bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic venous insufficiency, cardiovascular disease, and mortality: a population study
Authors: Prochaska Jürgen H , Arnold Natalie , Falcke Andrea , Kopp Sabrina , Schulz Andreas , Buch Gregor , Moll Sophie , Panova-Noeva Marina , Jünger Claus , Eggebrecht Lisa , Pfeiffer Norbert , Beutel Manfred , Binder Harald , Grabbe Stephan , Lackner Karl J , ten Cate-Hoek Arina , Espinola-Klein Christine , Münzel Thomas , Wild Philipp S 
Published: August 2021

Abstract

Aims
Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce.

Methods and results
Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40–80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6–37.4%], 13.3% [12.6–13.9%], and 40.8% [39.9–41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19–1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11–2.05), P = 0.009].

Conclusion
Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.
A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs
Authors: Doi Takahito , Langsted Anne , Nordestgaard Børge G 
Published: August 2021

Abstract

Aims
We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein.

Methods and results
In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93–0.99] mimicking REDUCE-IT and 0.94 (0.91–0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04–1.10) and 0.99 (0.98–0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84–0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68–0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93–0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90–1.09) in STRENGTH.

Conclusion
The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.
Strong error estimates for a space-time discretization of the linear-quadratic control problem with the stochastic heat equation with linear noise
Authors: Prohl Andreas , Wang Yanqing 
Published: August 2021

Abstract
We propose a time-implicit, finite-element-based space-time discretization of the necessary and sufficient optimality conditions for the stochastic linear-quadratic optimal control problem with the stochastic heat equation driven by linear noise of type $[X(t)+\sigma (t)]\,\,\textrm{d}W(t)$ and prove optimal convergence w.r.t. both space and time discretization parameters. In particular, we employ the stochastic Riccati equation as a proper analytical tool to handle the linear noise, and thus extend the applicability of the earlier work by Prohl & Wang (2021, Strong rates of convergence for a space-time discretization of the backward stochastic heat equation, and of a linear-quadratic control problem for the stochastic heat equation. ESAIM Control Optim. Calc. Var., 27, 54), where the error analysis was restricted to additive noise.
High unbound flucloxacillin fraction in critically ill patients
Authors: Wallenburg Eveline , ter Heine Rob , de Lange Dylan W , van Leeuwen Henk , Schouten Jeroen A , ten Oever Jaap , Kolwijck Eva , Burger David M , Pickkers Peter , Gieling Emilie M , de Maat Monique M , Frenzel Tim , Brüggemann Roger J 
Published: August 2021

Abstract

Objectives
To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies.

Patients and methods
Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR.

Results
The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of &gt;2.5 mg/L (100% fT&gt;5×MIC, MIC = 0.5 mg/L).

Conclusions
Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.
G. R. Driver’s Contribution to Neb’s Translation of Psalms 51–100
Authors: Clackson Ben 
Published: August 2021

Abstract
The influence of G. R. Driver on the translation of the Old Testament in The New English Bible has been controversial particularly in light of Barr’s critique of his use of comparative philology. This article takes a sample of 18 instances of translations of verses in Psalms 51–100 which reflected proposals made in his articles. It explains the proposals, examines their influence on recent Hebrew lexicography, and shows which proposals were subsequently dropped in Psalms: a New Translation for Worship or The Revised English Bible, in order to reassess which proposals have stood the test of time. It is concluded that about half of Driver’s proposals still seem probable, which suggests that wholesale rejection of Driver’s work is unwarranted.
High-energy radiation from luminous and magnetized stars
Authors: Bednarek W 
Published: August 2021

ABSTRACT
A part of early-type stars is characterized by strong dipole magnetic field that is modified by the outflow of dense wind from the stellar surface. At some distance from the surface (above the Alfvén radius), the wind drives the magnetic field into the reconnection in the equatorial region of the dipole magnetic field. We propose that electrons accelerated in these reconnection regions can be responsible for efficient Comptonization of stellar radiation producing gamma-ray emission. We investigate the propagation of electrons in the equatorial region of the magnetosphere by including their advection with the equatorial wind. The synchrotron and Inverse Compton (IC) spectra are calculated assuming that a significant part of the wind energy is transferred to relativistic electrons. As an example, the parameters of luminous, strongly magnetized star HD 37022 (Θ1 Ori C) are considered. The IC gamma-ray emission is predicted to be detected either in the GeV energy range by the Fermi-LAT telescope or in the sub-TeV energies by the Cherenkov Telescope Array. However, since the stellar winds are often time variable and the magnetic axis can be inclined to the rotational axis of the star, the gamma-ray emission is expected to show variability with the rotational period of the star and, on a longer time-scale, with the stellar circle of the magnetic activity. Those features might serve as tests of the proposed scenario for gamma-ray emission from single, luminous stars.
Imaging results from the legacy Giant Metrewave Radio Telescope Galaxy Cluster Key Project
Authors: George Lijo T , Kale Ruta , Wadadekar Yogesh 
Published: August 2021

ABSTRACT
We have used archival Giant Metrewave Radio Telescope (GMRT) data to image and study 39 galaxy clusters. These observations were made as part of the GMRT Key Project on galaxy clusters between 2001 and 2004. The observations presented in this sample include 14 observations at 610 MHz, 29 at 325 MHz, and three at 244 MHz covering a redshift range of 0.02–0.62. Multifrequency observations were made for eight clusters. We analysed the clusters using the spam processing software and detected the presence of radio halo emission for the first time in the clusters RXC J0510−0801 and RXC J2211.7−0349. We also confirmed the presence of extended emission in 11 clusters which were known from the literature. In clusters where haloes were not detected, upper limits were placed using our own semi-automated program. We plot our detections and non-detections on the empirical LX−P1.4 and M500−P1.4 relation in radio halo clusters and discuss the results. The best fits follow a power law of the form $L_{500} \propto P_{1.4}^{1.82}$ and $M_{500} \propto P_{1.4}^{3.001}$ which is in accordance with the best estimates in the literature.
LMD-05. Phase 1B Study of Avelumab and Whole Brain Radiotherapy (WBRT) in Patients with Leptomeningeal Disease (LMD): Preliminary Results
Authors: Pina Yolanda , Chen Ann , Arrington John , Macaulay Robert , Tran Nam , Liu James , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran , Creelan Ben , Gray Jhanelle , Khushalani Nikhil , Smalley Inna , Smalley Keiran , Vogelbaum Michael , Yu Michael , Forsyth Peter 
Published: August 2021

Abstract

Background
LMD has a dismal prognosis with median survivals of 8–10 weeks. Recently the first phase 2 trial of PD-1 inhibitor monotherapy in solid tumor LMD showed median overall survival (OS) 3.6 months. We aimed to determine the safety/efficacy of avelumab with WBRT in patients with LMD from solid malignancies (NCT0371768). This combination can treat tumor directly and increase the permeability of the blood-brain-barrier with increased egress of activated T cells into the meninges/CSF and facilitated Avelumab entry into the CSF.

Hypothesis
Combination radioimmunotherapy will produce an activated immunocyte/cytokine profile in CSF.

Methods
Patients received concurrent Avelumab 800mg IV q2weeks x≤5 cycles with WBRT 3000cGy, 10 fractions. Primary endpoints: Safety/DLTs and OS at 3 months. Secondary endpoints: CSF T-cell/cytokine profiles (scRNAseq/phosophoproteomics) and clinical outcomes, to be performed when all 15 patients are accrued to minimize batch effects.

Results
Ten patients (5 breast, 4 lung & 1 undifferentiated sinonasal carcinoma) were enrolled (n=8 females, n=2 males, ages 32–79); n=1 patient did not complete WBRT. Patients who received anti-PD-1/PD-1L/PD-L2/CD137/CTLA-4 therapy within 6 months prior to enrollment were excluded. 30% had grade 3 AEs at least possibly related to treatment (n=3 diarrhea, lymphopenia, decreased WBC count). There were no grade 4–5 toxicities. Six patients (66.7%) were alive at 3 months. The estimated median follow up in 9 patients (regardless whether patients failed or not) is 10.49 months (range, 0.95–19.82 months, 95% CI) and the estimated median follow up survival was 19.8 months assessed using the reverse Kaplan-Meier method. Median PFS is 4.27 months (range, 0.30–16.73 months, 95% CI).

Conclusions
In this pilot study, combination of Avelumab and WBRT is safe, and demonstrates encouraging activity in patients with solid tumor LMD. Multiple platform interrogation of CSF may determine mechanisms of LMD therapeutic effects and differentiate responders from non-responders.
RADI-03. A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance
Authors: Miarka Lauritz , Moteiro Catia , Dalmasso Celine , Fustero-Torre Coral , Yebra Natalia , Hegarty Aisling , Keelan Stephen , Goy Yvonne , Mohme Malte , Caleiras Eduardo , Damir Vareslija , Young Leonie , Soffietti Riccardo , Fernández-Alén Jose , Blasco Guillermo , Alcazar Lucia , Sepúlveda Juan Manuel , Perez Angel , Lain Aurelio , Siegfried Aurore , Wikman Harriet , Moyal Elisabeth Cohen-Jonathan , Valiente Manuel 
Published: August 2021

Abstract
Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.
RADI-19. The Incidence of New Brain Metastases in Patients with Non-Small Cell Lung Cancer Following Discontinuation of Systemic Therapy
Authors: London Dennis , Patel Dev , Donahue Bernadine , Navarro Ralph , Gurewitz Jason , Silverman Joshua , Sulman Erik , Bernstein Kenneth , Palermo Amy , Golfinos John , Sabari Joshua , Shum Elaine , Velcheti Vamsidhar , Chachoua Abraham , Kondziolka Douglas 
Published: August 2021

Abstract

Purpose
Patients with non-small cell lung cancer (NSCLC) metastatic to the brain increasingly are living longer due to improvements in systemic therapy and local modalities. The risk of new brain metastases when these patients stop systemic therapy is unknown. Recognizing patterns of new tumor occurrence is necessary to determine the frequency of follow-up and the need for further treatment.

Methods
We included patients in a prospective registry who had non-small cell lung cancer (NSCLC) brain metastases, discontinued systemic therapy for at least 90 days, and underwent active surveillance. 63 patients with 73 off-periods were studied. The risk factors for the development of new tumors were determined using Cox regression and multi-state Markov modeling.

Results
The median time to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase pathways (e.g. KRAS, EGFR) were more likely to develop new tumors (HR: 2.21, 95% CI: 1.25–3.91, p=6.3 x 10–3; HR: 2.03, 95% CI: 1.09–3.77, p=0.026, respectively).

Conclusion
The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or receptor tyrosine kinase pathway mutations have a higher rate of new metastases and should be followed more closely.
SURG-05. Neurosurgery for brain metastases from non-small cell lung cancer: survival outcome and prognostic factors
Authors: Li De-pei , Wang Zhen-ning , Duan Hao , Guo Cheng-cheng , Jiang Xiao-bing , Mou Yong-Gao 
Published: August 2021

Abstract

Background
Surgery is an important approach to treat non-small cell lung cancer (NSCLC) brain metastases (BM). Here, we analyzed the survival outcome and prognostic factors for patients with NSCLC after BM resection.

Methods
The Surveillance Epidemiology and End Results (SEER) database was employed to address the incidence of BM from NSCLC and the current prognosis at population level. 674 contemporaneous NSCLC patients received BM resection at Sun Yat-sen University Cancer Center (SYSUCC) were used for survival comparison and Cox proportional hazards model was applied for identifying prognostic factors.

Results
60,436 NSCLC patients diagnosed between 2010 to 2017 were enrolled from SEER database. Among them, 8,708 (14.4%) BM were identified at primary NSCLC diagnosis (synchronous BM, SBM). Median overall survival (OS) of SBM was 6 months with 1-, and 3-year survival percentages of 30.3% and 9.8%, respectively. Furthermore, the survival of BM patients without extracranial metastasis is significantly longer than those with extracranial metastases (median OS: 10 versus 5 months, P&lt;0.001). 225 SBM (cohort A) and 449 BM with treatment history on primary NSCLC (cohort B) were collected from SYSUCC. In cohort A, 86 BM with extracranial metastases were found (38.2%) and the median OS was significantly shorter than those without extracranial metastases (15.2 versus 23.7 months, P&lt;0.001). In cohort B, 255 cases with extracranial metastases were found (56.8%) and their prognosis was also worse than cases without extracranial metastases (median OS: 18.3 versus 22.1 months, P=0.002). Multivariate analyses revealed that younger age (HR=0.71, P=0.003), without extracranial metastases (HR=0.65, P&lt;0.001) and radiation for BM (HR=0.78, P=0.005) were independent factors for better OS.

Conclusion
Improved survival of patients received BM resection was observed in SYSUCC cohort as comparison with SEER patients with NSCLC and BM. Aggressive local treatment including surgery and radiation is still important in Modern management of BM from NSCLC.
SURG-07. Plasmonic gold nanostars to increase the efficiency and specificity of laser interstitial thermal therapy (LITT) in the treatment of brain tumors
Authors: Srinivasan Ethan , Chongsathidkiet Pakawat , Odion Ren , Liu Yang , Sankey Eric , Vo-Dinh Tuan , Fecci Peter 
Published: August 2021

Abstract

Introduction
Laser interstitial thermal therapy (LITT) is an effective minimally-invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT while better conforming to tumor boundaries and protecting surrounding tissue.
Materials and Methods: The 12nm GNS were synthesized using reduced HAuCl4 with Na3C6H5O7 seeds, mixed with AgNO3, C6H8O6, and HAuCL4, and coated with polyethylene glycol then functionalized with methoxy PEG thiol. CT-2A glioma cells were intracranially implanted into mice, followed 18 days later by IV injection of GNS. PET-CT was performed at 10-minutes, 24-, and 72-hours post-GNS administration, with autoradiography (AR) and histopathology (HP) on sacrifice after the last scan. To test the impact of GNS on LITT coverage capacity in appropriately sized ex vivo models, we utilized agarose gel-based phantoms incorporating control and GNS-infused central “tumors” in multiple shapes. LITT was administered with the NeuroBlate System.

Results
In vivo, GNS preferentially accumulated within intracranial tumors on PET-CT at the 24- and 72-hour timepoints. AR and HP confirmed high GNS accumulation within tumor. Ex vivo, in cuboid tumor phantoms, the GNS-infused phantom heated 5.5x faster than the control, rising 0.49°C per minute compared to 0.09°C. In a split-cylinder tumor phantom with half containing GNS, the GNS-infused border heated 2x faster and the surrounding area was exposed to 30% lower temperatures. In a GNS-infused star-shaped phantom, the heat spread contoured along phantom boundaries.

Conclusion
Our results provide evidence for use of GNS to improve the specificity, efficiency, and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors, and the GNS-infused phantom experiments demonstrate increased rates of heating within the tumor model, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.