bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac donation after circulatory determination of death: protocol for a mixed-methods study of healthcare provider and public perceptions in Canada
Authors: Honarmand Kimia , Ball Ian , Weiss Matthew , Slessarev Marat , Sibbald Robert , Sarti Aimee , Meade Maureen , D'Aragon Frédérick , Chasse Michael , Basmaji John , Parsons Leigh Jeanna
Published: July 2020

Introduction

Cardiac transplantation remains the best treatment for patients with end-stage heart disease that is refractory to medical or device therapies, however, a major challenge for heart transplantation is the persistent discrepancy between the number of patients on waiting lists and the number of available hearts. While other countries (eg, UK, Australia and Belgium) have explored and implemented alternative models of transplantation, such as cardiac donation after circulatory determination of death (DCDD) to alleviate transplantation wait times, ethical concerns have hindered implementation in some countries. This study aims to explore the attitudes and opinions of healthcare providers and the public about cardiac DCDD in order to identify and describe opportunities and challenges in ensuring that proposed cardiac DCDD procedures in Canada are consistent with Canadian values and ethical norms.

Methods and analysis

This study will include two parts that will be conducted concurrently. Part 1 is a qualitative study consisting of semi-structured interviews with Canadian healthcare providers who routinely care for organ donors and/or transplant recipients to describe their perceptions about cardiac DCDD. Part 2 is a convergent parallel mixed-methods design consisting of a series of focus groups and follow-up surveys with members of the Canadian general public to describe their perceptions about cardiac DCDD.

Ethics and dissemination

This study has been approved by the Research Ethics Board at Western University. The findings will be presented at regional and national conferences and reported in peer-reviewed publications.
HIP (HPA-screening in pregnancy) study: protocol of a nationwide, prospective and observational study to assess incidence and natural history of fetal/neonatal alloimmune thrombocytopenia and identifying pregnancies at risk
Authors: Winkelhorst Dian , de Vos Thijs W , Kamphuis Marije M , Porcelijn Leendert , Lopriore Enrico , Oepkes Dick , van der Schoot C Ellen , de Haas Masja
Published: July 2020

Introduction

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may lead to severe fetal or neonatal bleeding and/or perinatal death. Maternal alloantibodies, targeted against fetal human platelet antigens (HPAs), can result thrombocytopenia and bleeding complications. In pregnancies with known immunisation, fetal bleeding can be prevented by weekly maternal intravenous immunoglobulin infusions. Without population-based screening, immunisation is only detected after birth of an affected infant. Affected cases that might have been prevented, when timely identified through population-based screening. Implementation is hampered by the lack of knowledge on incidence, natural history and identification of pregnancies at high risk of bleeding. We designed a study aimed to obtain this missing knowledge.

Methods and analysis

The HIP (HPA-screening in pregnancy) study is a nationwide, prospective and observational cohort study aimed to assess incidence and natural history of FNAIT as well as identifying pregnancies at high risk for developing bleeding complications. For logistic reasons, we invite rhesus D-negative or rhesus c-negative pregnant women, who take part in the Dutch population-based prenatal screening programme for erythrocyte immunisation, to participate in our study. Serological HPA-1a typing is performed and a luminex-based multiplex assay will be performed for the detection of anti-HPA-1a antibodies. Results will not be communicated to patients or caregivers. Clinical data of HPA-1a negative women and an HPA-1a positive control group will be collected after birth. Samples of HPA-1a immunised pregnancies with and without signs of bleeding will be compared with identify parameters for identification of pregnancies at high risk for bleeding complications.

Ethics and dissemination

Ethical approval for this study has been obtained from the Medical Ethical Committee Leiden-The Hague-Delft (P16.002). Study enrolment began in March 2017. All pregnant women have to give informed consent for testing according to the protocol. Results of the study will be disseminated through congresses and publication in relevant peer-reviewed journals.

Trial registration number

NCT04067375.
Assessing the impact on intestinal microbiome and clinical outcomes of antibiotherapy optimisation strategies in haematopoietic stem cell transplant recipients: study protocol for the prospective multicentre OptimBioma study
Authors: Jiménez-Jorge Silvia , Labrador-Herrera Gema , Rosso-Fernández Clara M , Rodríguez-Torres Nancy , Pachón-Ibáñez María Eugenia , Smani Younes , Márquez-Malaver Francisco José , Limón Ramos Carmen , Solano Carlos , Vázquez-López Lourdes , Kwon Mi , Mora Barrios Joan Manuel , Aguilar-Guisado Manuela , Espigado Ildefonso
Published: July 2020

Introduction

Haematopoietic stem cell transplantation (HSCT) is a life-saving treatment for a number of haematological diseases. Graft versus host disease (GVHD) is its main complication and hampers survival. There is strong evidence that intestinal microbiota diversity of the recipient may increase the risk of GVHD worsening survival. Antibiotic regimens used during the early phase of the transplant may influence clinical outcomes by reducing intestinal microbiota diversity. Present guidelines of European Conference on Infections in Leukaemia exhort to optimising antibiotic use in haematological patients including HSCT recipients. The present study aims to investigate if, in HSCT recipients, the optimisation of antibacterial use may preserve intestinal microbiota composition reducing the incidence and severity of acute GVHD and improving relevant clinical outcomes.

Methods and analysis

This is a prospective longitudinal observational study of two cohorts of HSCT recipients: (1) the intervention cohort includes patients treated in centres in which a predefined strategy of antibiotherapy optimisation is implemented, with the objective of optimising and reducing antibiotic administration according to clinical criteria and (2) the control cohort includes patients treated in centres in which a classic permissive strategy of antibiotic prophylaxis and treatment is used. Adult patient receiving a first HSCT as a treatment for any haematological condition are included. Clinical variables are prospectively recorded and up to five faecal samples are collected for microbiota characterisation at prestablished peritransplant time points. Patients are followed since the preconditioning phase throughout 1-year post-transplant and four follow-up visits are scheduled. Faecal microbiota composition and diversity will be compared between both cohorts along with acute GVHD incidence and severity, severe infections rate, mortality and overall and disease-free survival.

Ethics and dissemination

The study was approved between 2017 and 2018 by the Ethical Committees of participant centres. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences.

Trial registration number

NCT03727113
Complex Large-Bore Radial percutaneous coronary intervention: rationale of the COLOR trial study protocol
Authors: Meijers Thomas A , Aminian Adel , Teeuwen Koen , van Wely Marleen , Schmitz Thomas , Dirksen Maurits T , van der Schaaf Rene J , Iglesias Juan F , Agostoni Pierfrancesco , Dens Joseph , Knaapen Paul , Rathore Sudhir , Ottervanger Jan Paul , Dambrink Jan-Henk E , Roolvink Vincent , Gosselink A T Marcel , Hermanides Renicus S , van Royen Niels , van Leeuwen Maarten A H
Published: July 2020

Introduction

The radial artery has become the standard access site for percutaneous coronary intervention (PCI) in stable coronary artery disease and acute coronary syndrome, because of less access site related bleeding complications. Patients with complex coronary lesions are under-represented in randomised trials comparing radial with femoral access with regard to safety and efficacy. The femoral artery is currently the most applied access site in patients with complex coronary lesions, especially when large bore guiding catheters are required. With slender technology, transradial PCI may be increasingly applied in patients with complex coronary lesions when large bore guiding catheters are mandatory and might be a safer alternative as compared with the transfemoral approach.

Methods and analysis

A total of 388 patients undergoing complex PCI will be randomised to radial 7 French access with Terumo Glidesheath Slender (Terumo, Japan) or femoral 7 French access as comparator. The primary outcome is the incidence of the composite end point of clinically relevant access site related bleeding and/or vascular complications requiring intervention. Procedural success and major adverse cardiovascular events up to 1 month will also be compared between both groups.

Ethics and dissemination

Ethical approval for the study was granted by the local Ethics Committee at each recruiting center (‘Medisch Ethische Toetsing Commissie Isala Zwolle’, ‘Commissie voor medische ethiek ZNA’, ‘Comité Medische Ethiek Ziekenhuis Oost-Limburg’, ‘Comité d’éthique CHU-Charleroi-ISPPC’, ‘Commission cantonale d'éthique de la recherche CCER-Republique et Canton de Geneve’, ‘Ethik Kommission de Ärztekammer Nordrhein’ and ‘Riverside Research Ethics Committee’). The trial outcomes will be published in peer-reviewed journals of the concerned literature.

Trial registration number

NCT03846752.
How much does quality matter: the value of data
Authors: Lyons Ronan A
Published: July 2020

In a world of competing priorities, accurate production of information on the scale of the injury burden and the effectiveness of prevention-orientated interventions and policies is important; hence, data quality matters. This article surveys the literature about what is known about data quality in the injury field and developments to improve the quality and usability of information, particularly through triangulation of data sources, data linkage and unlocking the potential for more deeply phenotyped data through natural language processing.
Effects of a moderate transition from 70% to 90% concentrate diet on early alterations in feeding behavior, rumen environment, reticulorumen motility, and blood acid–base status in beef heifers
Authors: Egert-McLean A.M. , Sama M.P. , Klotz J.L. , McLeod K.R. , Kristensen N.B. , Harmon D.L.
Published: July 2020

The objective of this study was to determine the early responses to a moderate concentrate increase in cattle diets with regards to various behavioral and physiological responses in cattle. Eight ruminally cannulated Angus crossbred beef heifers were adapted to a 70% concentrate diet (T70) and then switched to a 90% concentrate diet (H90). Measurements of feeding behavior, ruminal pH and temperature, rumen motility, liquid passage rate, and blood acid–base status were conducted on T70 as well as first day (d1) and second day (d2) of high-grain H90feeding to monitor the beginning of the transition period. Ruminal pH was below 5.6 for longer on both days of H90 compared with T70, suggesting animals experienced subacute ruminal acidosis while switching from T70 to H90. Transitioning did not affect dry matter intake (DMI). Eating rate during meals was reduced on d1 and d2 H90 compared with T70. Ruminal contraction amplitude was reduced on both days of H90 feeding. Contraction duration was reduced on d1 H90, and returned to T70 values by d2 H90. Results indicated that a moderate transition to a finishing diet influenced feeding behavior and reduced rumen motility at the beginning time after transition, but did not influence voluntary DMI.
Field assessment of horse-associated genetic markers HoF597 and mtCytb for detecting the source of contamination in surface waters
Authors: Gray Jessica , Masters Nicole , Wiegand Aaron , Katouli Mohammad
Published: July 2020

We investigated the specificity and sensitivity of two horse-associated markers, HoF597 and Horse mtCytb, and 12 mitochondrial and bacterial markers of six animal species (human, cow, pig, bird, dog, chicken) in the faecal samples of 50 individual horses. Both horse markers were detected in 48 (96%) faecal samples. Cross-reactivity with dog (BacCan545) and pig (P23-2) occurred in 88% and 72% of horse faecal samples, respectively. Several other bacterial and mitochondrial markers of non-target hosts were also detected; however, their specificities were >80%. Analyses of samples from surface waters (n = 11) on or adjacent to properties from which horse faecal samples had been collected showed only the presence of HoF597 but not horse mitochondrial marker. Our data suggest that while bacterial and (or) mitochondrial markers of other animal species may be present in horse faeces, dog and pig markers may predominantly be present in horse faecal samples, which points to their nonspecificity as markers for microbial source tracking. Although HoF597 and Horse mtCytb are highly sensitive and specific for the detection of horse faecal pollution, because of their low numbers, mitochondrial (mtDNA) markers may not be robust for screening surface waters.
Analysis and Design of High Gain-Bandwidth CMOS Distributed Amplifier Utilizing a Cascaded Pseudo Differential Distributed Amplifier
Authors: Babaeinik Majid , Dousti Massoud , Tavakoli Mohammad Bagher
Published: July 2020

Distributed amplifiers (DAs) are one of the most important and common wideband amplifiers that can use various arrangements in their gain cell structure. One of the gain cells that can be effective in increasing the bandwidth of a distributed amplifier is the pseudo-differential amplifier (PDA). Although pseudo-differential distributed amplifiers (PDDAs) have a wide bandwidth and amplify DC, they have a small voltage gain. In this paper, various circuits with the same power and chip area are proposed to improve the performance of PDDAs. For evaluating and comparing the performance of the proposed circuits, they are implemented in 0.18[Formula: see text][Formula: see text]m RF-CMOS technology. The simulation results reveal that two cascaded PDDAs with three stages have a better performance than three cascaded PDDAs with two stages; in two cascaded PDDAs with three stages, a gain of 9[Formula: see text]dB can be achieved for a bandwidth of 50[Formula: see text]GHz in 0.18[Formula: see text][Formula: see text]m RF-CMOS technology. In this amplifier, parameters S[Formula: see text], S[Formula: see text] and S[Formula: see text] are [Formula: see text]12, [Formula: see text]10 and [Formula: see text]18 dB, respectively; noise figure is 4.3–5.8[Formula: see text]dB, and [Formula: see text] is +4[Formula: see text]dBm. This amplifier consumes 220[Formula: see text]mW power and has a chip area of 0.58[Formula: see text]mm2.
On the complexity of the lattices of subvarieties and congruences
Authors: Kravchenko A. V. , Nurakunov A. M. , Schwidefsky M. V.
Published: July 2020

We find sufficient conditions guaranteeing that for a quasivariety [Formula: see text] of structures of finite type containing a [Formula: see text]-class with respect to [Formula: see text], there exists a subquasivariety [Formula: see text] and a structure [Formula: see text] such that the problems whether a finite lattice embeds into the lattice [Formula: see text] of [Formula: see text]-varieties and into the lattice [Formula: see text] are undecidable.
Scalar radiation emitted by a source around a spherically symmetric black hole
Authors: Bernar Rafael P.
Published: July 2020

We analyze the scalar radiation emitted by a source in a circular geodesic orbit around a spherically symmetric black hole. The black hole (BH) spacetime considered is quite general, in the sense that it encompasses the solutions of Schwarzschild and Reissner–Nordström, and also the Bardeen solution of a regular BH. We use the framework of quantum field theory in curved spaces to compute the one-particle emission amplitude of scalar particles and related quantities.
Outcome of Postcardiac Surgery Acute Myocardial Infarction and Role of Emergency Percutaneous Coronary Interventions
Authors: Laimoud Mohamed , Qureshi Rehan
Published: July 2020

Background. Cardiac surgery carries a well-known risk of perioperative myocardial infarction (MI), which is associated with high morbidity and both in-hospital and late mortality. The rapid haemodynamics deterioration and presence of myocardial ischemia early after cardiac surgical operations is a complex life-threatening condition where rapid diagnosis and management is of fundamental importance. Objective. To analyse the factors associated with mortality of patients with postcardiotomy MI and to study the role of emergency coronary angiography in management and outcome. Methods. We retrospectively enrolled adult patients diagnosed to have postcardiotomy MI and underwent emergency coronary angiography at our tertiary care hospital between January 2016 and August 2019. Results. Sixty-one patients from consecutive 1869 adult patients who underwent cardiac surgeries were enrolled in our study. The studied patients had a mean age of 49 ± 16.2 years with a mean BMI of 29.5 ± 6.6 and 65.6% of them were males. As compared to the survivors group, the nonsurvivors of perioperative MI had significant preoperative CKD, postoperative AKI, longer CPB time, frequent histories of previous PCI, previous cardiotomies, pre and postoperative ECMO use, higher median troponin I levels, higher peak and 24 hours median lactate levels. Regression analysis revealed that reoperation for revascularization (OR: 23; 95% CI: 8.27–217.06; P=0.034) and hyperlactataemia (OR: 3.21; 95% CI: 1.14–9.04; P=0.027) were independent factors associated with hospital mortality after perioperative MI. Hospital mortality occurred in 25.7% vs 86.7% (P<0.001), AKI occurred in 37.1% vs 93.3% (P<0.001), haemodialysis was used in 28.6% vs 80% (P=0.002), and mediastinal exploration for bleeding was performed in 31.4% vs 80% (P=0.006) in the PCI and reoperation groups, respectively, while there were no significant differences regarding gastrointestinal bleeding, cerebral strokes, or intracerebral bleeding. The median peak troponin level was 795 (IQR 630–1200) vs 4190 (IQR 3700–6300) (P<0.001) in the PCI and reoperation groups, respectively. Absence of significant angiographic findings occurred in 18% of patients. Conclusions. Perioperative MI is associated with significant morbidities and hospital mortality. Reoperation for revascularization and progressive hyperlactataemia are independent predictors of hospital mortality. Emergency coronary angiography is helpful in diagnosis and management of perioperative MI.
A New Method for Feature Extraction and Classification of Single-Stranded DNA Based on Collaborative Filter
Authors: Yan Bingyong , Cui Haixu , Fu Haitao , Zhou Jiale , Wang Huifeng
Published: July 2020

The traditional support vector machine algorithm is not enough to classify single-stranded DNA molecules, so this paper proposes an improved threshold extraction algorithm based on collaborative filter for the classification of single-stranded DNA. Firstly, according to the different characteristic curves of the blocking current signals formed by the four bases (A, T, C, and T) that make up DNA molecules crossing the nanopore, the collaborative filter feature extraction algorithm with improved threshold is proposed. Then, the feature information is reconstructed and sent to the SVM classifier for training. Finally, the unfiltered, collaborative filter, improved threshold collaborative filter, and Bessel filter data are, respectively, extracted and sent to the SVM classifier for classification and comparison research. The experimental results show that the improved collaborative filter algorithm has higher accuracy in single-stranded DNA molecular classification.
Fixed Point Results of a General Class of Monotone Nonexpansive Mappings in Hyperbolic Metric Spaces
Authors: Outass Rida , Chaira Karim , Marhrani El Miloudi , El Harmouchi Nour-eddine
Published: July 2020

In this paper, we introduce and study some properties of a new class of generalized monotone nonexpansive mappings in hyperbolic metric spaces. Further, we give some results on the convergence of the Mann iterative process for this class of mappings in hyperbolic ordered metric spaces with some interesting examples.
Anti‐Inflammatory Effects of Fermented Bark of Acanthopanax sessiliflorus and Its Isolated Compounds on Lipopolysaccharide‐Treated RAW 264.7 Macrophage Cells
Authors: Kim Min Ji , Wang Hye Soo , Lee Min Won
Published: July 2020

The fermentation was carried out on the bark of Acanthopanax sessiliflorus (AS). Acanthopanax species have been used in traditional medicine as tonics, sedatives, and antispasmodics. An activity‐guided isolation of the fermented bark of A. sessiliflorus (FAS) yielded several phytochemicals: acanthoside D (1), acanthoside B (2), daucosterol (3), protocatechuic acid (4), chlorogenic acid methyl ester (5), ciwujiatone (6), syringaresinol (7), farnesol (8), 3,4‐dicaffeoylquinic acid (9), and falcarindiol (10). HPLC analysis showed that content of lignan glycoside (1) was decreased and 4 and 7 were increased after fermentation. Anti‐inflammatory activities on FAS showed the decrease of nitric oxide (NO) production, and inhibitory activities of iNOS and COX‐2, proinflammatory cytokines (IL‐6 and tumor necrosis factor‐α), and collagenase. The aglycone, syringaresinol (7), which was increased through fermentation showed enhanced activity than 1. Thus, FAS may have the potential to treat inflammatory disorders, such as arthritis.
Top Quark Pair-Production in Noncommutative Standard Model
Authors: Fisli M. , Mebarki N.
Published: July 2020

The differential cross-section of the top quark pair production via the quark-antiquark annihilation subprocess in hadron collision is calculated within the noncommutative standard model. A pure NC analytical expression for the forward-backward asymmetry at the tree level is obtained. Moreover, using recent Tevatron results from the full RUN2 data, a new lower bound on the noncommutative geometry parameter is deduced.
Posttransplant Intrarenal Lymphangiectasia
Authors: Kord Ali , Benedetti Enrico , Bui James T.
Published: July 2020

Renal lymphangiectasia is an extremely rare benign condition in the setting of transplanted kidneys. We describe a 50-year-old female with a past medical history of lupus nephritis and renal transplants who presented with right lower quadrant pain and was found to have intrarenal lymphangiectasia on imaging and laboratory tests. The patient was treated with percutaneous drainage initially and then wide peritoneal fenestration and omentoplasty. An extremely rare adult case with intrarenal lymphangiectasia thirteen months after kidney transplant was described in this study. Imaging, particularly computed tomography (CT) and magnetic resonance imaging (MRI), plays a key role in the diagnosis of renal lymphangiectasia.
Effect of Surface Shape and Content of Steel Fiber on Mechanical Properties of Concrete
Authors: Zhang Lijuan , Zhao Jun , Fan Cunyuan , Wang Zhi
Published: July 2020

Steel fiber reinforced concrete (SFRC) has gained popularity in the last decades attributed to the improvement of brittleness and low tensile strength of concrete. This study investigates the effect of three shapes of steel fibers (straight, hooked end, and corrugated) with four contents (0.5%, 1%, 1.5%, and 2%) on the mechanical properties (compression, splitting tension, shear, and flexure) of concrete. Thirteen groups of concrete were prepared and investigated experimentally. Test results indicated that steel fiber had significant reinforcement on mechanical properties of concrete. When the steel fiber content increases from 0.5% to 2.0%, the compressive strengths increase about 4–24%, splitting tensile strengths increase about 33–122%, shear strengths increase about 31–79%, and flexural strengths increase about 25–111%. Corrugated steel fiber has the best reinforced effect on strength of SFRC, hooked end steel fiber takes the second place, and straight steel fiber is the least. Calculated formulas of compressive, splitting tensile, shear, and flexural strengths were established with consideration of the bonding properties between concrete and steel fiber. Influence factors of steel fiber (αf) and concrete matrix strength (αc) were put forward and determined by regression analysis of experimental data. Calculated results agree well with the experimental results.
The Role of Microfabric and Laminae on Pore Structure and Gas Transport Pathways of Marine Shales from Sichuan Basin, China
Authors: Shu Yi , Xu Shang , Yang Feng , Shu Zhiguo , Peng Pan , Huang Senxin , Zhen He
Published: July 2020

This study investigated the effects of microfabric and laminae on the pore structure and gas transport pathways of the Silurian Longmaxi shales from Sichuan Basin. 23 shale samples with varied lithofacies were comprehensively investigated by mineralogy, organic geochemistry, pycnometry, and low-pressure nitrogen adsorption analysis. The fabric and laminae of these samples were identified using petrographic microscope and scanning electron microscopy. Permeabilities were measured using the nonsteady-state method on both perpendicular and parallel to bedding shales. The effective pore diameter controlling gas transport was estimated from gas slippage factors obtained in permeability measurements. These values were also compared to those calculated using the Winland equation. Siliceous shales studied are faintly laminated to nonlaminated and have larger porosity and specific surface area. Argillaceous/siliceous mixed shales are well laminated, whereas argillaceous shales contain many oriented clay flakes along the lamination. Both porosity and surface area are positively correlated with TOC content. Unlike most conventional reservoirs, there is a negative correlation between porosity and permeability values of the samples studied. Permeabilities parallel to bedding, ranging from 0.4 to 76.6 μD, are in control of the oriented clay flakes and silty microlaminae. Permeability anisotropy values of the shales vary between 1.3 and 49.8. Samples rich in oriented clay flakes and microlaminated fabric have relatively larger permeability and permeability anisotropy values. The effective transport pore diameters derived from gas slippage measurements are slightly lower than those calculated from the Winland equation. However, both methods have shown that the effective transport pore diameters of argillaceous shales (averaging 552 nm) are significantly higher than siliceous shales (averaging 198 nm), which underlines the control of microfabric, rather than porosity, on gas transport pathways of the shales studied.
Study of Deformation Behaviors and Mechanical Properties of Central Diaphragm in a Large‐Span Loess Tunnel by the Upper Bench CD Method
Authors: Luo Yanbin , Shi Zhou , Chen Jianxun , Liu Weiwei , Li Yao , Wu Yunfei , Zhu Haoyang
Published: July 2020

The central diaphragm is often used to reduce the span to maintain the stability and safety of structure in the construction of large‐span loess tunnel due to the structure complexities. In this paper, relying on the field monitoring and measurement for Wangcun tunnel in Huangling‐Yan’an expressway expansion project, the crown settlement and horizontal convergence of primary support steel rib and central diaphragm steel rib during the construction are analyzed by the upper bench CD method. According to the internal force transfer, deformation coordination, and arch foot displacement between the two structures, the support system is regarded as the arch‐beam fixed structure with three times of statically indeterminate and movable abutment under the loads, and the mechanical calculation model of sidewall steel rib and the central diaphragm structure bearing loads and deformation together is established. Finally, through the mechanical model mentioned above, the deformation characteristics of central diaphragm structure and the horizontal convergence in the upper bench of tunnel are calculated and analyzed. The research shows the following: (1) the accumulated settlement of sidewall steel rib in Part I is greater than that of the sidewall steel rib in Part II, and the accumulated settlement of each part at the support structure during the tunnel excavation is less than the reserved deformation of 150 mm specified in the tunnel excavation; (2) the settlement located at the waist and maximum excavation line position of central diaphragm is mainly affected by the excavation of Parts I and II in upper bench; (3) during the whole excavation process, the excavation of Part I and Part II has the greatest influence on the convergence at arch waist and the maximum excavation line position in Part I, and the convergence at the above two positions all experienced four stages of “convergence‐expansion‐convergence‐gradual stability”; and (4) the errors between the horizontal convergence and the deformation of central diaphragm obtained by the mechanical model and the field monitoring data are between 12.7% and 27.5%. The calculated results are in good agreement with the actual situation. The research can provide a theoretical basis for the study of deformation and mechanical properties for support structure in the construction of large‐span loess tunnel by the upper bench CD method.
Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma
Authors: Xiao Yi , Clima Rosanna , Busch Jonas , Rabien Anja , Kilic Ergin , Villegas Sonia L. , Timmermann Bernd , Attimonelli Marcella , Jung Klaus , Meierhofer David
Published: July 2020

Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy.

Significance:

These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.
Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer
Authors: Dotan Efrat , Cardin Dana B. , Lenz Heinz-Josef , Messersmith Wells , O'Neil Bert , Cohen Steven J. , Denlinger Crystal S. , Shahda Safi , Astsaturov Igor , Kapoun Ann M. , Brachmann Rainer K. , Uttamsingh Shailaja , Stagg Robert J. , Weekes Colin
Published: July 2020

Purpose:

The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).

Patients and Methods:

Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.

Results:

A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2–4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4–18.4], median overall survival was 9.7 m (95% CI, 7.0–14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.

Conclusions:

Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.
Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (18F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer
Authors: Park Sonya Youngju , Na Sae Jung , Kumar Meena , Mosci Camila , Wardak Mirwais , Koglin Norman , Bullich Santiago , Mueller Andre , Berndt Mathias , Stephens Andrew W. , Cho Yong Mee , Ahn Hanjong , Chae Sun Young , Kim Hye Ok , Moon Dae Hyuk , Gambhir Sanjiv S. , Mittra Erik S.
Published: July 2020

Purpose:

(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a radiopharmaceutical for PET imaging of system xC− activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical.

Experimental Design:

Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of 18F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples.

Results:

18F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUVmax) for cancer was significantly higher than both normal (P < 0.005) and benign pathology (P = 0.011), while there was no significant difference between normal and benign pathology (P = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. 18F-FSPG accumulation showed moderate correlation with CD44 expression.

Conclusions:

18F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.
Genomic and Clinicopathologic Characterization ofATM-deficient Prostate Cancer
Authors: Kaur Harsimar , Salles Daniela C. , Murali Sanjana , Hicks Jessica L. , Nguyen Minh , Pritchard Colin C. , De Marzo Angelo M. , Lanchbury Jerry S. , Trock Bruce J. , Isaacs William B. , Timms Kirsten M. , Antonarakis Emmanuel S. , Lotan Tamara L.
Published: July 2020

Purpose:

The ATM (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and ATM mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized.

Experimental Design:

We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline ATM mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes.

Results:

ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic ATM inactivation. In a separate cohort with pathogenic germline ATM mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; P < 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic ATM alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables.

Conclusions:

ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.
A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors
Authors: Tolaney Sara M. , Do Khanh T. , Eder Joseph P. , LoRusso Patricia M. , Weekes Colin D. , Chandarlapaty Sarat , Chang Ching-Wei , Chen Shang-Chiung , Nazzal Denise , Schuth Eva , Brunstein Flavia , Carrasco-Triguero Montserrat , Darbonne Walter C. , Giltnane Jennifer M. , Flanagan William M. , Commerford S. Renee , Ungewickell Alexander , Shapiro Geoffrey I. , Modi Shanu
Published: July 2020

Purpose:

DLYE5953A is an antibody–drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors.

Patients and Methods:

This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies.

Results:

Sixty-eight patients received DLYE5953A (median, four cycles; range, 1–27). No dose-limiting toxicities were identified during dose escalation (0.2–2.4 mg/kg; n = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; n = 23) and non–small cell lung cancer (NSCLC; n = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg (n = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients.

Conclusions:

DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target.
A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer
Authors: Aggarwal Rahul R. , Schweizer Michael T. , Nanus David M. , Pantuck Allan J. , Heath Elisabeth I. , Campeau Eric , Attwell Sarah , Norek Karen , Snyder Margo , Bauman Lisa , Lakhotia Sanjay , Feng Felix Y. , Small Eric J. , Abida Wassim , Alumkal Joshi J.
Published: July 2020

Purpose:

ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods:

Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).

Results:

Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).

Conclusions:

ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial)
Authors: Kawazoe Akihito , Kuboki Yasutoshi , Shinozaki Eiji , Hara Hiroki , Nishina Tomohiro , Komatsu Yoshito , Yuki Satoshi , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Kuwata Takeshi , Kawazu Masahito , Mano Hiroyuki , Togashi Yosuke , Nishikawa Hiroyoshi , Yoshino Takayuki
Published: July 2020

Purpose:

This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).

Patients and Methods:

Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite stable, MSS). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles, and the consensus molecular subtypes (CMS) of colorectal cancer were assessed.

Results:

A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.

Conclusions:

Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.

See related commentary by Nusrat, p. 5775
Delayed Diagnosis in Pulmonary Embolism: Frequency, Patient Characteristics, and Outcome
Authors: Mansella Gregory , Keil Christoph , Nickel Christian H. , Eken Ceylan , Wirth Christian , Tzankov Alexandar , Peterson Caspar Joyce , Aujesky Drahomir , Bingisser Roland
Published: July 2020

Background: The incidence and the outcomes of pulmonary embolism (PE) missed during emergency department (ED) workup are largely unknown. Objectives: To describe the frequency, demographics, and outcomes of patients with delayed diagnosis of PE. Methods: We retrospectively compared patients diagnosed with PE during ED workup (early diagnosis) with patients diagnosed with PE thereafter (delayed diagnosis). Electronic health records (EHR) of 123,560 consecutive patients who attended a tertiary hospital ED were screened. Data were matched with radiology and pathology results from the EHR. Results: Of 1,119 patients presenting to the ED with early workup for PE, PE was diagnosed in 182 patients (80.5%) as early diagnosis. Delayed diagnosis was established in 44 cases (19.5%) using radiology and/or autopsy data. Median age of patients with early diagnosis was significantly lower as compared to delayed diagnosis (67 vs. 77.5 years). Main symptoms were dyspnea (109 patients [59.9%] in early, 20 patients [45.5%] in delayed diagnosis), chest pain (90 patients [49.5%] in early, 8 patients [18.2%] in delayed diagnosis), and nonspecific complaints (16 patients [8.8%] in early, 13 patients [29.5%] in delayed diagnosis). In-hospital mortality was 1.6% in early diagnosis and 43.2% in delayed diagnosis. Conclusions: Delayed diagnosis of PE carries a worse prognosis than early diagnosis. This discrepancy may arise from either delayed therapy, confounding variables (e.g., older age), or both. Possible reasons for delayed diagnoses are nonspecific presentations and symptoms overlapping with preexisting conditions.