bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study protocol of the global Effisayil 1 Phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare
Authors: Choon Siew Eng , Lebwohl Mark G , Marrakchi Slaheddine , Burden A David , Tsai Tsen-Fang , Morita Akimichi , Navarini Alexander A , Zheng Min , Xu Jinhua , Turki Hamida , Rajeswari Sushmita , Deng Hongjie , Tetzlaff Kay , Thoma Christian , Bachelez Hervé 
Published: March 2021

IntroductionGeneralized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare.Methods and analysisAt least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.Ethics and disseminationThe study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation’s Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.Trial registration detailsClinicalTrials.gov identifier:NCT03782792; Pre-results.
Multicentre prospective observational study exploring the predictive value of functional echocardiographic indices for early identification of preterm neonates at risk of developing chronic pulmonary hypertension secondary to chronic neonatal lung disease
Authors: Thomas Laura , Baczynski Michelle , Deshpande Poorva , Kharrat Ashraf , Joye Sébastien , Zhu Faith , Ibarra-Rios Daniel , Shah Prakesh S , Mertens Luc , Jankov Robert P , Ye Xiang Y , Neary Elaine , Ting Joseph , Castaldo Michael , Levy Philip , Smith Aisling , El-Khuffash Afif F , Giesinger Regan E , McNamara Patrick J , Weisz Dany E , Jain Amish 
Published: March 2021

IntroductionAlthough chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers.Methods and analysisIn this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest.Ethics and disseminationEthics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children’s and Women’s REB (H19-02738), and is under review at Boston Children’s Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals.Trail registration numberNCT04402645.
Mortality in adolescent trauma: a comparison of children’s, mixed and adult major trauma centres
Authors: Evans Jordan , Murch Hannah , Begley Roisin , Roland Damian , Lyttle Mark D , Bouamra Omar , Mullen Stephen 
Published: March 2021

ObjectiveWe aimed to compare adolescent mortality rates between different types of major trauma centre (MTC or level 1; adult, children’s and mixed).MethodsData were obtained from TARN (Trauma Audit Research Network) from English sites over a 6-year period (2012–2018), with adolescence defined as 10–24.99 years. Results are presented using descriptive statistics. Patient characteristics were compared using the Kruskal-Wallis test with Dunn’s post-hoc analysis for pairwise comparison and χ2test for categorical variables.Results21 033 cases met inclusion criteria. Trauma-related 30-day crude mortality rates by MTC type were 2.5% (children’s), 4.4% (mixed) and 4.9% (adult). Logistic regression accounting for injury severity, mechanism of injury, physiological parameters and ‘hospital ID’, resulted in adjusted odds of mortality of 2.41 (95% CI 1.31 to 4.43; p=0.005) and 1.85 (95% CI 1.03 to 3.35; p=0.041) in adult and mixed MTCs, respectively when compared with children’s MTCs. In three subgroup analyses the same trend was noted. In adolescents aged 14–17.99 years old, those managed in a children’s MTC had the lowest mortality rate at 2.5%, compared with 4.9% in adult MTCs and 4.4% in mixed MTCs (no statistical difference between children’s and mixed). In cases of major trauma (Injury Severity Score >15) the adjusted odds of mortality were also greater in the mixed and adult MTC groups when compared with the children’s MTC. Median length of stay (LoS) and intensive care unit LoS were comparable for all MTC types. Patients managed in children’s MTCs were less likely to have a CT scan (46.2% vs 62.8% mixed vs 64% adult).ConclusionsChildren’s MTC have lower crude and adjusted 30-day mortality rates for adolescent trauma. Further research is required in this field to identify the factors that may have influenced these findings.
Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study
Authors: Henry Brandon Michael , Cheruiyot Isaac , Benoit Stefanie W , Sanchis-Gomar Fabian , Lippi Giuseppe , Benoit Justin 
Published: March 2021

BackgroundThe mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis.MethodsBlood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65.ResultsA total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively).ConclusionNecrosis appears to be the main driver of hospitalisation, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.
Trimethylamine N-oxide (TMAO): a new attractive target to decrease cardiovascular risk
Authors: Swanepoel Ione , Roberts April , Brauns Chelsea , Chaliha Devahuti R , Papa Veronica , Palmer Raymond D , Vaccarezza Mauro 
Published: March 2021

AbstractCardiovascular disease (CVD) is one of the greatest disease burdens and takes the lives of many each year. There are many risk factors both modifiable and non-modifiable which contribute to the onset and progression of the disease. Trimethylamine N-oxide (TMAO) in recent years has been found to have a correlation with CVD onset. Those with increased levels of the metabolite have a markedly increased risk of future development of cardiometabolic disorders.This literature review aimed to critique past studies undertaken to find a consensus of the significance of the interrelationship between TMAO and cardiovascular risk. A definite link between TMAO levels and a CVD outcome was found. The majority of the literature stated the relationship with evidence; however, there is still some uncertainty as to why and how the correlation occurs. Further study needs to be done to further dissect and understand the relationship between TMAO and CVD risk.
High levels of undiagnosed rectal STIs suggest that screening remains inadequate among Black gay, bisexual and other men who have sex with men
Authors: Watson Ryan J , Collibee Charlene , Maksut Jessica L , Earnshaw Valerie A , Rucinski Katherine , Eaton Lisa 
Published: March 2021

ObjectiveTo better understand rectal STI screening practices for Black gay, bisexual and other men who have sex with men (BGBMSM).FindingsAlthough 15% of BGBMSM lab tested positive for a rectal STI, the majority of these (94%) were asymptomatic. Though all participants reported their status as HIV negative/unknown, 31 of 331 (9.4%) tested positive on HIV rapid tests. Neither condomless anal intercourse nor the number of male sex partners was associated with rectal STI or HIV diagnosis, although rectal STI diagnosis was positively related to testing HIV positive.ConclusionsFindings suggest that substantial numbers of BGBMSM have asymptomatic STIs but are not tested—an outcome that is likely a strong driver of onward HIV acquisition. Therefore, we must address the asymptomatic STI epidemic among GBMSM in order to reduce HIV transmission, as well as temper STI transmission, among this key population.
Anisotropic compact stars via embedding approach in general relativity: new physical insights of stellar configurations
Authors: Errehymy Abdelghani , Khedif Youssef , Daoud Mohammed 
Published: March 2021

AbstractThe main focus of this paper is to explore the possibility of providing a new family of exact solutions for suitable anisotropic spherically symmetric systems in the realm of general relativity involving the embedding spherically symmetric static metric into the five-dimensional pseudo-Euclidean space. In this regard, we ansatz a new metric potential $$\lambda (r)$$

λ
(
r
)

, and we obtained the other metric potential $$\nu (r)$$

ν
(
r
)

by mains of embedding class one approach. The unknown constants are determined by the matching of interior space-time with the Schwarzschild exterior space-time. The physical acceptability of the generating celestial model for anisotropic compact stars is approved via acting several physical tests of the main salient features viz., energy density, radial and tangential pressures, anisotropy effect, dynamical equilibrium, energy conditions, and dynamical stability, which are well-compared with experimental statistics of four different compact stars: PSR J1416-2230, PSR J1903+327, 4U 1820-30 and Cen X-3. Conclusively, all the compact stars under observations are realistic, stable, and are free from any physical or geometrical singularities. We find that the embedding class one solution for anisotropic compact stars is viable and stable, plus, it provides circumstantial evidence in favor of super-massive pulsars.
Foxe Platform and Basin Tectono-Sedimentary Element, Northeast Canada
Authors: Lavoie Denis , Pinet Nicolas , Zhang Shunxin 
Published: March 2021

Abstract
The Foxe Platform and Basin Tectono-Sedimentary Element (TSE) is an ovoid-shaped, predominantly marine basin located in the Canadian Arctic. The Paleozoic sedimentary succession (Cambrian–Silurian) unconformably overlies the Precambrian basement and reaches a maximum measured thickness of slightly over 500 m in the only exploration well drilled in this basin. The Lower Paleozoic Foxe Platform and Basin TSE is surrounded by Precambrian basement, and by the Paleozoic Arctic Platform to the north and by the Paleozoic–Mesozoic (?) Hudson Bay Strait Platform and Basin to the south. The Paleozoic succession consists of a Cambrian clastic-dominated interval overlain by Ordovician–lower Silurian predominantly shallow-marine carbonate. Other than a single well drilled in the northern part of the basin, no subsurface information is available. Thermally immature Upper Ordovician organic-matter-rich calcareous black shales have been mapped on the onshore extension of the basin to the SE. Potential hydrocarbon reservoirs consist of Cambrian porous coarse-grained clastics, as well as Upper Ordovician dolostones and reefs.
Cenozoic volcanism along Dahongliutan fault in the West Kunlun Mountains, China: implication from distribution of volcanic rocks, volcanic geology, and geochemistry
Authors: Zhao Bo , Wei Feixiang , Yang Wenjian , Xu Jiandong , Cui Xiaoge 
Published: March 2021

Abstract

In the West Kunlun Mountains, four volcanic fields (Kangxiwa, Dahongliutan, Qitaidaban and Quanshuigou) are distributed along the Dahongliutan fault, which is
c.
180 km long. Based on field investigations, chronological measurements and geochemical analysis of some volcanic fields, the results of geological, geochemical and geophysical research in previous studies in the corresponding study areas are summarized. The volcanic activities in these areas were mainly effusive eruptions, explosive eruptions and phreatomagmatic eruptions. In this study, we discovered the Qitaiyanhu volcanic field for the first time and determined that the
14
C age of the lacustrine strata underlying the Qitaiyanhu lava flows is 13.110 ± 0.04 ka BP, indicating that there may still have been volcanic activities in the late Pleistocene and even the Holocene in the Dahongliutan fault area. Base surge deposits, which are the products of the interaction between magma and water, were found in the Kangxiwa volcanic field. The four shoshonitic rock fields of Kangxiwa, Dahongliutan, Qitaidaban and Quanshuigou are likely to be products of different evolution stages from the same magma source area. The magmatic origin of these volcanic fields may be related to the upwelling of the asthenosphere, triggered by the collision between the Indian and Tarim plates.
Geomorphology and geochemistry of the Late Cenozoic volcanoes in the Halaha River–Chaoer River volcanic fields, western Greater Hinggan Mountain Range, NE China
Authors: Zhao Yong-Wei , Zou Haibo , Li Ni 
Published: March 2021

Abstract

The Halaha River–Chaoer River (HC) volcanic field in the Greater Hinggan Mountain Range (NE China) consists of at least 41 monogenetic basaltic volcanoes. Strombolian, violent Strombolian and phreatomagmatic eruptions, as well as the transitional eruptions, generated simple volcanic cones (single vent) and composite volcanic cones (multiple vents). The simple elongated cone is the most abundant geomorphology type. By analysing the elongated crater and coalescent aligned circular crater, cone breaching and depression, and aligned vents, we identified a number of magma-feeding fissures. The majority of these fissures strike NE–ENE. Accordingly, we infer that the regional stress field affected volcanism in the HC field. The lavas in this field are alkali basalts that are enriched in light rare earth elements (La/Yb
N
= 7.9–24.5). Their ocean island basalt-like rare earth element and spider-diagram patterns, high Nb/U ratios and high TiO
2
contents (>2 wt%) indicate that the basalts were derived from the asthenosphere mantle. Both the asthenosphere upwelling and the tectonic forces are the key controlling factors of the volcanism in the HC field.
An Interview with Lionel Briand - ACM Fellow 2020
Authors: Pfahl Dietmar 
Published: March 2021

Lionel Briand is one of the five ACM Fellows of the 2020 cohort who are also active SIGSOFT members. To celebrate his award, we invited him to a question/answer session.
Lionel is professor of software engineering and has shared appointments between the University of Ottawa and the University of Luxembourg. He holds a Canada Research Chair (Tier 1) and an ERC Advanced grant. Over the last 25 years, Lionel has been an engineer, a researcher, a research institute department head, a research center leader, a university professor, and a consultant in the IT industry. His experience spans six countries and over the years he has run research and innovation projects with or worked for 30+ industry partners and public institutions. He has not only an impressive publication and research record as well as a long list of awards but also has served as editor-in-chef, editorial board member, steering committee member, general chair and program chair of top-level journals and conferences in the software engineering community.
An Fc-free EGFR-specific 4-1BB-agonistic Trimerbody Displays Broad Antitumor Activity in Humanized Murine Cancer Models without Toxicity
Authors: Compte Marta , Harwood Seandean L. , Erce-Llamazares Ainhoa , Tapia-Galisteo Antonio , Romero Eduardo , Ferrer Irene , Garrido-Martin Eva M. , Enguita Ana B. , Ochoa Maria C. , Blanco Belén , Oteo Marta , Merino Nekane , Nehme-Álvarez Daniel , Hangiu Oana , Domínguez-Alonso Carmen , Zonca Manuela , Ramírez-Fernández Angel , Blanco Francisco J. , Morcillo Miguel A. , Muñoz Ines G. , Melero Ignacio , Rodriguez-Peralto José L. , Paz-Ares Luis , Sanz Laura , Alvarez-Vallina Luis 
Published: March 2021

Abstract

Purpose:
The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell–mediated antitumor response. Systemic administration of anti-4-1BB–agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.

Experimental Design:
Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo.

Results:
In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non–small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer.

Conclusions:
These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.
ABCB1 and ABCG2 Restrict Brain and Testis Accumulation and, Alongside CYP3A, Limit Oral Availability of the Novel TRK Inhibitor Selitrectinib
Authors: Li Wenlong , Sparidans Rolf W. , Martins Margarida L.F. , El-Lari Mujtaba , Lebre Maria C. , van Tellingen Olaf , Beijnen Jos H. , Schinkel Alfred H. 
Published: March 2021

Abstract
Selitrectinib (BAY2731954; LOXO-195) is a promising oral tropomyosin receptor kinase (TRK) inhibitor currently in phase I/II clinical trials for the treatment of histology-agnostic cancers positive for TRK fusions. With therapeutic resistance eventually developing with first-generation TRK inhibitors, selitrectinib was designed to overcome resistance mediated by acquired kinase domain mutations. Using genetically modified mouse models and pharmacological inhibitors, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzyme complex in selitrectinib pharmacokinetics. In vitro, selitrectinib was markedly transported by mouse Abcg2 and human ABCB1, and modestly by human ABCG2. Following oral administration at 10 mg/kg, selitrectinib brain-to-plasma ratios were increased in Abcb1a/1b−/− (twofold) and Abcb1a/1b;Abcg2−/− (5.8-fold) compared with wild-type mice, but not in single Abcg2−/− mice. Testis distribution showed similar results. mAbcb1a/1b and mAbcg2 each restricted the plasma exposure of selitrectinib: With both systems absent oral availability increased by 1.7-fold. Oral administration of the ABCB1/ABCG2 inhibitor elacridar boosted plasma exposure and brain accumulation in wild-type mice to the same levels as seen in Abcb1a/1b;Abcg2−/− mice. In Cyp3a−/− mice, plasma exposure of selitrectinib over 4 hours was increased by 1.4-fold and subsequently reduced by 2.3-fold upon transgenic overexpression of human CYP3A4 in liver and intestine. The relative tissue distribution of selitrectinib remained unaltered. Thus, selitrectinib brain accumulation and oral availability are substantially restricted by ABCB1 and ABCG2, and this can be reversed by pharmacological inhibition. Moreover, oral availability of selitrectinib is limited by CYP3A activity. These insights may be useful to optimize the clinical application of selitrectinib.