bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCT-24 THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS
Authors: Grant Melanie , Fortiz Maria , Wang Lu , Lang Haili , Datar Anushree , Reynolds Emily , Terpilowski Madeleine , Geiger Ashley , Lazarski Chris , Tanna Jay , Pitino Adriana , Zhang Nan , Hoq Fahmida , Hanley Patrick , Cruz C Russell , Kilburn Lindsay , Packer Roger , Rood Brian , Bollard Catherine 
Published: June 2021

Abstract

Background
Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity.

Methods
Patients (n=18) received autologous tumor antigen-associated T cells (TAAT) (up to 8x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response.

Results/Discussion
16/18 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Adverse events were minimal despite multiple pretreatments in Group B. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) respectively. Specificity for 1–3 TAAs was demonstrated in 11/18 TAAT by a-IFN-γ ELISPOT. Dose escalation is complete, and clinical and immunologic response assessments are ongoing. Plasma cytokine and proteomic analyses demonstrated dynamic post-infusion immune cytokine and protein responses. Consistent with an infusion-mediated immune response all patients in Grp A showed increased T cell effector, inflammatory and immune-stimulatory cytokines IFN-γ, TNF-α, IL-2, IL-5, IL-7, IL-1β, IL-6, IL-8, IL-12p70, IL-17A and GM-CSF at Weeks 1 and 2 post-infusion (n = 6). Of 9 patients who have been tested, 29/92 plasma proteins showed significant differences between dose levels 1 and 2, including increased IL-7 (p &lt;0.0004) and CD40L (p &lt;0.046) and reduced IL-4 (p &lt;0.0004). T cell receptor sequencing showed expansion and persistence of clones detected in infusion products. In summary, TAAT have thus far been safe and elicit immune responses in vivo. Clinical and immunologic response assessments are ongoing.
Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment
Authors: Al Feghali Karine A , Randall James W , Liu Diane D , Wefel Jeffrey S , Brown Paul D , Grosshans David R , McAvoy Sarah A , Farhat Maguy A , Li Jing , McGovern Susan L , McAleer Mary F , Ghia Amol J , Paulino Arnold C , Sulman Erik P , Penas-Prado Marta , Wang Jihong , de Groot John , Heimberger Amy B , Armstrong Terri S , Gilbert Mark R , Mahajan Anita , Guha-Thakurta Nandita , Chung Caroline 
Published: June 2021

Abstract

Background
This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO).

Methods
Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. “Clinical progression” was based on a clinical radiology report of progression and/or change in treatment for progression.

Results
Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4–14.7) months; 10.8 months IMRT versus 11.2 months PT (P = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT (P = .24). RANO-PFS was significantly shorter than clinical PFS overall (P = .001) and for both the IMRT (P = .01) and PT (P = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria.

Conclusions
Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.
Closure relations during the plateau emission of Swift GRBs and the fundamental plane
Authors: Dainotti Maria Giovanna , Lenart Aleksander Ł , Fraija Nissim , Nagataki Shigehiro , Warren Donald C , De Simone Biagio , Srinivasaragavan Gokul , Mata Aurora 
Published: June 2021

Abstract
The Neil Gehrels Swift observatory observes gamma-ray burst (GRB) plateaus in X-rays. We test the reliability of the closure relations through the fireball model when dealing with GRB plateau emissions. We analyze 455 X-ray light curves collected by Swift from 2005 January until 2019 August for which the redshifts are either known or unknown using the phenomenological Willingale 2007 model. Using these fits, we analyze the emission mechanisms and astrophysical environments of these GRBs through the closure relations within the time interval of the plateau emission. Finally, we test the three-dimensional fundamental plane relation (Dainotti relation) which connects the prompt peak luminosity, the time at the end of the plateau (rest frame), and the luminosity at that time, for the GRBs with redshift, concerning groups determined by the closure relations. This allows us to check if the intrinsic scatter σint of any of these groups is reduced compared to previous literature. The most fulfilled environments for the electron spectral distribution, p &gt; 2, are wind slow cooling (SC) and interstellar material (ISM) slow cooling for cases in which the parameter q, which indicates the flatness of the plateau emission and accounts for the energy injection, is 0 and 0.5, respectively, in cases with both known and unknown redshifts. We also find that for short GRBs all ISM environments with q = 0 have the smallest σint = 0.04 ± 0.15 in terms of the fundamental plane relation holding a probability of occurring by chance of p = 0.005. We have shown that the majority of GRBs presenting plateau emission fulfill the closure relations, including the energy injection, with a particular preference for the wind SC environment. The subsample of GRBs that fulfill the given relations can be used as possible standard candles and can suggest a way to reduce the intrinsic scatter of these studied relationships.
Covid-19 and the future of charitable foundations—renewal in crisis?
Authors: Strasser Claudia 
Published: June 2021

Abstract
The effects of Covid-19 are tangible around the globe with emerging and third world countries being particularly affected by the economic and social consequences of the pandemic. The author explains the impact of Covid-19 on the work of foundations and the role of the latter in addressing global challenges. Foundations that are set up in perpetuity are often deemed slow and dilatory when it comes to taking decisions. Covid-19, however, demands fast, not to say unbureaucratic action. This is often contrary to the character of foundations and the way in which many of them pursue their programmatic goals. Foundations, therefore, risk falling short of their social mission and even missing the opportunity to offer society pioneering solutions. Yet, the current crisis has also underlined the importance of strategic partnerships between foundations and other players and of involving local people in bringing about social change. This being said, by their very nature, foundations are eminently predisposed to provide sustainable relief in crises such as Covid-19 and to mitigate long-term societal impact.
New Approach Methodology for Assessing Inhalation Risks of a Contact Respiratory Cytotoxicant: Computational Fluid Dynamics-Based Aerosol Dosimetry Modeling for Cross-Species and In Vitro Comparisons
Authors: Corley Richard A , Kuprat Andrew P , Suffield Sarah R , Kabilan Senthil , Hinderliter Paul M , Yugulis Kevin , Ramanarayanan Tharacad S 
Published: June 2021

Abstract
Regulatory agencies are considering alternative approaches to assessing inhalation toxicity that utilizes in vitro studies with human cells and in silico modeling in lieu of additional animal studies. In support of this goal, computational fluid-particle dynamics models were developed to estimate site-specific deposition of inhaled aerosols containing the fungicide, chlorothalonil, in the rat and human for comparisons to prior rat inhalation studies and new human in vitro studies. Under bioassay conditions, the deposition was predicted to be greatest at the front of the rat nose followed by the anterior transitional epithelium and larynx corresponding to regions most sensitive to local contact irritation and cytotoxicity. For humans, simulations of aerosol deposition covering potential occupational or residential exposures (1–50 µm diameter) were conducted using nasal and oral breathing. Aerosols in the 1–5 µm range readily penetrated the deep region of the human lung following both oral and nasal breathing. Under actual use conditions (aerosol formulations &gt;10 µm), the majority of deposited doses were in the upper conducting airways. Beyond the nose or mouth, the greatest deposition in the pharynx, larynx, trachea, and bronchi was predicted for aerosols in the 10–20 µm size range. Only small amounts of aerosols &gt;20 µm penetrated past the pharyngeal region. Using the ICRP clearance model, local retained tissue dose metrics including maximal concentrations and areas under the curve were calculated for each airway region following repeated occupational exposures. These results are directly comparable with benchmark doses from in vitro toxicity studies in human cells leading to estimated human equivalent concentrations that reduce the reliance on animals for risk assessments.
Reporting and Misreporting of Sex Differences in the Biological Sciences
Authors: Garcia-Sifuentes Yesenia , Maney Donna L. 
Published: June 2021

AbstractAs part of an initiative to improve rigor and reproducibility in biomedical research, the U. S. National Institutes of Health now requires the consideration of sex as a biological variable in preclinical studies. This new policy has been interpreted by some as a call to compare males and females with each other. Researchers testing for sex differences may not be trained to do so, however, increasing risk for misinterpretation of results. Using a list of recently published articles curated by Woitowich et al. (eLife, 2020; 9:e56344), we examined reports of sex differences and non-differences across nine biological disciplines. Sex differences were claimed in the majority of the 147 articles we analyzed; however, statistical evidence supporting those differences was often missing. For example, when a sex-specific effect of a manipulation was claimed, authors usually had not tested statistically whether females and males responded differently. Thus, sex-specific effects may be over-reported. In contrast, we also encountered practices that could mask sex differences, such as pooling the sexes without first testing for a difference. Our findings support the need for continuing efforts to train researchers how to test for and report sex differences in order to promote rigor and reproducibility in biomedical research.
Development and operationalization of an electronic palliative care registry in a large integrated health system
Authors: Sudat Sylvia EK , Blanton Kathy 
Published: June 2021

ABSTRACTBackgroundPalliative care teams generally lack prospective tools to identify individuals who could benefit from specialty palliative care, which hinders their ability to find and treat patients early in their illness trajectories. Health systems are also limited in their ability to assess how well their palliative care services reach the population in need, which in turn makes it much more difficult to determine the quality, value, and effectiveness of those services. This study describes the creation, validation, and operationalization of an electronic registry of patients potentially eligible for palliative care at Sutter Health, a large integrated health system in northern California, US.ResultsThe electronic palliative care eligibility algorithm performed well within the chart review validation sample, with an area under the receiver operating characteristic curve (AUROC) of 0.903 and area under the precision-recall curve (AUPRC) of 0.545. Within the 2.4 million individuals who contacted the SH electronic health record (EHR) during 2017, the final algorithm identified 1.1%-1.8% of patients (26,773-42,847) as potentially eligible for palliative care services. This included approximately 12.9%-17.7% of inpatients (16,392-22,507 out of 126,916), and 1.2%-1.9% of ambulatory care patients (20,140-32,212 out of 1.7 million).ConclusionsA palliative care electronic patient registry was successfully created and operationalized. Performance based on an extensive chart review sample of Sutter Health patients indicated good capture of the palliative care-appropriate population, and this is further supported by successful identification of a majority of enrollees in Sutter Health’s palliative care programs during 2017.
Forecasting COVID-19 Number of Cases by Implementing ARIMA and SARIMA with Grid Search in United States
Authors: Abolmaali Saina , Shirzaei Samira 
Published: June 2021

AbstractCOVID-19 has surged in the United States since January 2020. Since then, social distancing and lockdown have helped many people to avoid infectious diseases. However, this did not help the upswing of the number of cases after the lockdown was finished. Modeling the infectious disease can help the health care providers and governors to plan ahead for obtain the needed resources. In this manner, precise short-term determining of the number of cases can be imperative to the healthcare system. Many models have been used since the pandemic has started. In this paper we will compare couple of time series models like Simple Moving Average, Exponentially Weighted Moving Average, Holt-Winters Double Exponential Smoothing Additive, ARIMA, and SARIMA. Two models that have been used to predict the number of cases are ARIMA and SARIMA. A grid search has been implemented to select the best combination of the parameters for both models. Results show that in the case of modeling, the Holt-Winters Double Exponential model outperforms Exponentially Weighted Moving Average and Simple Moving Average while forecasting ARIMA outperforms SARIMA.
Covid-19: Comparisons by Country and Implications for Future Pandemics
Authors: Lewis Mehl-Madrona Bangor , Orono Maine , Bricaire François , Cuyugan Adrian , Barac Jovan , Parvaiz Asadullah , Jamil Ali Bin , Iqbal Sajid , Vally Ryan , Koliali Meryem , Sellier Mohamed Karim 
Published: June 2021

AbstractBackgroundWe set out in this paper to compare Covid-19 results by country to better understand the factors leading to the differing results found internationally.MethodsWe used publicly available large datasets to explore differences by country for Covid-19 mortality statistics. We continuously challenged our projections with reality and numbers from countries around the world, allowing us to refine our models and better understand the progression of the epidemic. All our predictions and findings were discussed and validated from a clinical viewpoint.ResultsWhile no lockdown resulted in higher mortality, the difference between strict lockdown and lax lockdown was not terribly different and favored lax lockdown. Only one of the top 44 countries had long and strict restrictions. Strict restrictions were more common in the worst performing countries in terms of Covid mortality. The United States had both the largest economic growth coupled with the largest rate of mortality. Those who did well economically, had lower mortality and less pressure on their population. Yet they had less mortality than average and less than their neighbors.ConclusionsCountries with the least restrictions fared best economically. Some of them fared well in terms of mortality, even better than neighboring countries with similar social structures and more severe restrictions. The mortality rates in the USA, however, appeared to suffer from very high obesity rates. Norway and the northern European countries have less strict restrictions from the rest of Europe and had lower mortality rates. COVID-19 mortality was associated with vitamin D status.
Admission criteria in critically ill COVID-19 patients: a physiology-based approach
Authors: Ceruti Samuele , Glotta Andrea , Biggiogero Maira , Maida Pier Andrea , Marzano Martino , Urso Patrizia , Bona Giovanni , Garzoni Christian 
Published: June 2021

ABSTRACTIntroductionThe COVID-19 pandemic required a careful management of intensive care unit (ICU) admissions, to reduce ICU overload while facing resources’ limitations. We implemented standardized, physiology-based, ICU admission criteria and analyzed the mortality rate of patients refused from the ICU.Materials and MethodsCOVID-19 patients proposed for ICU admission were consecutively analyzed; Do-not-resuscitate patients were excluded. Patients presenting a SpO2 lower than 85% and/or dyspnea and/or mental confusion resulted eligible for ICU admission; patients not presenting these criteria remained in the ward with an intensive monitoring protocol. Primary outcome was both groups’ survival rate. Secondary outcome was a sub analysis correlating SpO2 cutoff with ICU admission.ResultsFrom March 2020 to January 2021, 1623 patients were admitted to our Center; 208 DNR patients were excluded; 97 patients underwent intensivist evaluation. The ICU-admitted group mortality rate resulted 15.9% at 28 days and 27% at 40 days; the ICU-refused group mortality rate resulted 0% at both intervals (p < 0.001). With a SpO2 cut-off of 92%, the hypoxia rate distribution did not correlate with ICU admission (p = 0.26); with a SpO2 cut-off of 85%, a correlation was found (p = 0.009). A similar correlation was also found with dyspnea (p =0.0002).ConclusionIn COVID-19 patients, standardized ICU admission criteria appeared to reduce safely ICU overload. In the absence of dyspnea and/or confusion, a SpO2 cutoff up to 85% for ICU admission was not burdened by negative outcomes. In a pandemic context, the SpO2 cutoff of 92%, as a threshold for ICU admission, needs critical re-evaluation.
Evaluation of a clinical decision support tool for matching cancer patients to clinical trials using simulation-based research
Authors: Gardner Clarissa , Halligan Jack , Fontana Gianluca , Fernandez Crespo Roberto , Prime Matthew , Guo Chaohui , Ekinci Okan , Ghafur Saira , Darzi Ara 
Published: June 2021

AbstractSimulation-based research (SBR) methods have been proposed as an alternative methodology for evaluating digital health solutions; however, applicability remains to be established. This study used SBR to evaluate a clinical decision support (CDS) tool used for matching cancer patients to clinical trials. 25 clinicians and research staff were recruited to match 10 synthetic patient cases to clinical trials using both the CDS tool and publicly available online trial databases. Participants were significantly more likely to report having sufficient time (p = 0.020) and to require less mental effort (p = 0.001) to complete trial matching with the CDS tool. Participants required less time for trial matching using the CDS tool, but the difference was not significant (p = 0.093). Most participants reported that they had sufficient guidance to participate in the simulations (96%). This study demonstrates the use of SBR methods is a feasible approach to evaluating digital health solutions.
Contributions of PTSD polygenic risk and environmental stress to suicidality in preadolescents
Authors: Daskalakis Nikolaos P , Schultz Laura M , Visoki Elina , Moore Tyler M , Argabright Stirling T , Harnett Nathaniel G , DiDomenico Grace E , Warrier Varun , Almasy Laura , Barzilay Ran 
Published: June 2021

AbstractSuicidal ideation and attempts (i.e., suicidality) are complex behaviors driven by environmental stress, genetic susceptibility, and their interaction. Preadolescent suicidality is a major health problem with rising rates, yet its underlying biology is understudied. Here we studied effects of genetic stress susceptibility, estimated by polygenic risk score (PRS) for post-traumatic-stress-disorder (PTSD), on preadolescent suicidality in participants from the Adolescent Brain Cognitive Development (ABCD) Study®. We further evaluated PTSD-PRS effects on suicidality in the presence of environmental stressors that are established suicide risk factors. Analyses included both European and African ancestry participants using PRS calculated based on summary statistics from ancestry-specific genome-wide association studies. In European ancestry participants (N=4,619, n=378 suicidal), PTSD-PRS was associated with preadolescent suicidality (odds ratio [OR]=1.12, 95%CI 1-1.25, p=0.038). Results in African ancestry participants (N=1,334, n=130 suicidal) showed a similar direction but were not statistically significant (OR=1.21, 95%CI 0.93-1.57, p=0.153). Sensitivity analyses using non-psychiatric polygenic score for height and using cross-ancestry PTSD-PRS did not reveal any association with suicidality, supporting the specificity of the association of ancestry-specific PTSD-PRS with suicidality. Environmental stressors were robustly associated with suicidality across ancestries with moderate effect size for negative life events and family conflict (OR 1.27-1.6); and with large effect size (OR ∼ 4) for sexual-orientation discrimination. When combined with environmental factors, PTSD-PRS showed marginal additive effects in explaining variability in suicidality, with no evidence for G X E interaction. Results support use of cross-phenotype PRS, specifically stress-susceptibility, as a robust genetic marker for suicidality risk early in the lifespan.
A one-step real-time RT-PCR assay for simultaneous typing of SARS-CoV-2 mutations associated with the E484K and N501Y spike protein amino-acid substitutions
Authors: Chaintoutis Serafeim C. , Chassalevris Taxiarchis , Tsiolas George , Balaska Sofia , Vlatakis Ioannis , Mouchtaropoulou Evangelia , Siarkou Victoria I. , Tychala Areti , Koutsioulis Dimitris , Skoura Lemonia , Argiriou Anagnostis , Dovas Chrysostomos I. 
Published: June 2021

AbstractThe emergence of SARS-CoV-2 mutations resulting in the S protein amino-acid substitutions N501Y and E484K, which have been associated with enhanced transmissibility and immune escape, respectively, necessitates immediate actions, for which their rapid identification is crucial. For the simultaneous typing of both of these mutations of concern (MOCs), a one-step real-time RT-PCR assay employing four locked nucleic acid (LNA) modified TaqMan probes was developed. The assay is highly sensitive with a LOD of 117 copies/reaction, amplification efficiencies >94% and a linear range of over 5 log10 copies/reaction. Validation of the assay using known SARS-CoV-2-positive and negative samples from human and animals revealed its ability to correctly identify wild type strains, and strains possessing either one or both targeted amino-acid substitutions, thus comprising a useful pre-screening tool for rapid MOC identification. The basic principles of the methodology for the development of the assay are explained in order to facilitate the rapid design of similar assays able to detect emerging MOCs.