bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patients with pretreatment leukoencephalopathy and older patients have more cognitive decline after whole brain radiotherapy
Authors: Chan Matthew , Ferguson David , Ni Mhurchu Elaine , Yuan Ren , Gondara Lovedeep , McKenzie Michael , Olson Robert , Thiessen Brian , Lalani Nafisha , Ma Roy , Nichol Alan 
Published: November 2020

Abstract
Purpose
To investigate predictors of cognitive decline after whole brain radiotherapy (WBRT) for brain metastases.

Methods
A secondary analysis of a phase 2 clinical trial was conducted in patients who received stereotactic radiosurgery for 1–10 brain metastases and WBRT (NCT01046123). The Montreal Cognitive Assessment (MoCA) was performed at baseline and every 3 months after WBRT. Baseline T2-weighted fluid attenuation inversion recovery magnetic resonance imaging was independently assessed by two neuroradiologists for the presence of white matter hyperintensities (WMH) using the Fazekas visual rating scale. WMH were also manually segmented for volumetric analysis. Univariable and multivariable logistic regression were used to test the association between baseline variables and MoCA score decline.

Results
Forty-six patients survived ≥ 3 months after treatment. Age (OR 1.12 (1.04–1.21), p < 0.01), baseline WMH volume (OR 1.20, 95% CI 1.06–1.52, p = 0.02) and baseline Fazekas score ≥ 3/6 (OR 6.4, 95% CI 1.7–24.7, p < 0.01) were predictive of MoCA score decline. In multivariable analysis, age was the only significant predictor of MoCA decline. However, all three patients with pre-treatment leukoencephalopathy (Fazekas score = 6/6) had notable adverse outcomes due to cognitive impairment: one required full-time home nursing support and two were institutionalized.

Conclusion
A greater decline in cognition after WBRT was observed in older patients and patients with a higher baseline WMH burden. Although this study is small and hypothesis-generating, we propose that radiation oncologists should exercise caution in prescribing WBRT if leukoencephalopathy is present on pre-treatment imaging.
Trial Registration: clinicaltrials.gov identifier NCT01046123. First posted January 11, 2010. https://clinicaltrials.gov/ct2/show/NCT01046123
Transplantation of a heart donated after circulatory death via thoraco-abdominal normothermic regional perfusion and results from the first Spanish case
Authors: Pérez Redondo Marina , Alcántara Carmona Sara , Villar García Susana , Forteza Gil Alberto , Villanueva Fernández Héctor , Hernández-Pérez Francisco José , Campo-Cañaveral de la Cruz José Luis , Velasco Calvo Rocío , Segovia-Cubero Javier , Alonso Menárguez Beatriz , del Río Gallegos Francisco , Coll Elisabeth , Domínguez-Gil González Beatriz , Rubio Muñoz Juan José 
Published: November 2020

Abstract
Background
Controlled donation after circulatory death (cDCD) has emerged as one of the main strategies for increasing the organ donor pool. Because of the ischemic injury that follows the withdrawal of life-sustaining therapies, hearts from cDCD donors have not been considered for transplantation until recently. The ex-situ perfusion of hearts directly procured from cDCD donors has been used to allow the continuous perfusion of the organ and the assessment of myocardial viability prior to transplantation. Based on our experience with abdominal normothermic regional perfusion in cDCD, we designed a protocol to recover and validate hearts from cDCD donors using thoraco-abdominal normothermic regional perfusion without the utilization of an ex-situ device.

Case presentation
We describe the first case of a cDCD heart transplant performed with this approach in Spain. The donor was a 43-year-old asthmatic female diagnosed with severe hypoxic encephalopathy. She was considered a potential cDCD donor and a suitable candidate for multiorgan procurement including the heart via thoraco-abdominal normothermic regional perfusion. The heart recipient was a 60-year-old male diagnosed with amyloid cardiomyopathy. Cold ischemia time was 55 min. The surgery was uneventful.

Conclusions
This case report, the first of its kind in Spain, supports the feasibility of evaluating and successfully transplanting cDCD hearts without the need for ex-situ perfusion based on the use of thoraco-abdominal normothermic regional perfusion opening the way for multiorgan donation in cDCD.
Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway
Authors: Qiu Jun-Jun , Sun Shu-Gen , Tang Xiao-Yan , Lin Ying-Ying , Hua Ke-Qin 
Published: November 2020

Abstract
Background
The E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. However, whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear.

Methods
A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of EV-Wnt7b in HPV E6-induced CC angiogenesis. The prognostic value of serum EV-Wnt7b was determined and a predictive nomogram model was established.

Results
HPV 16/18 E6 upregulated Wnt7b mRNA expression in four HPV 16/18-positive CC cell lines and their EVs. In vitro and in vivo experiments demonstrated that EV-Wnt7b mRNA was transferred to and modulated human umbilical vein endothelial cells (HUVECs) toward more proliferative and proangiogenic behaviors by impacting β-catenin signaling. Clinically, serum EV-Wnt7b levels were elevated in CC patients and significantly correlated with an aggressive phenotype. Serum EV-Wnt7b was determined to be an independent prognostic factor for CC overall survival (OS) and recurrence-free survival (RFS). Notably, we successfully established a novel predictive nomogram model using serum EV-Wnt7b, which showed good prediction of 1- and 3-year OS and RFS.

Conclusions
Our results illustrate a potential crosstalk between HPV 16/18-positive CC cells and HUVECs via EVs in the TME and highlight the potential of circulating EV-Wnt7b as a novel predictive biomarker for CC prognosis.
Prediction of hypotension events with physiologic vital sign signatures in the intensive care unit
Authors: Yoon Joo Heung , Jeanselme Vincent , Dubrawski Artur , Hravnak Marilyn , Pinsky Michael R. , Clermont Gilles 
Published: November 2020

Abstract
Background
Even brief hypotension is associated with increased morbidity and mortality. We developed a machine learning model to predict the initial hypotension event among intensive care unit (ICU) patients and designed an alert system for bedside implementation.

Materials and methods
From the Medical Information Mart for Intensive Care III (MIMIC-3) dataset, minute-by-minute vital signs were extracted. A hypotension event was defined as at least five measurements within a 10-min period of systolic blood pressure ≤ 90 mmHg and mean arterial pressure ≤ 60 mmHg. Using time series data from 30-min overlapping time windows, a random forest (RF) classifier was used to predict risk of hypotension every minute. Chronologically, the first half of extracted data was used to train the model, and the second half was used to validate the trained model. The model’s performance was measured with area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Hypotension alerts were generated using risk score time series, a stacked RF model. A lockout time were applied for real-life implementation.

Results
We identified 1307 subjects (1580 ICU stays) as the hypotension group and 1619 subjects (2279 ICU stays) as the non-hypotension group. The RF model showed AUROC of 0.93 and 0.88 at 15 and 60 min, respectively, before hypotension, and AUPRC of 0.77 at 60 min before. Risk score trajectories revealed 80% and > 60% of hypotension predicted at 15 and 60 min before the hypotension, respectively. The stacked model with 15-min lockout produced on average 0.79 alerts/subject/hour (sensitivity 92.4%).

Conclusion
Clinically significant hypotension events in the ICU can be predicted at least 1 h before the initial hypotension episode. With a highly sensitive and reliable practical alert system, a vast majority of future hypotension could be captured, suggesting potential real-life utility.
Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort
Authors: Wang Shao-Ming , Pfeiffer Ruth M. , Gierach Gretchen L. , Falk Roni T. 
Published: November 2020

Abstract
Background
Menopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.

Methods
We investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50–71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women’s Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.

Results
Eight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95–1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04–1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44–1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39–2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99–1.30).

Conclusions
ET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.
Combined the SMAC mimetic and BCL2 inhibitor sensitizes neoadjuvant chemotherapy by targeting necrosome complexes in tyrosine aminoacyl-tRNA synthase-positive breast cancer
Authors: Lee Kyung-Min , Lee Hyebin , Han Dohyun , Moon Woo Kyung , Kim Kwangsoo , Oh Hyeon Jeong , Choi Jinwoo , Hwang Eun Hye , Kang Seong Eun , Im Seock-Ah , Lee Kyung-Hun , Ryu Han Suk 
Published: November 2020

AbstractBackgroundChemotherapy is the standard treatment for breast cancer; however, the response to chemotherapy is disappointingly low. Here, we investigated the alternative therapeutic efficacy of novel combination treatment with necroptosis-inducing small molecules to overcome chemotherapeutic resistance in tyrosine aminoacyl-tRNA synthetase (YARS)-positive breast cancer.MethodsPre-chemotherapeutic needle biopsy of 143 invasive ductal carcinomas undergoing the same chemotherapeutic regimen was subjected to proteomic analysis. Four different machine learning algorithms were employed to determine signature protein combinations. Immunoreactive markers were selected using three common candidate proteins from the machine-learning algorithms and verified by immunohistochemistry using 123 cases of independent needle biopsy FFPE samples. The regulation of chemotherapeutic response and necroptotic cell death was assessed using lentiviral YARS overexpression and depletion 3D spheroid formation assay, viability assays, LDH release assay, flow cytometry analysis, and transmission electron microscopy. The ROS-induced metabolic dysregulation and phosphorylation of necrosome complex by YARS were assessed using oxygen consumption rate analysis, flow cytometry analysis, and 3D cell viability assay. The therapeutic roles of SMAC mimetics (LCL161) and a pan-BCL2 inhibitor (ABT-263) were determined by 3D cell viability assay and flow cytometry analysis. Additional biologic process and protein-protein interaction pathway analysis were performed using Gene Ontology annotation and Cytoscape databases.ResultsYARS was selected as a potential biomarker by proteomics-based machine-learning algorithms and was exclusively associated with good response to chemotherapy by subsequent immunohistochemical validation. In 3D spheroid models of breast cancer cell lines, YARS overexpression significantly improved chemotherapy response via phosphorylation of the necrosome complex. YARS-induced necroptosis sequentially mediated mitochondrial dysfunction through the overproduction of ROS in breast cancer cell lines. Combination treatment with necroptosis-inducing small molecules, including a SMAC mimetic (LCL161) and a pan-BCL2 inhibitor (ABT-263), showed therapeutic efficacy in YARS-overexpressing breast cancer cells.ConclusionsOur results indicate that, before chemotherapy, an initial screening of YARS protein expression should be performed, and YARS-positive breast cancer patients might consider the combined treatment with LCL161 and ABT-263; this could be a novel stepwise clinical approach to apply new targeted therapy in breast cancer patients in the future.
DNA polymerase epsilon is required for heterochromatin maintenance in Arabidopsis
Authors: Bourguet Pierre , López-González Leticia , Gómez-Zambrano Ángeles , Pélissier Thierry , Hesketh Amy , Potok Magdalena E. , Pouch-Pélissier Marie-Noëlle , Perez Magali , Da Ines Olivier , Latrasse David , White Charles I. , Jacobsen Steven E. , Benhamed Moussa , Mathieu Olivier 
Published: November 2020

AbstractBackgroundChromatin organizes DNA and regulates its transcriptional activity through epigenetic modifications. Heterochromatic regions of the genome are generally transcriptionally silent, while euchromatin is more prone to transcription. During DNA replication, both genetic information and chromatin modifications must be faithfully passed on to daughter strands. There is evidence that DNA polymerases play a role in transcriptional silencing, but the extent of their contribution and how it relates to heterochromatin maintenance is unclear.ResultsWe isolate a strong hypomorphicArabidopsis thalianamutant of the POL2A catalytic subunit of DNA polymerase epsilon and show that POL2A is required to stabilize heterochromatin silencing genome-wide, likely by preventing replicative stress. We reveal that POL2A inhibits DNA methylation and histone H3 lysine 9 methylation. Hence, the release of heterochromatin silencing in POL2A-deficient mutants paradoxically occurs in a chromatin context of increased levels of these two repressive epigenetic marks. At the nuclear level, the POL2A defect is associated with fragmentation of heterochromatin.ConclusionThese results indicate that POL2A is critical to heterochromatin structure and function, and that unhindered replisome progression is required for the faithful propagation of DNA methylation throughout the cell cycle.
Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases
Authors: Burren Oliver S. , Reales Guillermo , Wong Limy , Bowes John , Lee James C. , Barton Anne , Lyons Paul A. , Smith Kenneth G. C. , Thomson Wendy , Kirk Paul D. W. , Wallace Chris 
Published: November 2020

AbstractBackgroundGenome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging.MethodsExploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension “basis” that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging.ResultsWe identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations.ConclusionsRequiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities.
Discordance between patient and physician global assessment of disease activity in Behçet’s syndrome: a multicenter study cohort
Authors:   the BODI Project collaborators, Floris Alberto , Espinosa Gerard , Serpa Pinto Luisa , Kougkas Nikolaos , Lo Monaco Andrea , Lopalco Giuseppe , Orlando Ida , Bertsias George , Cantarini Luca , Cervera Ricard , Correia João , Govoni Marcello , Iannone Florenzo , Mathieu Alessandro , Neri Piergiorgio , Martins Silva Ana , Vasconcelos Carlos , Muntoni Monica , Cauli Alberto , Piga Matteo 
Published: November 2020

Abstract
Background
To compare the patients’ and physician’s global assessment of disease activity in Behçet’s syndrome (BS) and investigate the frequency, magnitude, and determinants of potential discordance.

Methods
A total of 226 adult BS patients with a median (IQR) age of 46.9 (35.6–55.2) years were enrolled across Italy, Greece, Portugal, and Spain. Demographic, clinical, and therapeutic variables, as well as the patient reported outcomes, were collected at the recruitment visit. The physical (PCS) and mental (MCS) component summary scores of the Short Form Questionnaire 36 (SF-36) and the Behçet’s syndrome Overall Damage Index (BODI) were calculated. Disease activity was assessed by the patients’ (PtGA) and physician’s global assessment (PGA) in a 10-cm visual analog scale, as well as the Behçet Disease Current Activity Form (BDCAF). Discordance (∆) was calculated by subtracting the PGA from the PtGA and defined as positive (PtGA>PGA) and negative (PtGA<PGA) discordance using both a more stringent (∆ = ±2) and a less stringent (∆ = ±1) cutoff. Univariate and multivariate logistic regressions were performed.

Results
Median PtGA and PGA scores were 2.0 (0.3–5.0) and 1.0 (0.0–3.0) cm, respectively. The discordance prevalence varied (from 29.6 to 55.3%) according to the cutoff applied, and the majority (> 80%) of disagreements were due to patients rating higher their disease activity. Higher values of BDCAF were associated to increased rate of positive discordance. When BDCAF = 0, the median (IQR) values of PtGA and PGA were 0.2 (0–2) and 0 (0–1), respectively. PCS (adjusted odds ratio (adjOR) 0.96 per unit, 95% CI 0.93–0.98, p = 0.006) and MCS (adjOR 0.96 per unit, 95% CI 0.93–0.99, p = 0.003) were independently associated with positive discordance using both cutoffs. Active ocular involvement emerged as a potential determinant of negative discordance (adjOR 5.88, 95% CI 1.48–23.30, p = 0.012).

Conclusions
PtGA and PGA should be considered as complementary measures in BS, as patients and physicians may be influenced by different factors when assessing active disease manifestations. Particularly, PtGA may be a useful tool in the assessment of BS disease activity, as it carries a low risk to misclassify an inactive disease, and may allow to capture aspects of the patient’s health that negatively affect his well-being and the treatment.
Optic nerve sheath diameter sonography during the acute stage of intracerebral hemorrhage: a potential role in monitoring neurocritical patients
Authors: Bender M. , Lakicevic S. , Pravdic N. , Schreiber S. , Malojcic B. 
Published: November 2020

Abstract
Background
Optic nerve sheath diameter (ONSD) sonography has been proposed as a reliable bedside tool for the detection of increased intracranial pressure (ICP). ONSD reacts almost simultaneously to oscillations in ICP. The aim of this study was to investigate the ONSD dynamics in the acute stage of intracerebral hemorrhage (ICH) and to compare ONSD dynamics to the clinical outcome.

Methods
We enrolled 35 acute ICH patients and 20 healthy volunteers in this prospective study. At the admission, all patients underwent brain CT scan and ONSD sonography. We repeated the ONSD on the second and the third day in all patients while CT scan was repeated if a patient condition deteriorated. The changes in serial ONSD measurements were termed as stable or unstable ONSD trend. ONSD trend was considered as unstable if variations of average ONSD were above 5%. The outcome of the patient was assessed with the Modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS).

Results
In healthy volunteers serial ONSD recordings for 3 days revealed a stable trend in 100%. However, in the study group, 23 patients had unstable and 12 had stable ONSD trend during the acute stage of ICH. The patients with unstable ONSD trend were more likely to have worse outcomes (p value 0.003).

Conclusion
In patients with ICH, the acute-phase ONSD dynamics can help in predicting the clinical outcome.
Low prevalence of Moraxella catarrhalis in the patients who suffered from conjunctivitis in the southwest of Iran
Authors: Farajzadeh Sheikh Ahmad , Feghhi Mustafa , Torabipour Maryam , Saki Morteza , Veisi Hojat 
Published: November 2020

Abstract
Objective
Moraxella catarrhalis is a non-motile Gram-negative diplococcus bacterium that contributed to several human infections including conjunctivitis. This study aimed to reveal the prevalence of M. catarrhalis in patients who suffered from conjunctivitis in Ahvaz city, southwest of Iran.

Results
Out of 100 conjunctiva swab specimens, M. catarrhalis was isolated only from one (1%) conjunctivitis cases using the culture method. This strain was isolated from a 34 years old female patient. Also, the results of the polymerase chain reaction (PCR) were in agreement with the culture method, and the specimen that showed positive culture was also positive for specific gene of M. catarrhalis. The remaining 99 specimens did not show positive results with any of the culture and PCR methods.