ADM2 accelerated bone regeneration, as revealed by improved radiological and histological manifestations and biomechanical parameters, accompanied by improved M2 macrophage polarization in diabetic DO rats, and these effects were partially blocked by GW9662 administration.

Conclusions
These results indicate that ADM2 enhances diabetic bone regeneration during DO, by attenuating AGE-induced imbalances in macrophage polarization, partly through PPARγ/NF-κB signaling, and improving AGE-impaired osteogenic differentiation of BMSCs simultaneously. These findings reveal that ADM2 may serve as a potential bioactive factor for promoting bone regeneration under diabetic conditions, and imply that management of inflammation and osteogenesis, in parallel, may present a promising therapeutic strategy for diabetic patients during DO treatment.
Comparison of structure- and ligand-based scoring functions for deep generative models: a GPCR case study
Authors: Thomas Morgan , Smith Robert T. , O’Boyle Noel M. , de Graaf Chris , Bender Andreas 
Published: May 2021

AbstractDeep generative models have shown the ability to devise both valid and novel chemistry, which could significantly accelerate the identification of bioactive compounds. Many current models, however, use molecular descriptors or ligand-based predictive methods to guide molecule generation towards a desirable property space. This restricts their application to relatively data-rich targets, neglecting those where little data is available to sufficiently train a predictor. Moreover, ligand-based approaches often bias molecule generation towards previously established chemical space, thereby limiting their ability to identify truly novel chemotypes. In this work, we assess the ability of using molecular docking via Glide—a structure-based approach—as a scoring function to guide the deep generative model REINVENT and compare model performance and behaviour to a ligand-based scoring function. Additionally, we modify the previously published MOSES benchmarking dataset to remove any induced bias towards non-protonatable groups. We also propose a new metric to measure dataset diversity, which is less confounded by the distribution of heavy atom count than the commonly usedinternal diversitymetric. With respect to the main findings, we found that when optimizing the docking score against DRD2, the model improves predicted ligand affinity beyond that of known DRD2 active molecules. In addition, generated molecules occupy complementary chemical and physicochemical space compared to the ligand-based approach, and novel physicochemical space compared to known DRD2 active molecules. Furthermore, the structure-based approach learns to generate molecules that satisfy crucial residue interactions, which is information only available when taking protein structure into account. Overall, this work demonstrates the advantage of using molecular docking to guide de novo molecule generation over ligand-based predictors with respect to predicted affinity, novelty, and the ability to identify key interactions between ligand and protein target. Practically, this approach has applications in early hit generation campaigns to enrich a virtual library towards a particular target, and also in novelty-focused projects, where de novo molecule generation either has no prior ligand knowledge available or should not be biased by it.