bluuebunny/crossref_metadata_2025 huggingface dataset:
Parascapular Sub‐Iliocostalis Plane Block: Comparative Description of a Novel Technique for Posterior Rib Fractures
Authors: Almeida Carlos Rodrigues
Published: February 2021

We describe a new analgesic technique, parascapular sub‐iliocostalis plane block (PSIP), for lateral‐posterior rib fractures as an alternative to other regional techniques in a high‐risk patient who suffered a decompensation of her cardiorespiratory function after posterior chest trauma. We performed a continuous ultrasound‐guided left PSIP block in the sub‐iliocostalis plane next to the fourth rib to optimize analgesia and minimize complications. The patient had total pain relief with marked improvement in her cardiorespiratory condition. No complications were reported. The efficacy of the PSIP block may potentially depend on different mechanisms of action: (1) direct action in the fracture site by craniocaudal myofascial spread underneath the erector spinae muscle (ESM); (2) spread to deep layers through tissue disruption caused by trauma, to reach the proximal intercostal nerves; (3) further medial spread through deeper layers to the midline to block the posterior and ventral spinal nerves; (4) medial spread below the ESM, to reach the posterior spinal nerves (more reliably than rhomboid intercostal / sub‐serratus [RISS] block); and (5) lateral spread in the sub‐serratus (SS) plane to reach the lateral cutaneous branches of the intercostal nerves; while avoiding significant negative hemodynamic effects associated with techniques such as the paravertebral block (PVB), erector spinae plane (ESP) block or its variations, or thoracic epidural analgesia (TEA). A comparative comprehensive overview of the regional techniques described for posterior chest trauma is presented, including TEA, PVB, ESP block, retrolaminar block, mid‐point to transverse process block, costotransverse foramen block, RISS, and serratus anterior plane (SAP) block.
A statistical protocol to describe differences among nutrient utilization patterns of Fusarium spp. and Trichoderma gamsii
Authors: Lasinio Giovanna Jona , Pollice Alessio , Pappalettere Livia , Vannacci Giovanni , Sarrocco Sabrina
Published: February 2021

The Biolog phenotype microarrays (PM) system offers a simple and cheap tool to rapidly provide a high throughput of information about the phenotypes of fungal isolates in a short time. In order to improve the use of the PM system in fungal ecology studies, the present work proposes a new statistical protocol based on two approaches, that is, a functional principal components analysis to describe similarity patterns of growth curves, and a Bayesian generalized additive model (GAM) to allow inferences on specific growth features, in order to analyse nutrient fungal utilization in a model system including four causal agents of Fusarium head blight, the natural competitor Fusarium oxysporum, and the beneficial isolate Trichoderma gamsii T6085. Analysis of data collected by the Biolog PM in our biological system showed a different nutritional competitive potential of the four pathogens, as well as an intermediate behaviour of the natural competitor and of our biocontrol agent. This protocol, applicable to different fungal phenotypical studies at both isolate and community level, allows a full exploitation of data obtained by the PM system and provides important information about the nutritional pattern of a single isolate compared to those of other fungi, a key factor to be exploited in biocontrol strategies.
A prospective, observational study to compare effect of DTT treatment and heat inactivation on ABO isoagglutinin titers in O blood group donors
Authors: Pandey Prashant , Setya Divya , Ranjan Shweta , Singh Mukesh Kumar
Published: February 2021

Background and aims

In order to determine actual concentration of clinically significant IgG antibodies, there is a need to inactivate IgM antibodies, which can be performed by DTT or heat. The aim of the present study was to compare the effect of DTT treatment and heat inactivation (HI) on ABO isoagglutinin titres performed by column agglutination technology (CAT) and conventional tube technique (CTT).

Materials and methods

This was a prospective, observational study conducted from October 2018 to March 2020. All consecutive O group donors were included. Serum from each donor was treated with DTT, and heat and tests were performed by CTT and CAT before and after treatment.

Results

A total of 2005 donors were included. 401 (20%) samples had inter‐observer variation by CTT, and 69 (3·4%) had inter‐observer variation by CAT. Median anti‐A and anti‐B titre results were higher with CAT as compared to CTT. Median anti‐A and anti‐B IgG titre results showed a one‐ to twofold difference between CTT and CAT with higher titres reported by CAT. Median IgM titres decreased two‐ to threefold after DTT treatment, whereas onefold decrease was confirmed after HI. Concordance was found to be poor. However, correlation was found to be strong.

Conclusion

There is overestimation of ABO IgG antibody titres and hence, estimation of ABO IgG titres after inactivation of IgM antibodies is strongly recommended. DTT treatment was found to be superior to HI in terms of efficiency in elimination of IgM activity.
Malle's conjecture for for
Authors: Wang Jiuya
Published: February 2021

We propose a framework to prove Malle's conjecture for the compositum of two number fields based on proven results of Malle's conjecture and good uniformity estimates. Using this method, we prove Malle's conjecture for $S_n\times A$ over any number field $k$ for $n=3$ with $A$ an abelian group of order relatively prime to 2, for $n= 4$ with $A$ an abelian group of order relatively prime to 6, and for $n=5$ with $A$ an abelian group of order relatively prime to 30. As a consequence, we prove that Malle's conjecture is true for $C_3\wr C_2$ in its $S_9$ representation, whereas its $S_6$ representation is the first counter-example of Malle's conjecture given by Klüners. We also prove new local uniformity results for ramified $S_5$ quintic extensions over arbitrary number fields by adapting Bhargava's geometric sieve and averaging over fundamental domains of the parametrization space.
A Hyper-Ellipsoid Approach for Inverse Lack-of-Knowledge Uncertainty Quantification
Authors: Ludwig Norbert , Duddeck Fabian , Daub Marco
Published: February 2021

This paper presents a novel methodology to solve an inverse uncertainty quantification problem where only the variation of the system response is provided by a small set of experimental data. Furthermore, the method is extended for cases where the uncertainty of the response quantities is given by an incomplete set of statistical moments. For both cases, the uncertainty on the output space is represented by a minimum volume enclosing ellipsoid (MVEE). The actual inverse uncertainty quantification is conducted by identifying also a hyper-ellipsoid for the input parameters, which has an image on the output space that matches the MVEE as close as possible. Hence, the newly introduced approach is a contribution to the field of nonprobabilistic uncertainty quantification methods. Compared to literature, the new approach has often superior accuracy and especially an improved efficiency for high-dimensional problems. The method is validated first by an analytical test case and subsequently applied to a jet engine performance model, where this type of inverse uncertainty quantification has to be solved to allow for a consistent and integrated solution procedure. In both cases, the results are compared with an inverse method where the variability on the input side is quantified by a multidimensional interval. It can be shown that the hyper-ellipsoid approach is superior with respect to the computation time in high-dimensional problems encountered not only in jet engine design.
Shell Buckling With Polymorphic Uncertain Surface Imperfections and Sensitivity Analysis
Authors: Fina Marc , Panther Lukas , Weber Patrick , Wagner Werner
Published: February 2021

In a probabilistic design approach for cylindrical shells, Gaussian random fields are used to simulate geometric imperfections. The shape of imperfections depends, among others, on the autocorrelation properties of the random field. Underlying uncertainties such as a small sample size or imprecise measurements make it practically impossible to define a crisp correlation function. For a more realistic description of the imprecise correlation structure, the classical probabilistic approach is extended to a fuzzy stochastic approach. More exactly, the polymorphic uncertainty approach is used taking into account natural variability and incompleteness. Consequently, geometric imperfections are represented as fuzzy probability based random fields. Therefore, the required correlation parameters are described as polymorphic uncertain parameters. The quantification of uncertainties is demonstrated on real data. Furthermore, the polynomial chaos surrogate model is used for the alpha-level optimization in the fuzzy analysis. The sensitivity indices as a by-product of the surrogate model show the influence of the input parameters on the statistical parameters of the critical buckling load factor. The main purpose of this paper is to show how the presented methods can support the design process of cylindrical shells.
Sensitivity Analysis of Epistemic Uncertainty on Input Parameters and System Structure Using Dempster-Shafer Theory
Authors: Hou Yunhui
Published: February 2021

In this article, a method is proposed to conduct a global sensitivity analysis of epistemic uncertainty on both system input and system structure, which is very common in early stage of system development, using Dempster-Shafer theory (DST). In system reliability assessment, the input corresponds to component reliability and system structure is given by system reliability function, cut sets, or truth table. A method to propagate real-number mass function through set-valued mappings is introduced and applied on system reliability calculation. Secondly, we propose a method to model uncertain system with multiple possible structures and how to obtain the mass function of system level reliability. Finally, we propose an indicator for global sensibility analysis. Our method is illustrated, and its efficacy is proved by numerical application on two case studies.
To Study the Effect of Microstructures on Machinability of Inconel-718 Superalloy in Micro-Drilling Process
Authors: Singh Shashi Ranjan , Vasavada Jitesh , Mote Rakesh Ganpat , Mishra Sushil Kumar
Published: February 2021

Nickel-based superalloys have been extensively used in the aerospace industry due to their excellent mechanical properties at elevated temperatures. The mechanical properties of the Inconel-718 majorly depend on its microstructure which can be controlled using thermomechanical treatments. Machining of the heat-treated Inconel-718 component is very difficult due to very high hardness. This paper investigates the relationship between the material microstructure developed through a thermomechanical process and the machinability through micro-drilling of Inconel-718. In this study, a wide range of microstructures with hardness ranging from 179 HV to 461 HV was achieved by different thermomechanical and heat-treatment processes. Flank wear, thrust force, and burr height analysis were carried out to understand the machining behavior after micro-drilling. Electron back scattered diffraction (EBSD) technique was used to characterize the microstructure. No correlation between grain size and thrust force was observed. However, a clear trend between thrust force and hardness was established. It was also observed through misorientation analysis that the machined surface deforms significantly with material hardness.
Early Detection of Fatigue Crack Damage in Ductile Materials: A Projection-Based Probabilistic Finite State Automata Approach
Authors: Bhattacharya Chandrachur , Dharmadhikari Susheel , Basak Amrita , Ray Asok
Published: February 2021

Fatigue failure occurs ubiquitously in mechanical structures when they are subjected to cyclic loading well below the material’s yield stress. The tell-tale sign of a fatigue failure is the emergence of cracks at the internal or surface defects. In general, a machinery component has a finite fatigue life based on the number of cycles, it can sustain before a fracture occurs. However, the estimated life is generally conservative and often a large factor of safety is applied to make the component fail-safe. From the perspective of better utilization of a machinery component, it is, however, desirable to have maximum usage of the component without a catastrophic failure. It is, therefore, conducive to have a measure that can capture precursors to failure to facilitate active diagnosis of the machinery health. In this study, a precursor detection method is developed upon modifications of probabilistic finite state automata (PFSA). The efficacy of the proposed method is demonstrated on cold-rolled AL7075-T6 notched specimens in a computer-instrumented and computer-controlled fatigue testing apparatus. The results show that the proposed method is capable of detecting the emergence of cracks (at ∼95% accuracy) and also can capture precursors with good fidelity.
Stationary Shoulder Friction Stir Assisted Scribe Technique for Dissimilar Joining
Authors: Das Hrishikesh , Upadhyay Piyush
Published: February 2021

We report on implementation of a stationary shoulder in dissimilar joints of Al-steel and Al-carbon fiber reinforced polymer (CFRP) using friction stir assisted scribe technology (FaST). Viable joint strength similar to the conventional FaST process was demonstrated in Al-Steel. A significant improvement in as-welded surface roughness for both Al-steel and Al-CFRP cases was also achieved. Interrupted lap shear tests performed on Al-steel joints and a corresponding computational model indicate the joint failure typically occurs in Al sheet via a crack that originates at the steel hook tip on the loading side. A similar fracture path was observed in an Al-CFRP joint.
A Receding-Horizon Framework for Co-Optimizing the Velocity and Power-Split of Automated Plug-In Hybrid Electric Vehicles
Authors: Chen Di , Huang Mike , Stefanopoulou Anna , Kim Youngki
Published: February 2021

This paper presents a control framework to co-optimize the velocity and power-split operation of a plug-in hybrid vehicle (PHEV) online in the presence of traffic constraints. The principal challenge in its online implementation lies in the conflict between the long control horizon required for global optimality and limits in available computational power. To resolve the conflict between the length of horizon and its computation complexity, we propose a receding-horizon strategy where co-states are used to approximate the future cost, helping to shorten the prediction horizon. In particular, we update the co-state using a nominal trajectory and the temporal-difference (TD) error based on co-state dynamics. Our simulation results demonstrate a 12% fuel economy improvement over the sequential/layered control strategy for a given driving scenario. Moreover, its real-time practicality is evidenced by a computation time per model predictive controller (MPC) step on average of around 80 ms within a 10 s prediction horizon.
Design and Development of a Mobile Platform Mimicking Skating With Continuous Contact
Authors: Gupta Varan , Kumar Rajesh , Agarwal Shantnav , Kar Indra N. , Khatait Jitendra P.
Published: February 2021

This paper describes skating locomotion in a straight line based on continuous contact of rollers with the surface. Two skates traverse in and out while changing their orientation. Net traction force is generated because of no-slip conditions of rollers at the contact. The two skates are in continuous contact with the surface and therefore the balancing problem is circumvented. Different designs are developed and evaluated in order to replicate the desired motion. A heuristic-based architecture is developed to move the robot in a straight line.
Kinetostatic Modeling of Planar Compliant Mechanisms With Flexible Beams, Linear Sliders, Multinary Rigid Links, and Multiple Loops
Authors: Chi I-Ting , Chang Pei-Lun , Tran Ngoc Dang Khoa , Wang Dung-An
Published: February 2021

This paper presents kinetostatic models of planar compliant mechanisms with multinary rigid links, multinary joints, sliders, and multiple loops based on the chained beam constraint model. The focus is on modeling of several building blocks of the beam type compliant mechanisms to aid in their design. The modeling approaches are based on the loop-closure equations and the static equilibrium conditions. Models of the multinary rigid links, multinary joints, and sliders are presented. As a result, the kinetostatic models of the compliant mechanisms can be systematically formulated by using these building blocks. Several mechanisms constructed by the building blocks are modeled and verified by finite element analyses. A case study is provided to demonstrate the application of the developed models. These models pave the way for versatile applications of the chained beam constraint model for the design and analysis of beam type planar compliant mechanisms.
Synthesis of Watt-Type Timed Curve Generators and Selection From Continuous Cognate Spaces
Authors: Baskar Aravind , Plecnik Mark
Published: February 2021

Following recent work on Stephenson-type mechanisms, the synthesis equations of Watt six-bar mechanisms that act as timed curve generators are formulated and systematically solved. Four variations of the problem arise by assigning the actuator and end effector onto different links. The approach produces exact synthesis of mechanisms up to eight precision points. Polynomial systems are formulated and their maximum number of solutions is estimated using the algorithm of random monodromy loops. Certain variations of Watt timed curve generators possess free parameters that do not affect the output motion, indicating a continuous space of cognate mechanisms. Packaging compactness, clearance, and dimensional sensitivity are characterized across the cognate space to illustrate trade-offs and aid in selection of a final mechanism.
Modeling and Simulation of a Vertical Multi-Effect Diffusion Solar Still Coupled With a Tracking Solar System and a PV/T-SWH System
Authors: Boubekri M. , Chaker A. , Saadi S.
Published: February 2021

This paper aims to study the productivity of a vertical multi-effect diffusion solar still (VMEDSS) coupled with a solar tracking system and a photovoltaic/thermal solar water heater system (PV/T-SWH). The studied system can run continuously over 24 h to have a continuous production. The experimental climatic conditions of Ksar Challala (35 deg 13′ 12.835″ N, 2 deg 19′ 2.035″ E, Altitude: 800 m) in Algeria are used in this study, for 2 days: one in summer and one in winter. The obtained results were compared with those of the vertical still oriented southward. The results show clearly the effect of the solar tracking system on the increase of the still production during summer and winter. The production percentage increase has reached: 293.01% in summer and 15.1% in winter. Feeding the still equipped with a tracking system with hot water produced by the PV/T-SWH system gives good productivities during summer and winter where the increase in production reaches, respectively, 733.76% and 415.55%. The percentage production growth of the vertical still oriented southward fed with hot water is 376.38% and 394.78% of the days of summer and winter, respectively.
Anaerobic Threshold Prediction Using the OMNI-Walk/Run Scale in Long-Distance Runners: A Preliminary Study
Authors: Campos Yuri de Almeida Costa , Vianna Jeferson M. , Guimarães Miller P. , Souza Hiago L.R. , Domínguez Raúl , Novaes Jefferson S. , Leitão Luis F.M. , Silva Sandro F. , Reis Victor M.
Published: February 2021

Purpose: To identify the anaerobic threshold through the lactate threshold determined by Dmax and rating of perceived exertion (RPE) threshold by Dmax and to evaluate the agreement and correlation between lactate threshold determined by Dmax and RPE threshold by Dmax during an incremental test performed on the treadmill in long-distance runners. Methods: A total of 16 long-distance runners volunteered to participate in the study. Participants performed 2 treadmill incremental tests for the collection of blood lactate concentrations and RPE separated by a 48-hour interval. The incremental test started at 8 km·h−1, increasing by 1.2 km·h−1 every third minute until exhaustion. During each stage of the incremental test, there were pauses of 30 seconds for the collection of blood lactate concentration and RPE. Results: No significant difference was found between methods lactate threshold determined by Dmax and RPE threshold by Dmax methods (P = .664). In addition, a strong correlation (r = .91) and agreement through Bland–Altman plot analysis were found. Conclusions: The study demonstrated that it is possible to predict anaerobic threshold from the OMNI-walk/run scale curve through a single incremental test on the treadmill. However, further studies are needed to evaluate the reproducibility and objectivity of the OMNI-walk/run scale for anaerobic threshold determination.
Influence of Game Design, Physical Demands, and Skill Involvement on the Subjective Task Load Associated With Various Small-Sided Games Among Elite Junior Rugby League Players
Authors: Dobbin Nick , Atherton Anthony , Hill Colin
Published: February 2021

Purpose: To determine if small-sided games (SSGs) could be designed to target specific task loads using the National Aeronautics and Space Administration task load index as well as reporting the influence of the physical and technical demands. Methods: Using a within-session, repeated-measures design, 26 junior rugby league players completed 5 SSGs focused on physical, technical, temporal, cognitive, and frustration task loads. National Aeronautics and Space Administration task load index responses were evaluated after each game; the physical demands were recorded using microtechnology; and skill involvement recorded using video analysis. Results: In each SSG, the task load emphasized (eg, physical load/physical game) emerged with a higher score than the other loads and SSGs. The physical demands were lowest during the physical game (effect size = −3.11 to 3.50) and elicited greater defensive involvements (effect size = 0.12 to 3.19). The highest physical demands and attacking involvements were observed during the temporal game. Lower intensity activities were generally negatively associated with physical, performance, temporal, and total load (η2 = −.07 to −.43) but positively associated with technical, effort, cognitive, and frustration (η2 = .01 to .33). Distance covered in total and at higher speeds was positively associated with physical, effort, performance, total load (η2 = .18 to .65), and negatively associated with technical, frustration, and cognitive load (η2 = −.10 to −.36). Attacking and defensive involvements generally increased the respective task loads (η2 = .03 to .41). Conclusion: Coaches and sport scientists can design SSGs specifically targeted at subjective task loads in a sport-specific manner and through manipulation of the physical and technical demands.
Localization of Bacterial Communities within Gut Compartments acrossCephalotesTurtle Ants
Authors: Flynn Peter J. , D’Amelio Catherine L. , Sanders Jon G. , Russell Jacob A. , Moreau Corrie S.
Published: February 2021

Gut compartments play an important role in structuring the microbial community within individual ants. The gut chambers of the turtle ant digestive tract differ remarkably in symbiont abundance and diversity.
Rift Valley Fever: a Threat to Pregnant Women Hiding in Plain Sight?
Authors: McMillen Cynthia M. , Hartman Amy L.
Published: February 2021

The potential for emerging mosquito-borne viruses to cause fetal infection in pregnant women was overlooked until the Zika fever outbreak several years ago. Rift Valley fever virus (RVFV) is an emerging arbovirus with a long history of fetal infection and death in pregnant livestock.
Molecular Signatures of Inflammatory Profile and B-Cell Function in Patients with Severe Fever with Thrombocytopenia Syndrome
Authors: Park Angela , Park Su-Jin , Jung Kyle L. , Kim Se Mi , Kim Eun-Ha , Kim Young-Il , Foo Suan-Sin , Kim Sunghyun , Kim Seong-Gyu , Yu Kwang-Min , Choi Younho , Kim Ji Yeun , Baek Yun Hee , Song Min-Suk , Kim Seung Ryul , Kim Seok-Yong , Jeong Hye Won , Kim Sung-Han , Jung Jae U. , Choi Young Ki
Published: February 2021

SFTSV is an emerging virus discovered in China in 2009; it has since spread to other countries in East Asia. Although the fatality rates of SFTSV infection range from 5.3% to as high as 27%, the mechanisms underlying clinical manifestations are largely unknown.
How Phagocytic Cells Kill Different Bacteria: a Quantitative Analysis Using Dictyostelium discoideum
Authors: Jauslin Tania , Lamrabet Otmane , Crespo-Yañez Xenia , Marchetti Anna , Ayadi Imen , Ifrid Estelle , Guilhen Cyril , Leippe Matthias , Cosson Pierre
Published: February 2021

Phagocytic cells ingest and kill bacteria, a process essential for the defense of the human body against infections. Many potential killing mechanisms have been identified in phagocytic cells, including free radicals, toxic ions, enzymes, and permeabilizing peptides.
HBV Core Protein Is in Flux between Cytoplasmic, Nuclear, and Nucleolar Compartments
Authors: Nair Smita , Zlotnick Adam
Published: February 2021

HBV is an endemic virus. More than 250 million people suffer from chronic HBV infection and about 800,000 die from HBV-associated disease each year.
Chaperone-Mediated Stress Sensing in Mycobacterium tuberculosis Enables Fast Activation and Sustained Response
Authors: Rao Satyajit D. , Datta Pratik , Gennaro Maria Laura , Igoshin Oleg A.
Published: February 2021

Gene regulatory networks controlling stress response in mycobacterial species have been linked to persistence switches that enable bacterial dormancy within a host. However, the mechanistic basis of switching and stress sensing is not fully understood.
Production and Excretion of Polyamines To Tolerate High Ammonia, a Case Study on Soil Ammonia-Oxidizing Archaeon “
Candidatus
Nitrosocosmicus agrestis”
Authors: Liu Liangting , Liu Mengfan , Jiang Yiming , Lin Weitie , Luo Jianfei
Published: February 2021

Ammonia tolerance of AOA is usually much lower than that of the AOB, which makes the AOB rather than AOA a predominant ammonia oxidizer in agricultural soils, contributing to global N
2
O emission. Recently, some AOA species from the genus “
Ca.
Nitrosocosmicus” were also found to have high ammonia tolerance.
Quantifying Live Microbial Load in Human Saliva Samples over Time Reveals Stable Composition and Dynamic Load
Authors: Marotz Clarisse , Morton James T. , Navarro Perris , Coker Joanna , Belda-Ferre Pedro , Knight Rob , Zengler Karsten
Published: February 2021

Human microbiomes are dynamic ecosystems often composed of hundreds of unique microbial taxa. To detect fluctuations over time in the human oral microbiome, we developed a novel workflow to quantify live microbial cells with flow cytometry in parallel with next-generation sequencing, and applied this method to over 150 unstimulated, timed saliva samples.
The
Azospirillum brasilense
Core Chemotaxis Proteins CheA1 and CheA4 Link Chemotaxis Signaling with Nitrogen Metabolism
Authors: Ganusova Elena E. , Vo Lam T. , Abraham Paul E. , O’Neal Yoder Lindsey , Hettich Robert L. , Alexandre Gladys
Published: February 2021

Bacterial chemotaxis is widespread in bacteria, increasing competitiveness in diverse environments and mediating associations with eukaryotic hosts ranging from commensal to beneficial and pathogenic. In most bacteria, chemotaxis signaling is tightly linked to energy metabolism, with this coupling occurring through the sensory input of several energy-sensing chemoreceptors.
Human Milk-Fed Piglets Have a Distinct Small Intestine and Circulatory Metabolome Profile Relative to That of Milk Formula-Fed Piglets
Authors: Rosa Fernanda , Matazel Katelin S. , Elolimy Ahmed A. , Adams Sean H. , Bowlin Anne , Williams Keith D. , Bode Lars , Yeruva Laxmi
Published: February 2021

Exclusive HM feeding for newborns is recommended at least for the first 6 months of life. However, when breastfeeding is not possible, MF is recommended as a substitute.
Using web-based technology to improve depression screening in primary care settings
Authors: Jeffrey Jessica , Do Minh-Chau T , Hajal Nastassia , Lin Yu-Hsiang , Linonis Rachel , Grossman Mark S , Lester Patricia E
Published: February 2021

Background

Given the high rates at which patients present with behavioural health (BH) concerns in primary care (PC), this setting has become the de facto mental health system. As a result, screening for depression and other BH conditions in PC has become a critical target for improving patient outcomes. However, integration of screening into busy PC workflows can be challenging due to barriers such as limited time and resources.

Methodology

A digital, cloud-based BH assessment tool, which included electronic health record enhancements, was developed and implemented in two urban PC practices as a prelude to a planned larger-scale implementation. The implementation strategies included a reorganisation of workflows within the PC setting, comprehensive training for staff and PC physicians, and institution of an incentive programme for PC clinic managers. To examine whether the introduction of the cloud-based BH assessment tool and associated implementation strategies was associated with increased screening rates, we compared rates of screening from January through June 2017 to rates of screening from January through June 2018 (subsequent to implementation). We also examined BH symptomatology reported by patients in PC.

Results

Following the implementation process, rate of BH screening with Patient Health Questionnaire-2 (PHQ-2) increased from 50.5% to 57% (p<0.00000000000000022) and rates of subsequent screening with PHQ-9, for those scoring at risk, defined as a score of ≥1, on PHQ-2, increased from 34.5% to 91.4% (p<0.00000000000000022). Additionally, high rates of ‘moderate’ and ‘severe’ symptoms of depression (40.3%), anxiety (42.6%) and substance use (26.7% alcohol; 31.2% other substance use) were observed among PC patients.

Conclusions

Results suggest that a comprehensive implementation plan, including digitisation of BH assessment, reduced the burden of systematic screening. High rates of BH symptomatology underscore the need for comprehensive BH assessment and systems planning to address the high need for BH services among PC patients.
Prognostic significance of BMI after PCI treatment in ST-elevation myocardial infarction: a cohort study from the Swedish Coronary Angiography and Angioplasty Registry
Authors: Jamaly Shabbar , Redfors Bjorn , Omerovic Elmir , Carlsson Lena , Karason Kristjan
Published: February 2021

Background

Obesity along with clustering of cardiovascular risk factors is a promoter for coronary artery disease. On the other hand, a high body mass index (BMI) appears to exert a protective effect with respect to outcomes after a coronary artery event, termed the obesity paradox.

Methods

The Swedish Coronary Angiography and Angioplasty Registry collects information on all patients who undergo percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) in Sweden along with demographic and procedure-related data. We studied the predictability of four categories of BMI for 1-year all-cause mortality in people with STEMI undergoing PCI.

Results

Among 25 384 patients, mean (SD) age 67.7 (12.1) years and 70.2% male, who underwent PCI for STEMI, a total of 5529 (21.8%) died within 1 year. Using normal weight (BMI 18.5–24.9 kg/m2) as a reference, subjects with obesity (BMI ≥30 kg/m2) had a low 1-year all-cause mortality risk in unadjusted analysis, HR 0.59 (95% CI 0.53 to 0.67). However, after adjustment for age, sex and other covariates, the difference became non-significant, HR 0.88 (95% CI 0.75 to 1.02). Patients with overweight (BMI 25.0–29.9 kg/m2) had the lowest 1-year mortality risk in analysis adjusted for age, sex and other covariates, HR 0.87 (95% CI 0.79 to 0.97), whereas those with underweight (BMI <18.5 kg/m2) had the highest mortality in both unadjusted HR 2.22 (95% CI 1.69 to 2.92) and adjusted analysis, HR 1.62 (95% CI 1.18 to 2.23).

Conclusion

The protective effect of obesity with respect to 1-year mortality after coronary intervention became non-significant after adjusting for age, sex and relevant covariates. Instead, overweight people displayed the lowest risk and underweight individuals the highest risk for adjusted all-cause mortality.

Trial registration number

NCT02311231.
Volcaniclastic deposit (tonstein) in the Balcomie Beds, Lower Carboniferous, East Fife
Authors: Batchelor Richard A.
Published: February 2021

A volcanogenic clay bed (tonstein) has been identified in the Balcomie Beds of the Inverclyde Group near Crail, East Fife. Its chemical composition suggests an undersaturated alkaline magma source. This horizon may be contemporaneous with the early Carboniferous Garleton Hills trachytic lavas of East Lothian (346 Ma). This would make it the earliest expression of Carboniferous volcanism preserved in Fife, and also the earliest occurrence of a tonstein in Fife.
Adaptive Therapy and the Cost of Drug-Resistant Mutants
Authors: Wodarz Dominik
Published: February 2021

The concept of adaptive cancer therapy proposes that the use of drugs at less than maximum tolerated dose can provide clinical benefits by allowing persisting drug-sensitive cells to competitively suppress drug-resistant cells; this can delay the outgrowth of these cell clones. The adaptive therapy concept has been developed with mathematical models and has subsequently been explored in clinical trials with promising results. In studies performed so far, a fitness cost of drug-resistant cells has been invoked for this treatment approach to be beneficial. In new work, it is shown that a clinical benefit can be achieved even in the absence of a fitness cost for resistant cells, which broadens the applicability of adaptive therapy.

See related article by Strobl et al., p. 1135
Abstract OT-28-06: A phase 1, first in human study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor in subjects with HER2 overexpressing solid tumors
Authors: Grover Natalie , Barton Debora , Ronczka Amy , Bauml Joshua
Published: February 2021

Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into and more abundantly present in the tumor microenvironment (TME) as compared to T cells. Tumor- associated macrophages (TAMs), typically evince immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR confers on the macrophages the ability to selectively recognize and phagocytose antigen overexpressing cancer cells. CAR macrophages can also potentially interact with, stimulate, and present neoantigens to T cells. Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in many cancers, including but not limited to breast and gastroesophageal cancers (Table 1). CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. In vitro and in vivo studies have shown that CT-0508 leads to cancer cell phagocytosis sparing normal cells, decreased tumor burden and prolonged survival. CT-0508 cells were safe in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. This is a FIH Phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 on approximately 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 who have failed available therapies including anti-HER2 therapies when indicated.Filgrastim, will be used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. CT-0508 cell product will be manufactured, prepared and cryopreserved. Group 1 will receive CT-0508 infusion split over D1, 3 and 5. Subjects will be continually assessed for acute and cumulative toxicity. Dose limiting toxicities will be observed and addressed by a Safety Review Committee. Group 2 will receive the full CT-0508 infusion on D1. Pre and post treatment biopsies and blood samples will be collected to investigate correlates of trafficking, persistence, TME modulation, immune response and safety.

Citation Format: Natalie Grover, Debora Barton, Amy Ronczka, Joshua Bauml. A phase 1, first in human study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor in subjects with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-06.
Abstract PD10-04: Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens
Authors: Viansone Alessandro , Omarini Claudia , Boggiani Daniela , Sikokis Angelica , Uliana Vera , Pellegrino Benedetta , Piacentini Federico , Michiara Maria , Musolino Antonino
Published: February 2021

Background: HER2-amplified breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinico-histological characteristics and prognosis of this subgroup of patients. Materials and Methods: Using a retrospective matched cohort design, we collected data from 728 women who were diagnosed with breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinical and histological characteristics of the primary tumor, time to relapse, and survival were analyzed by BRCA and HER2 status. Results: One hundred and twenty HER2-positive, BRCA mutated cases were evaluated with respect to three control groups: HER2-positive, BRCA wild-type (n=136); HER2-negative, BRCA-mutated (n=226); HER2-negative, BRCA wild-type (n=246). Breast cancers with hormone receptor-negative status or high histologic grade (odds ratio=1.7; 95% confidence interval [CI]: 1.0-2.9) were more likely HER2-positive, with no restriction by BRCA mutation status. Disease-free and overall survival for HER2-positive, BRCA mutated cases were lower than those for the other subgroups. An interaction between BRCA mutations and HER2-positive status was found for poorer overall survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Germline BRCA mutations confer worse prognosis in patients with HER2-positive breast cancer. Ongoing trials testing novel therapeutic approaches (e.g. anti-HER2 therapies combined with PARP inhibitors) are warranted.

Citation Format: Alessandro Viansone, Claudia Omarini, Daniela Boggiani, Angelica Sikokis, Vera Uliana, Benedetta Pellegrino, Federico Piacentini, Maria Michiara, Antonino Musolino. Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-04.
Abstract PD15-02: Cx3cl1-cx3cr1 axis in liver metastasis of triple negative breast cancer
Authors: Heo Woohang , Son Hye-Youn , Kim Ju hee , Lee Kyu Jin , Jeon Myeonghee , Li Songbin , Jang Jeehee , Noh Dong-Young , Han Wonsik , Moon Hyeong-Gon
Published: February 2021

Triple negative breast cancer (TNBC) is a breast cancer subtype with increased risk of distant metastasis, especially to visceral organs. However, the detailed molecular mechanism underlying the visceral metastasis of TNBC is unknown. We used three patient-derived xenograft models derived from TNBC tumors with different metastatic capacities. PDX1 and PDX2 model developed distant metastasis in only lung and liver, respectively. In contrast, PDX3 tumor metastasized to both lung and liver. RNA sequencing of the primary tumor and distant metastatic sites of these three PDX models was performed. The gene expression profiles of the primary tumors of the three models showed minimally overlapping genes. However, the microenvironment gene expression profiles, measured by using the sequencing reads aligned to mouse genome, showed distinct difference between the models. Among the differentially expressed genes, we identified Cx3cr1 as a significantly upregulated gene in the liver microenvironment of the PDX models that metastasized to liver. Next, we used 4T1 syngeneic mouse mammary carcinoma model to validate the Cx3cr1 in the mouse liver tissues. Interestingly, the Cx3cr1 up-regulation occurred during the pre-metastatic period, and Cx3cl1, the ligand of the Cx3cr1, was also up-regulated in the liver tissue prior to the development of metastasis suggesting the Cx3cr1 regulates the formation of pre-metastatic niche. Cx3cl1, the ligand of the Cx3cr1, was also up-regulated in the liver tissue prior to the development of metastasis. These data suggest that Cx3cl1 and Cx3cr1-mediated tumor-microenvironment interaction is critical in developing liver metastasis in TNBC. Cx3cl1 increased the invasion and migration of Raw264.7 monocyte/macrophage cells and this effect was abrogated by the Cx3cr1 silencing in Raw264.7 cells or treating Cx3cl1 neutralizing antibody. Pathway analysis of the RNA sequencing data showed that genes involved in extracellular matrix remodeling was significantly dysregulated in the liver tissues including Lysyl Oxidase (Lox). Cx3cl1 treatment in Raw264.7 cells resulted in increased expression of Lox and MMP9 mRNA in three-dimensional culture system. The Raw264.7 cells caused increased invasion of 4T1 cells in vitro. In conclusion, our data suggest that Cx3cl1-Cx3cr1 axis plays critical role during the liver metastasis of TNBC.

Citation Format: Woohang Heo, Hye-Youn Son, Ju hee Kim, Kyu Jin Lee, Myeonghee Jeon, Songbin Li, Jeehee Jang, Dong-Young Noh, Wonsik Han, Hyeong-Gon Moon. Cx3cl1-cx3cr1 axis in liver metastasis of triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-02.
Abstract PD15-05: Sipa1 effects rock pathway in human breast cancer linking to HGF mediated changes in tight junction functions controlling metastasis
Authors: Liu Chang , Ruge Fiona , Ye Lin , Harrison Gregory M. , Jiang Wen G. , Martin Tracey A.
Published: February 2021

Background: SIPA1 (Signal-induced proliferation-associated gene 1) is a mitogen-inducible gene encoding a GTPase-activating protein for Rap1 and Rap2 and has been suggested to be involved in metastatic progression. We have previously shown SIPA1 may regulate barrier function in breast cancer cells as part of hepatocyte growth factor-determined changes and that this may be via a number of regulatory pathways, most likely via the ROCK pathway. Our aim with this current work was to definitively identify which pathway is involved. Methods: After knockdown of SIPA1 in MDA-MB-231 cells, they were treated to a number of inhibitors to proteins involved in pathways involved in TJ barrier function (ROCK, N-WASP, ARPs, WAVEs, MAPK, ERK, PLC-gamma). Following the identification of suitable inhibitor a large scale in vivo study was carried out using a tumour model of SIPA1 knockdown versus WT control was treated with/without inhibitors and immunohistochemistry (IHC) used to assess changes in tumour growth, architecture and protein expression. We also assessed the expression of SIPA-1 in a cohort of human breast cancer tissues using IHC. Results: After knockdown of SIPA1 in MDA-MB-231 cells, we subjected cells to a number of inhibitors to proteins involved in pathways involved barrier function (ROCK, N-WASP, ARPs, WAVEs, MAPK, ERK, PLC-gamma). Analysis of behaviour showed that knockdown cells no longer responded to the ROCK inhibitor (ROCKi Y-27632, p<0.05, n=10). In vivo tumour samples were assessed for expression of ROCKI, expression of phospho-ROCK, and any differences when treated with ROCKi. Control tissues showed good levels of all three proteins (SIPA1, ROCKI and phosphor-ROCK). Knockdown tissues exhibited significantly lower levels of ROCK and phosphor-ROCK (p<0.01, n=12). In control tumours, phosphor-ROCK was increased after treatment with ROCKi; conversely, in SIPA1 knockdown tumours, phosphor-ROCK was decreased after treatment with ROCKi (p<0.05). In SIPA1 knockdown tissues, ROCK and phosphor-ROCK was diffuse in staining pattern when compared to the control where the staining was located at the cell membrane. Conclusion: Our results confirm our hypothesis that SIPA1 is involved in the control of TJ in breast cancer and that this is through the ROCK pathway. Moreover, these results demonstrate that this may be due to the effect that SIPA1 has on cellular ratios of ROCK to phosphor-ROCK in breast cancer.

Citation Format: Chang Liu, Fiona Ruge, Lin Ye, Gregory M. Harrison, Wen G. Jiang, Tracey A. Martin. Sipa1 effects rock pathway in human breast cancer linking to HGF mediated changes in tight junction functions controlling metastasis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-05.
Abstract PD15-10: Identification of BBOX1 as a therapeutic target in triple-negative breast cancer
Authors: Liao Chengheng , Zhang Yang , Fan Cheng , Herring Laura E. , Liu Juan , Locasale Jason W. , Takada Mamoru , Zhou Jin , Zurlo Giada , Hu Lianxin , Simon Jeremy M. , Ptacek Travis S. , Andrianov Victor G. , Loza Einars , Peng Yan , Yang Huanghe , Perou Charles M. , Zhang Qing
Published: February 2021

Triple-negative breast cancer (TNBC), which accounts for 15-20% of breast cancers, causes the highest mortality rate among all breast cancer subtypes. Due to its heterogeneity and lack of estrogen and progesterone receptor or human epidermal growth factor receptor 2 expression, valuable targeted therapy is limited. Therefore, it is critical to identify novel therapeutic targets in TNBC. 2-oxoglutarate (2-OG)-dependent enzymes, including prolyl hydroxylases (EglN1-3), histone demethylases (for example, KDM5A) and DNA hydroxylases (such as TET1-3), are associated with cancer progression. However, the role of these enzymes in TNBC has never been systematically studied. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth, while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3 mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1 mediated glycolysis, which leads to apoptosis and impaired cell cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacological inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC.

Citation Format: Chengheng Liao, Yang Zhang, Cheng Fan, Laura E. Herring, Juan Liu, Jason W. Locasale, Mamoru Takada, Jin Zhou, Giada Zurlo, Lianxin Hu, Jeremy M. Simon, Travis S. Ptacek, Victor G. Andrianov, Einars Loza, Yan Peng, Huanghe Yang, Charles M. Perou, Qing Zhang. Identification of BBOX1 as a therapeutic target in triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-10.