bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model
Authors: Feinauer Manuel J. , Schneider Stefan W. , Berghoff Anna S. , Robador Jose Ramon , Tehranian Cedric , Karreman Matthia A. , Venkataramani Varun , Solecki Gergely , Grosch Julia Katharina , Gunkel Katharina , Kovalchuk Bogdana , Mayer Frank Thomas , Fischer Manuel , Breckwoldt Michael O. , Brune Maik , Schwab Yannick , Wick Wolfgang , Bauer Alexander T. , Winkler Frank 
Published: December 2020

Abstract
Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (&gt;95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.
Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study
Authors: Fakhouri Fadi , Fila Marc , Hummel Aurélie , Ribes David , Sellier-Leclerc Anne-Laure , Ville Simon , Pouteil-Noble Claire , Coindre Jean-Philippe , Le Quintrec Moglie , Rondeau Eric , Boyer Olivia , Provôt François , Djeddi Djamal , Hanf William , Delmas Yahsou , Louillet Ferielle , Lahoche Annie , Favre Guillaume , Châtelet Valérie , Launay Emma Allain , Presne Claire , Zaloszyc Ariane , Caillard Sophie , Bally Stéphane , Raimbourg Quentin , Tricot Leïla , Mousson Christiane , Le Thuaut Aurélie , Loirat Chantal , Frémeaux-Bacchi Véronique 
Published: December 2020

Abstract
The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.
Identification of novel alternative splicing biomarkers for breast cancer with LC/MS/MS and RNA-Seq
Authors: Zhang Fan , Deng Chris K. , Wang Mu , Deng Bin , Barber Robert , Huang Gang 
Published: December 2020

Abstract
Background
Alternative splicing isoforms have been reported as a new and robust class of diagnostic biomarkers. Over 95% of human genes are estimated to be alternatively spliced as a powerful means of producing functionally diverse proteins from a single gene. The emergence of next-generation sequencing technologies, especially RNA-seq, provides novel insights into large-scale detection and analysis of alternative splicing at the transcriptional level. Advances in Proteomic Technologies such as liquid chromatography coupled tandem mass spectrometry (LC–MS/MS), have shown tremendous power for the parallel characterization of large amount of proteins in biological samples. Although poor correspondence has been generally found from previous qualitative comparative analysis between proteomics and microarray data, significantly higher degrees of correlation have been observed at the level of exon. Combining protein and RNA data by searching LC–MS/MS data against a customized protein database from RNA-Seq may produce a subset of alternatively spliced protein isoform candidates that have higher confidence.

Results
We developed a bioinformatics workflow to discover alternative splicing biomarkers from LC–MS/MS using RNA-Seq. First, we retrieved high confident, novel alternative splicing biomarkers from the breast cancer RNA-Seq database. Then, we translated these sequences into in silico Isoform Junction Peptides, and created a customized alternative splicing database for MS searching. Lastly, we ran the Open Mass spectrometry Search Algorithm against the customized alternative splicing database with breast cancer plasma proteome. Twenty six alternative splicing biomarker peptides with one single intron event and one exon skipping event were identified. Further interpretation of biological pathways with our Integrated Pathway Analysis Database showed that these 26 peptides are associated with Cancer, Signaling, Metabolism, Regulation, Immune System and Hemostasis pathways, which are consistent with the 256 alternative splicing biomarkers from the RNA-Seq.

Conclusions
This paper presents a bioinformatics workflow for using RNA-seq data to discover novel alternative splicing biomarkers from the breast cancer proteome. As a complement to synthetic alternative splicing database technique for alternative splicing identification, this method combines the advantages of two platforms: mass spectrometry and next generation sequencing and can help identify potentially highly sample-specific alternative splicing isoform biomarkers at early-stage of cancer.
Increased usability, algorithmic improvements and incorporation of data mining for structure calculation of proteins with REDCRAFT software package
Authors: Cole Casey , Parks Caleb , Rachele Julian , Valafar Homayoun 
Published: December 2020

Abstract
Background
Traditional approaches to elucidation of protein structures by Nuclear Magnetic Resonance spectroscopy (NMR) rely on distance restraints also known as Nuclear Overhauser effects (NOEs). The use of NOEs as the primary source of structure determination by NMR spectroscopy is time consuming and expensive. Residual Dipolar Couplings (RDCs) have become an alternate approach for structure calculation by NMR spectroscopy. In previous works, the software package REDCRAFT has been presented as a means of harnessing the information containing in RDCs for structure calculation of proteins. However, to meet its full potential, several improvements to REDCRAFT must be made.

Results
In this work, we present improvements to REDCRAFT that include increased usability, better interoperability, and a more robust core algorithm. We have demonstrated the impact of the improved core algorithm in the successful folding of the protein 1A1Z with as high as ±4 Hz of added error. The REDCRAFT computed structure from the highly corrupted data exhibited less than 1.0 Å with respect to the X-ray structure. We have also demonstrated the interoperability of REDCRAFT in a few instances including with PDBMine to reduce the amount of required data in successful folding of proteins to unprecedented levels. Here we have demonstrated the successful folding of the protein 1D3Z (to within 2.4 Å of the X-ray structure) using only N-H RDCs from one alignment medium.

Conclusions
The additional GUI features of REDCRAFT combined with the NEF compliance have significantly increased the flexibility and usability of this software package. The improvements of the core algorithm have substantially improved the robustness of REDCRAFT in utilizing less experimental data both in quality and quantity.
Physiological and transcriptomic analyses reveal the roles of secondary metabolism in the adaptive responses of Stylosanthes to manganese toxicity
Authors: Jia Yidan , Li Xinyong , Liu Qin , Hu Xuan , Li Jifu , Dong Rongshu , Liu Pandao , Liu Guodao , Luo Lijuan , Chen Zhijian 
Published: December 2020

Abstract
Background
As a heavy metal, manganese (Mn) can be toxic to plants. Stylo (Stylosanthes) is an important tropical legume that exhibits tolerance to high levels of Mn. However, little is known about the adaptive responses of stylo to Mn toxicity. Thus, this study integrated both physiological and transcriptomic analyses of stylo subjected to Mn toxicity.

Results
Results showed that excess Mn treatments increased malondialdehyde (MDA) levels in leaves of stylo, resulting in the reduction of leaf chlorophyll concentrations and plant dry weight. In contrast, the activities of enzymes, such as peroxidase (POD), phenylalanine ammonia-lyase (PAL) and polyphenol oxidase (PPO), were significantly increased in stylo leaves upon treatment with increasing Mn levels, particularly Mn levels greater than 400 μM. Transcriptome analysis revealed 2471 up-regulated and 1623 down-regulated genes in stylo leaves subjected to Mn toxicity. Among them, a set of excess Mn up-regulated genes, such as genes encoding PAL, cinnamyl-alcohol dehydrogenases (CADs), chalcone isomerase (CHI), chalcone synthase (CHS) and flavonol synthase (FLS), were enriched in secondary metabolic processes based on gene ontology (GO) analysis. Numerous genes associated with transcription factors (TFs), such as genes belonging to the C2H2 zinc finger transcription factor, WRKY and MYB families, were also regulated by Mn in stylo leaves. Furthermore, the C2H2 and MYB transcription factors were predicted to be involved in the transcriptional regulation of genes that participate in secondary metabolism in stylo during Mn exposure. Interestingly, the activation of secondary metabolism-related genes probably resulted in increased levels of secondary metabolites, including total phenols, flavonoids, tannins and anthocyanidins.

Conclusions
Taken together, this study reveals the roles of secondary metabolism in the adaptive responses of stylo to Mn toxicity, which is probably regulated by specific transcription factors.
Time series prediction of under-five mortality rates for Nigeria: comparative analysis of artificial neural networks, Holt-Winters exponential smoothing and autoregressive integrated moving average models
Authors: Adeyinka Daniel Adedayo , Muhajarine Nazeem 
Published: December 2020

AbstractBackgroundAccurate forecasting model for under-five mortality rate (U5MR) is essential for policy actions and planning. While studies have used traditional time series modeling techniques (e.g., autoregressive integrated moving average (ARIMA) and Holt-Winters smoothing exponential methods), their appropriateness to predict noisy and non-linear data (such as childhood mortality) has been debated. The objective of this study was to model long-term U5MR with group method of data handling (GMDH)-type artificial neural network (ANN), and compare the forecasts with the commonly used conventional statistical methods—ARIMA regression and Holt-Winters exponential smoothing models.MethodsThe historical dataset of annual U5MR in Nigeria from 1964 to 2017 was obtained from the official website of World Bank. The optimal models for each forecasting methods were used for forecasting mortality rates to 2030 (ending of Sustainable Development Goal era). The predictive performances of the three methods were evaluated, based on root mean squared errors (RMSE), root mean absolute error (RMAE) and modified Nash-Sutcliffe efficiency (NSE) coefficient. Statistically significant differences in loss function between forecasts of GMDH-type ANN model compared to each of the ARIMA and Holt-Winters models were assessed with Diebold-Mariano (DM) test and Deming regression.ResultsThe modified NSE coefficient was slightly lower for Holt-Winters methods (96.7%), compared to GMDH-type ANN (99.8%) and ARIMA (99.6%). The RMSE of GMDH-type ANN (0.09) was lower than ARIMA (0.23) and Holt-Winters (2.87). Similarly, RMAE was lowest for GMDH-type ANN (0.25), compared with ARIMA (0.41) and Holt-Winters (1.20). From the DM test, the mean absolute error (MAE) was significantly lower for GMDH-type ANN, compared with ARIMA (difference = 0.11,p-value = 0.0003), and Holt-Winters model (difference = 0.62, p-value< 0.001). Based on the intercepts from Deming regression, the predictions from GMDH-type ANN were more accurate (β0 = 0.004 ± standard error: 0.06; 95% confidence interval: − 0.113 to 0.122).ConclusionsGMDH-type neural network performed better in predicting and forecasting of under-five mortality rates for Nigeria, compared to the ARIMA and Holt-Winters models. Therefore, GMDH-type ANN might be more suitable for data with non-linear or unknown distribution, such as childhood mortality. GMDH-type ANN increases forecasting accuracy of childhood mortalities in order to inform policy actions in Nigeria.
Risk factors for a positive SARS-CoV-2 PCR in patients with common cold symptoms in a primary care setting – a retrospective analysis based on a joint documentation standard
Authors: Just Johannes , Puth Marie-Therese , Regenold Felix , Weckbecker Klaus , Bleckwenn Markus 
Published: December 2020

Abstract
Background
Combating the COVID-19 pandemic is a major challenge for health systems, citizens and policy makers worldwide. Early detection of affected patients within the large and heterogeneous group of patients with common cold symptoms is an important element of this effort, but often hindered by limited testing resources, false-negative test results and the lack of pathognomonic symptoms in COVID-19. Therefore, we aimed to identify anamnestic items with an increased/decreased odds ratio for a positive SARS-CoV-2 PCR (CovPCR) result in a primary care setting.

Methods
We performed a multi-center cross-sectional cohort study on predictive clinical characteristics for a positive CovPCR over a period of 4 weeks in primary care patients in Germany.

Results
In total, 374 patients in 14 primary care centers received CovPCR and were included in this analysis. The median age was 44.0 (IQR: 31.0–59.0) and a fraction of 10.7% (n = 40) tested positive for COVID-19. Patients who reported anosmia had a higher odds ratio (OR: 4.54; 95%-CI: 1.51–13.67) for a positive test result while patients with a sore throat had a lower OR (OR: 0.33; 95%-CI: 0.11–0.97). Furthermore, patients who had a first grade contact with an infected persons and showed symptoms themselves also had an increased OR for positive testing (OR: 5.16; 95% CI: 1.72–15.51). This correlation was also present when they themselves were still asymptomatic (OR: 12.55; 95% CI: 3.97–39.67).

Conclusions
Several anamnestic criteria may be helpful to assess pre-test probability of COVID-19 in patients with common cold symptoms.
Mortality is not increased with Diabetes in hospitalised very old adults: a multi-site review
Authors: Smerdely Peter 
Published: December 2020

Abstract
Background
Few data exist regarding hospital outcomes in people with diabetes aged beyond 75 years. This study aimed to explore the association of diabetes with hospital outcome in the very old patient.

Methods
A retrospective review was conducted of all presentations of patients aged 65 years or more admitted to three Sydney teaching hospitals over 6 years (2012–2018), exploring primarily the outcomes of in-hospital mortality, and secondarily the outcomes of length of stay, the development of hospital-acquired adverse events and unplanned re-admission to hospital within 28 days of discharge. Demographic and outcome data, the presence of diabetes and comorbidities were determined from ICD10 coding within the hospital’s electronic medical record. Logistic and negative binomial regression models were used to assess the association of diabetes with outcome.

Results
A total of 139,130 separations (mean age 80 years, range 65 to 107 years; 51% female) were included, with 49% having documented comorbidities and 26.1% a diagnosis of diabetes.
When compared to people without diabetes, diabetes was not associated with increased odds of mortality (OR: 0.89 SE (0.02), p < 0.001). Further, because of a significant interaction with age, diabetes was associated with decreased odds of mortality beyond 80 years of age. While people with diabetes overall had longer lengths of stay (10.2 days SD (13.4) v 9.4 days SD (12.3), p < 0.001), increasing age was associated with shorter lengths of stay in people aged more than 90 years. Diabetes was associated with increased odds of hospital-acquired adverse events (OR: 1.09 SE (0.02), p < 0.001) and but not 28-day re-admission (OR: 0.88 SE (0.18), p = 0.523).

Conclusion
Diabetes has not been shown to have a negative impact on mortality or length of stay in hospitalised very old adults from data derived from hospital administrative records. This may allow a more measured application of diabetic guidelines in the very old hospitalised patient.
Emphasise capability, not disability: exploring public perceptions, facilitators and barriers to living well with dementia in Northern Ireland
Authors: Mitchell Gary , McTurk Victoria , Carter Gillian , Brown-Wilson Christine 
Published: December 2020

AbstractBackgroundImproving public knowledge and understanding about dementia has been identified as a priority area by people living with the condition, researchers, educators, and policymakers for several years. Societies that have a better understanding of the condition are more likely to enable people living with dementia to enjoy a better quality of life. The aim of this study was to explore current public perceptions of dementia along with the facilitators and barriers to living well from the perspective of people living with the condition in Northern Ireland.MethodsFour focus group interviews were conducted with a total of 20 people living with dementia across three Northern Irish Counties in June 2019. These interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. Ethical approval was obtained for this study prior to data collection.FindingsFollowing thematic analysis, three themes emerged in relation to barriers and facilitators to living well with dementia. These were: ‘Emphasis on Disability NOT Capability’, which highlighted societal misconceptions about the activities and modes of life which people with dementia could or could not do; ‘Normalise Dementia – We Don’t Want a Fool’s Pardon’, which focused on how the public could encourage people living with the condition to enjoy greater independence, and ‘Dementia isn’t a Death Sentence’, which considered how professionals, family members and friends treated the person after diagnosis.ConclusionsPublic perceptions about dementia have the potential to act as both facilitators and barriers to living well with dementia. People with dementia stated that they are more likely sustain wellbeing when they are valued and can maintain independence. On the contrary, poor public and professional attitudes to dementia had the potential to disempower people living with dementia.
Continuous renal replacement therapy rescues severe haemorrhagic fever with renal syndrome in pregnancy: a case report
Authors: Ying Xiang , Lai Xiaoli , Jin Xiaoxiao , Cai Linghong , Li Xiaotian 
Published: December 2020

Abstract
Background
Haemorrhagic fever with renal syndrome (HFRS) is a natural epidemic disease caused by various types of viruses of the genus Hantavirus, which are mainly transmitted by contact with the infected rodents and their droppings. Pregnancy complicated with HFRS is rare; however, adverse maternal and foetal outcomes may be noted. In this report, we describe a case involving a pregnant woman with HFRS who was in a state of multiple organ dysfunction syndrome (MODS) and was successfully treated with continuous renal replacement therapy (CRRT).

Case presentation
A 32-year-old pregnant woman at 29 weeks of gestation was hospitalised for a fever and upper respiratory tract infection due to HFRS in winter. Persistent fever, coagulation disorder, thrombocytopenia, electrolyte imbalance, abnormal liver function, and renal failure were noted during the progression of the disease. The patient was treated with CRRT. She recovered after 21 days, and delivered a live infant by caesarean section at 38 weeks of gestation. Furthermore, obvious abnormalities were not detected during the follow-up of the mother and infant at 42 days, 3 months, 6 months, and 1 year after the delivery.

Conclusions
Early diagnosis, timely application of CRRT, and comprehensive treatment may be essential for the successful treatment of patients with HFRS during pregnancy.