bluuebunny/crossref_metadata_2025 huggingface dataset:
Function Block-Based Multimodal Control for Symbiotic Human–Robot Collaborative Assembly
Authors: Liu Sichao , Wang Lihui , Wang Xi Vincent
Published: February 2021

In human–robot collaborative assembly, robots are often required to dynamically change their preplanned tasks to collaborate with human operators in close proximity. One essential requirement of such an environment is enhanced flexibility and adaptability, as well as reduced effort on the conventional (re)programming of robots, especially for complex assembly tasks. However, the robots used today are controlled by rigid native codes that cannot support efficient human–robot collaboration. To solve such challenges, this article presents a novel function block-enabled multimodal control approach for symbiotic human–robot collaborative assembly. Within the context, event-driven function blocks as reusable functional modules embedded with smart algorithms are used for the encapsulation of assembly feature-based tasks/processes and control commands that are transferred to the controller of robots for execution. Then, multimodal control commands in the form of sensorless haptics, gestures, and voices serve as the inputs of the function blocks to trigger task execution and human-centered robot control within a safe human–robot collaborative environment. Finally, the performed processes of the method are experimentally validated by a case study in an assembly work cell on assisting the operator during the collaborative assembly. This unique combination facilitates programming-free robot control and the implementation of the multimodal symbiotic human–robot collaborative assembly with the enhanced adaptability and flexibility.
Additive Manufacturing of 316L Stainless Steel by a Printing-Debinding-Sintering Method: Effects of Microstructure on Fatigue Property
Authors: Jiang Dayue , Ning Fuda
Published: February 2021

Additive manufacturing (AM) technology has been broadly applied to the fabrication of metallic materials. However, current approaches consume either high energy or large investment that considerably elevates their entry threshold. An economic extrusion-based AM method followed by debinding and sintering could efficiently produce the metal parts with relatively low cost and high material utilization. However, an in-depth analysis of the fatigue performance of the component built by such a technology has been little documented so far. Herein, the 316L stainless steel was fabricated throughout the printing-debinding-sintering (PDS) pathway and its fatigue properties were comprehensively assessed. Tensile and flexural fatigue tests were conducted to reveal the fatigue strength and fractural behaviors under different loading conditions, while the fatigue crack growth (FCG) test was performed to quantify the crack propagation. The results indicated the number of 105 cycles can be reached for the tensile specimens under the fatigue loading of 120 MPa, whereas 1.37 × 105 cycles were endured by the flexural specimens under 150 MPa. The fractural morphology indicated an adverse impact of the pore-induced voids on the tensile fatigue crack propagation, but such a drawback could be alleviated in the flexural loading condition. The FCG test unveiled the crack growth rate with the number of cycles and determined the material-related coefficients in the fatigue crack growth model. The research findings provided valuable insights into the effects of the PDS process and microstructures on the resultant fatigue properties of the metal component.
Application of Floquet Theory to Human Gait Kinematics and Dynamics
Authors: Bhat Sandesh G. , Subramanian Susheelkumar C. , Sugar Thomas S. , Redkar Sangram
Published: February 2021

In this work, the lower extremity physiological parameters are recorded during normal walking gait, and the dynamical systems theory is applied to determine a stability analysis. The human walking gait pattern of kinematic and dynamical data is approximated to periodic behavior. The embedding dimension analysis of the kinematic variable's time trace and use of Taken's theorem allows us to compute a reduced-order time series that retains the essential dynamics. In conjunction with Floquet theory, this approach can help determine the system's stability characteristics. The Lyapunov–Floquet (L-F) transformation application results in constructing an invariant manifold resembling the form of a simple oscillator system. It is also demonstrated that the simple oscillator system, when re-mapped back to the original domain, reproduces the original system's time evolution (hip angle or knee angle, for example). A reinitialization procedure is suggested that improves the accuracy between the processed data and actual data. The theoretical framework proposed in this work is validated with the experiments using a motion capture system.
Effects of Vertical Motions on Roll of Planing Hulls
Authors: Tavakoli Sasan , Dashtimanesh Abbas , Mancini Simone , Mehr Javad A. , Milanesi Stefano
Published: February 2021

Roll motion of a planing hull can be easily triggered at high speeds, causing a significant change in hydrodynamic pressure pattern, which can threaten the stability of the vessel. Modeling and investigating roll motion of a planing vessel may require a strong coupling between motions in vertical and transverse planes. In the present paper, we have used a mathematical model to analyze the roll of a planing hull by coupling surge, heave, pitch, and roll motions using 2D + T theory to study the effects of roll-induced vertical motions on roll coefficients and response. Mathematically computed forces and moments as well as roll dynamic response of the vessel are seen to be in fair quantitative agreement with experimentally measured values of previously published data. Using the 2D + T method, it has been shown that to model the roll of a planing hull at high speeds, we need to consider the effects of heave, pitch, and surge motions. Through our mathematical modeling, it is found that freedom in vertical motions increases time-dependent roll damping and added mass coefficients, especially at early planing speeds. The results of dynamic response simulations suggest that freedom in the vertical plane can decrease the roll response.
Salvesen’s Method for Added Resistance Revisited
Authors: Amini-Afshar Mostafa
Published: February 2021

Almost 4 years after the appearance of Salvesen–Tuck–Faltinsen (STF) strip theory (Salvesen et al., 1970, “Ship Motions and Sea Loads,” Annual Meeting of the Society of Naval Architecture and Marine Engineers (SNAME), New York, Nov. 12–13), Salvesen in 1974 published his popular method for calculation of added resistance (Salvesen, 1974, “Second-Order Steady State Forces and Moments on Surface Ships in Oblique Regular Waves,” Vol. 22; Salvesen, 1978, “Added Resistance of Ships in Waves,” J. Hydronautics, 12(1), pp. 24–34). His method is based on an exact near-field formulation; however, he applied the long-wave and the weak-scatterer assumptions to present his approximate method using the integrated quantities (hydrodynamic and geometrical coefficients). Considering the available computational powers in the 1970s, both of these assumptions were absolutely justifiable. The intention of this paper is to disseminate the results of a recent study at the Technical University of Denmark, whereby the Salvesen’s formulation has been revisited and the added resistance is computed from the original exact equation without invoking the weak-scatterer or the long-wave assumptions. This is performed using the solutions of the radiation and the scattering problems, obtained by a low-order boundary element method and the two-dimensional free-surface Green function inside our in-house STF theory implementation (Bingham and Amini-Afshar, 2020, DTU_Strip Theory Solver). The weak-scatterer assumption is then removed through a direct calculation of the x-derivatives of the velocity potentials and the normal vectors along the body. Knowing the velocity potentials over each panel, the long-wave assumption is also avoided by a piece-wise analytical integration of sectional Kochin Function (Kochin, 1936, “On the Wave Resistance and Lift of Bodies Submerged in Fluid,” Transactions of the Conference on the Theory of Wave Resistance, Moscow.). The presented results for five ship geometries testify that the correct treatment of the original equation is achieved only after both of the above-mentioned assumptions are removed. Implemented in this manner, Salvesen’s method proves to be relatively more accurate and robust than has been generally perceived during all these years.
Evaluation of Optical Transmissivity of Transparent Materials on the Performance of Solar Flat Plate Collectors
Authors: Shaik Saboor , Bhardwaj Manvendra , Agarwal Somya , Yendaluru Raja Sekhar , Hasanuzzaman Md. , Sharma K. V.
Published: February 2021

The energy gain of domestic solar water heating systems is determined by solar to thermal energy conversion and glazing optical efficiency. For this study, solar transmission properties of different transparent glazing materials such as acrylic, low-iron, medium-iron, and high-iron glasses were measured. The collector thermal efficiency under natural convection mode was compared for different transparent covers determined by numerical simulation using the Hottel–Whillier–Bliss equation. The low-iron glass (LiG-12 mm) has 16.3% and 20% higher thermal efficiency than medium- (MiG-12 mm) and high-iron glasses (HiG-12 mm), respectively, for a peak summer day. The effect of glass thickness on thermal performance is noteworthy in glasses than in acrylic glass sheets. Low-iron content glass with 6 mm thickness has the highest thermal and optical efficiency of 63.2% and 75.65%, respectively, for the collector optimum tilt for Vellore city in Tamil Nadu, India. The results are useful in the selection of glass covers for energy-efficient solar flat plate collectors.
Determinants of Peak Fat Oxidation Rates During Cycling in Healthy Men and Women
Authors: Chrzanowski-Smith Oliver J. , Edinburgh Robert M. , Thomas Mark P. , Hengist Aaron , Williams Sean , Betts James A. , Gonzalez Javier T.
Published: February 2021

This study explored lifestyle and biological determinants of peak fat oxidation (PFO) during cycle ergometry, using duplicate measures to account for day-to-day variation. Seventy-three healthy adults (age range: 19–63 years; peak oxygen consumption ; n = 32 women]) completed trials 7–28 days apart that assessed resting metabolic rate, a resting venous blood sample, and PFO by indirect calorimetry during an incremental cycling test. Habitual physical activity (combined heart rate accelerometer) and dietary intake (weighed record) were assessed before the first trial. Body composition was assessed 2–7 days after the second identical trial by dual-energy X-ray absorptiometry scan. Multiple linear regressions were performed to identify determinants of PFO (mean of two cycle tests). A total variance of 79% in absolute PFO (g·min−1) was explained with positive coefficients for (strongest predictor), FATmax (i.e the % of that PFO occurred at), and resting fat oxidation rate (g·min−1), and negative coefficients for body fat mass (kg) and habitual physical activity level. When expressed relative to fat-free mass, 64% of variance in PFO was explained: positive coefficients for FATmax (strongest predictor), , and resting fat oxidation rate, and negative coefficients for male sex and fat mass. This duplicate design revealed that biological and lifestyle factors explain a large proportion of variance in PFO during incremental cycling. After accounting for day-to-day variation in PFO, and FATmax were strong and consistent predictors of PFO.
Effect of 10 Weeks of Complex Training on Speed and Power in Academy Soccer Players
Authors: Gee Thomas I. , Harsley Paul , Bishop Daniel C.
Published: February 2021

Purpose: This study investigated the effects of complex-paired and reverse-contrast 10-week training programs on sprint, power, and change-of-direction speed performance of elite academy soccer players. Methods: Seventeen elite academy soccer players each performed assessments of the 10- and 40-m sprint, Abalakov vertical jump, seated medicine-ball throw, and Arrowhead change-of-direction speed test, both prior to and after a twice-weekly 10-week resistance-training program. The participants were randomly split into 2 groups; the complex-paired training group (CPT, n = 9) performed 4 different complex pairs (heavy-resistance exercises paired with plyometric and Olympic lifting–style exercises), with each pair being interspersed with an 8-minute recovery period in line with recommended guidelines. The comparative group—the reverse-contrast training group (RCT, n = 8)—performed the same exercises; however, all of the plyometric and Olympic lifting exercises preceded the heavy-resistance exercises. Results: Both groups achieved postintervention increases in the seated medicine-ball throw test (CPT +1.8% and RCT +1.6%, P < .05), whereas VJ performance improved only in the CPT group (+3.4%, P = .003). No significant improvements were observed in either the 10- and the 40-m sprint or Arrowhead change-of-direction speed test for either group. Conclusions: The CPT experienced a small but significant within-group improvement in jump performance. However, no significant between-groups differences were observed in any of the testing variables postintervention. Subsequently, for academy soccer athletes, the CPT approach did not produce meaningful benefits to performance compared with a more time-efficient reverse-contrast approach.
Comparative Genome Analyses of Lactobacillus crispatus Isolates from Different Ecological Niches Reveal an Adaptation of This Species to the Human Vaginal Environment
Authors: Mancabelli Leonardo , Mancino Walter , Lugli Gabriele Andrea , Milani Christian , Viappiani Alice , Anzalone Rosaria , Longhi Giulia , van Sinderen Douwe , Ventura Marco , Turroni Francesca
Published: February 2021

The vaginal microbiota is defined as the community of bacteria residing in the human vaginal tract. Recent studies have demonstrated that the high prevalence of
Lactobacillus crispatus
species is commonly associated with a healthy vaginal environment.
Structural Characterization of Diazabicyclooctane β-Lactam “Enhancers” in Complex with Penicillin-Binding Proteins PBP2 and PBP3 of Pseudomonas aeruginosa
Authors: Rajavel Malligarjunan , Kumar Vijay , Nguyen Ha , Wyatt Jacob , Marshall Steven H. , Papp-Wallace Krisztina M. , Deshpande Prasad , Bhavsar Satish , Yeole Ravindra , Bhagwat Sachin , Patel Mahesh , Bonomo Robert A. , van den Akker Focco
Published: February 2021

Antibiotic resistance is a significant clinical problem. Developing novel antibiotics that overcome known resistance mechanisms is highly desired.
Tiny Earth: A Big Idea for STEM Education and Antibiotic Discovery
Authors: Hurley Amanda , Chevrette Marc G. , Acharya Deepa D. , Lozano Gabriel L. , Garavito Manuel , Heinritz Jen , Balderrama Luis , Beebe Mara , DenHartog Martel L. , Corinaldi Kamiyah , Engels Renee , Gutierrez Alyssa , Jona Orli , Putnam Josephine H. I. , Rhodes Brody , Tsang Tiffany , Hernandez Simon , Bascom-Slack Carol , Blum Jessamina E. , Price Paul A. , Davis Debra , Klein Joanna , Pultorak Joshua , Sullivan Nora L. , Mouncey Nigel J. , Dorrestein Pieter C. , Miller Sarah , Broderick Nichole A. , Handelsman Jo
Published: February 2021

The world faces two seemingly unrelated challenges—a shortfall in the STEM workforce and increasing antibiotic resistance among bacterial pathogens. We address these two challenges with Tiny Earth, an undergraduate research course that excites students about science and creates a pipeline for antibiotic discovery.
A Grad-seq View of RNA and Protein Complexes in Pseudomonas aeruginosa under Standard and Bacteriophage Predation Conditions
Authors: Gerovac Milan , Wicke Laura , Chihara Kotaro , Schneider Cornelius , Lavigne Rob , Vogel Jörg
Published: February 2021

Stable complexes by cellular proteins and RNA molecules lie at the heart of gene regulation and physiology in any bacterium of interest. It is therefore crucial to globally determine these complexes in order to identify and characterize new molecular players and regulation mechanisms.
Viral Interactions and Pathogenesis during Multiple Viral Infections inAgaricus bisporus
Authors: Dobbs Edward , Deakin Greg , Bennett Julie , Fleming-Archibald Caoimhe , Jones Ian , Grogan Helen , Burton Kerry
Published: February 2021

How viruses interact in a multiple-virus infection was examined by quantifying the levels of 18 viral RNAs in fruiting cultures of the agriculturally cultivated fungusAgaricus bisporusand statistically analyzing and modeling their abundance. Synergistic, antagonistic, and neutral interactions occurred simultaneously in cultures.
Tracking the Emergence of Azithromycin Resistance in Multiple Genotypes of Typhoidal
Salmonella
Authors: Sajib Mohammad S. I. , Tanmoy Arif M. , Hooda Yogesh , Rahman Hafizur , Andrews Jason R. , Garrett Denise O. , Endtz Hubert P. , Saha Samir K. , Saha Senjuti
Published: February 2021

In the early 1900s, with mortality of ∼30%, typhoid and paratyphoid (caused by
Salmonella
Typhi and Paratyphi A) ravaged parts of the world; with improved water, sanitation, and hygiene in resource-rich countries and the advent of antimicrobials, mortality dwindled to <1%. Today, the burden rests disproportionately on South Asia, where the primary means for combatting the disease is antimicrobials.
Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission
Authors: Zangari Tonia , Ortigoza Mila B. , Lokken-Toyli Kristen L. , Weiser Jeffrey N.
Published: February 2021

Respiratory tract infections are a leading cause of childhood mortality and, globally,Streptococcus pneumoniaeis the leading cause of mortality due to pneumonia. Transmission ofS. pneumoniaeprimarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood.
A Glycoprotein Mutation That Emerged during the 2013–2016 Ebola Virus Epidemic Alters Proteolysis and Accelerates Membrane Fusion
Authors: Fels J. Maximilian , Bortz Robert H. , Alkutkar Tanwee , Mittler Eva , Jangra Rohit K. , Spence Jennifer S. , Chandran Kartik
Published: February 2021

The 2013–2016 outbreak of Ebola virus disease in West Africa demonstrated the potential for previously localized outbreaks to turn into regional, or even global, health emergencies. With over 28,000 cases and 11,000 confirmed deaths, this outbreak was over 50 times as large as any previously recorded.
Mutations in the Hemagglutinin Stalk Domain Do Not Permit Escape from a Protective, Stalk-Based Vaccine-Induced Immune Response in the Mouse Model
Authors: Roubidoux Ericka Kirkpatrick , Carreño Juan Manuel , McMahon Meagan , Jiang Kaijun , van Bakel Harm , Wilson Patrick , Krammer Florian
Published: February 2021

Broadly protective or universal influenza virus vaccines target viral epitopes that appear to be conserved. However, it is unclear whether the virus will be able to escape once immunological pressure is applied to these epitopes through vaccination of large proportions of the population. Studies that investigate the fitness and antigenic characteristics of viruses that escape immunological pressure on these conserved epitopes are therefore urgently needed.
A Novel Mode of Photoprotection Mediated by a Cysteine Residue in the Chlorophyll Protein IsiA
Authors: Chen Hui-Yuan Steven , Niedzwiedzki Dariusz M. , Bandyopadhyay Anindita , Biswas Sandeep , Pakrasi Himadri B.
Published: February 2021

Cyanobacteria, oxygenic photosynthetic microbes, constantly experience varying light regimes. Light intensities higher than those that saturate the photosynthetic capacity of the organism often lead to redox damage to the photosynthetic apparatus and often cell death.
Microbiota Assessments for the Identification and Confirmation of Slit Defect-Causing Bacteria in Milk and Cheddar Cheese
Authors: Xue Zhengyao , Brooks Jason T. , Quart Zachary , Stevens Eric T. , Kable Mary E. , Heidenreich Jessie , McLeod Jeremy , Marco Maria L.
Published: February 2021

Food production involves numerous control points for microorganisms to ensure quality and safety. These control points (e.g., pasteurization) are difficult to develop for fermented foods wherein some microbial contaminants are also expected to provide positive contributions to the final product and spoilage microbes may constitute only a small proportion of all microorganisms present.
Endophytic Lifestyle of Global Clones of Extended-Spectrum β-Lactamase-Producing Priority Pathogens in Fresh Vegetables: a Trojan Horse Strategy Favoring Human Colonization?
Authors: Lopes Ralf , Fuentes-Castillo Danny , Fontana Herrison , Rodrigues Larissa , Dantas Karine , Cerdeira Louise , Henriques Isabel , Lincopan Nilton
Published: February 2021

Extended-spectrum β-lactamases (ESBL)-producing
Enterobacterales
are a leading cause of human and animal infections, being classified as critical priority pathogens by the World Health Organization. Epidemiological studies have shown that spread of ESBL-producing bacteria is not a problem restricted to hospitals, but also represents a growing problem involving environmental and food safety.
High-Spin Cobalt(II) Complex with Record-Breaking Anisotropy of the Magnetic Susceptibility According to Paramagnetic NMR Spectroscopy Data
Authors: Pankratova Ya. A. , Nelyubina Yu. V. , Novikov V. V. , Pavlov A. A.
Published: February 2021

The tetrahedral cobalt(II) complex [CoL2](HNEt3)2 (I), where L is 1,2-bis(methanesulfonamido)benzene, exhibiting the properties of a single-molecule magnet is synthesized and characterized. The electronic structure parameters of complex I are determined by paramagnetic NMR spectroscopy. They completely reproduce the results of less available methods of studying single-molecule magnets. The value of axial anisotropy of the magnetic susceptibility estimated for complex I (Δχax = 34.5 × 10–32 m3 at 20°C) is record-breaking among all transition metal complexes studied by the NMR method, which provides wide possibilities for the use of complex I as a paramagnetic label for structural biology or as a contrast agent and even a temperature sensor for medical diagnostics. The data obtained indicate the advantages of paramagnetic NMR spectroscopy as a method of investigation of the magnetic properties and electronic structures of highly anisotropic transition metal complexes, which are precursors of many functional materials.
Paediatric severe asthma biologics service: from hospital to home
Authors: Makhecha Sukeshi , Jamalzadeh Angela , Irving Samantha , Hall Pippa , Sonnappa Samatha , Saglani Sejal , Bush Andrew , Fleming Louise
Published: February 2021

Children with severe asthma may be treated with biologic agents normally requiring 2–4 weekly injections in hospital. In March 2020, due to COVID-19, we needed to minimise hospital visits. We assessed whether biologics could be given safely at home. The multidisciplinary team identified children to be considered for home administration. This was virtually observed using a video link, and home spirometry was also performed. Feedback was obtained from carers and young people. Of 23 patients receiving biologics, 16 (70%) families agreed to homecare administration, 14 administered by parents/patients and 2 by a local nursing team. Video calls for omalizumab were observed on 56 occasions, mepolizumab on 19 occasions over 4 months (April–July). Medication was administered inaccurately on 2/75 occasions without any adverse events. Virtually observed home biologic administration in severe asthmatic children, supported by video calls and home spirometry, is feasible, safe and is positively perceived by children and their families
Different doses of prucalopride in treating chronic idiopathic constipation: a meta-analysis and Bayesian analysis
Authors: Yang Tao , Wang Kaili , Cao Yibo , Wen Jianxia , Wei Shizhang , Li Haotian , Yang Xiangdong , Xiao Tianbao
Published: February 2021

Objective

This study aims to explore the incremental benefit of different doses of prucalopride in treating chronic idiopathic constipation (CIC).

Methods

PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database, China National Knowledge Infrastructure, VIP medicine information and Wanfang databases were comprehensively searched up to March 2020. Prospective trials with different doses of prucalopride versus placebo were selected. The frequency of spontaneous bowel movements (SBMs) per week and the treatment-emergent adverse events (TEAEs), such as headache, arrhythmia, diarrhoea, dizziness, nausea and vomiting, were first synthesised in a meta-analysis. The probability of optimal dose of prucalopride was then ranked by random-effects within Bayesian analysis.

Results

14 high-quality randomised controlled trials with 4328 patients were ultimately included. SBMs per week increased significantly after using 1 mg (OR: 2.40, 95% CI 1.32 to 4.37), 2 mg (OR: 2.55, 95% CI 1.93 to 3.36) and 4 mg (OR: 2.51, 95% CI 1.92 to 3.28) prucalopride. Bayesian analysis demonstrated 1 mg dose obtained the maximum SBMs per week (OR: 3.31, 95% credible interval 1.72 to 6.16, probability rank=0.70) indirectly compared with 2 mg and 4 mg doses. TEAEs were higher significantly in 2 mg (risk ratio (RR): 1.20, 95% CI 1.09 to 1.33) and 4 mg (RR: 1.14, 95% CI 1.07 to 1.22) prucalopride. The 1 mg dose did not reach statistical significance (RR: 1.17, 95% CI 0.94 to 1.44).

Conclusions

The study concludes that 1 mg dose at commencement could be safer in treating CIC and that 2 mg prucalopride could be more efficacious in terms of SBMs per week outcome receiving.

PROSPERO registration number

CRD42019136679.
Protected code blue: using in situ simulation to develop a protected code blue and modify staff training protocol—experience in a large community teaching hospital during the COVID-19 pandemic
Authors: Youssef Fady A , Patel Monique , Park Hyunsoon , Patel Jay V , Leo James , Tanios Maged A
Published: February 2021

The surge in clinical demand, shortage in personal protective equipment and high-exposure risk for healthcare workers during the COVID-19 pandemic has challenged hospital common practices and forced a reassessment of care delivery models. Code blue teams are highly specialised units that partake in life-saving situations that can jeopardise the safety of team members. There is a paucity of guidance in regards to proper infection control measures to protect the responders.

This study describes a methodical approach to assessing vulnerabilities to transmission of SARS-CoV-2 within existing code blue practices, modalities to limit the number of code blue team responders and modifications to the protocol at a large community teaching hospital. The effort undertaken faced challenges due to the nature of the pandemic and the increased demand on healthcare workers. Quality improvement methods facilitated our protocol design and implementation. To this date, there has been no identified COVID-19 disease in any protected code blue (PCB) team members. We recommend that similar practices be considered and adopted widely and practised periodically.
Identifying research waste from surgical research: a protocol for assessing compliance with the IDEAL framework and recommendations
Authors: Yu Jiajie , Shan Fei , Hirst Allison , McCulloch Peter , Li Youping , Sun Xin
Published: February 2021

Introduction

Approximately £1130 billion was invested in research worldwide in 2016, and 9.6% of this was on biomedical research. However, about 85% of biomedical research investment is wasted. The Lancet published a series to identify five categories relating to research waste and in 2014. Some categories of research waste in surgery are avoidable by complying with the Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) framework for it enables researchers to design, conduct and report surgical studies robustly and transparently. This review aims to examine the extent to which surgical studies adhered to the IDEAL framework and estimate the amount of overall research waste that could be avoided if compliance was improved.

Methods

We will search for potential studies published in English and between 1 January 2018 and 31 December 2018 via PubMed. Teams of paired reviewers will screen titles, abstracts and full texts independently. Two researchers will extract data from each paper. Data will be collected about general information and specialised information in each stage, and our IDEAL Compliance Appraisal tool will be used to analyse included studies. Descriptive statistics and χ2or Fisher’s exact tests for comparisons will be presented.

Discussion

Our study will provide important information about whether compliance with the specific IDEAL Recommendations has reduced research waste in surgical and therapeutic device studies. And we will identify particular key aspects that are worse and need to focus on improving those in future education.
Back to simplicity: a four-marker blood cell score to quantify prognostically relevant myeloid cells in melanoma patients
Authors: Huber Veronica , Di Guardo Lorenza , Lalli Luca , Giardiello Daniele , Cova Agata , Squarcina Paola , Frati Paola , Di Giacomo Anna Maria , Pilla Lorenzo , Tazzari Marcella , Camisaschi Chiara , Arienti Flavio , Castelli Chiara , Rodolfo Monica , Beretta Valeria , Di Nicola Massimo , Maio Michele , Del Vecchio Michele , de Braud Filippo , Mariani Luigi , Rivoltini Licia
Published: February 2021

Background

Myeloid-derived suppressor cells (MDSC), a cornerstone of cancer-related immunosuppression, influence response to therapy and disease outcomes in melanoma patients. Nevertheless, their quantification is far from being integrated into routine clinical practice mostly because of the complex and still evolving phenotypic signatures applied to define the cell subsets. Here, we used a multistep downsizing process to verify whether a core of few markers could be sufficient to capture the prognostic potential of myeloid cells in peripheral blood mononuclear cells (PBMC) of metastatic melanoma patients.

Methods

In baseline frozen PBMC from a total of 143 stage IIIc to IV melanoma patients, we first assessed the relevant or redundant expression of myeloid and MDSC-related markers by flow cytometry (screening set, n=23 patients). Subsequently, we applied the identified panel to the development set samples (n=59 patients undergoing first/second-line therapy) to obtain prognostic variables associated with overall survival (OS) and progression-free survival (PFS) by machine learning adaptive index modeling. Finally, the identified score was confirmed in a validation set (n=61) and compared with standard clinical prognostic factors to assess its additive value in patient prognostication.

Results

This selection process led to the identification of what we defined myeloid index score (MIS), which is composed by four cell subsets (CD14+, CD14+HLA-DRneg, CD14+PD-L1+ and CD15+ cells), whose frequencies above cut-offs stratified melanoma patients according to progressively worse prognosis. Patients with a MIS=0, showing no over-threshold value of MIS subsets, had the best clinical outcome, with a median survival of >33.6 months, while in patients with MIS 1→3, OS deteriorated from 10.9 to 6.8 and 6.0 months as the MIS increased (p<0.0001, c-index=0.745). MIS clustered patients into risk groups also according to PFS (p<0.0001). The inverse correlation between MIS and survival was confirmed in the validation set, was independent of the type of therapy and was not interfered by clinical prognostic factors. MIS HR was remarkably superior to that of lactate dehydrogenase, tumor burden and neutrophil-to-lymphocyte ratio.

Conclusion

The MIS >0 identifies melanoma patients with a more aggressive disease, thus acting as a simple blood biomarker that can help tailoring therapeutic choices in real-life oncology.
Phosphorylation of SMAD3 in immune cells predicts survival of patients with early stage non-small cell lung cancer
Authors: Marwitz Sebastian , Ballesteros-Merino Carmen , Jensen Shawn M , Reck Martin , Kugler Christian , Perner Sven , Drömann Daniel , Goldmann Torsten , Fox Bernard A
Published: February 2021

Background

The interplay of immune and cancer cells takes place in the tumor microenvironment where multiple signals are exchanged. The transforming growth factor beta (TGFB) pathway is known to be dysregulated in lung cancer and can impede an effective immune response. However, the exact mechanisms are yet to be determined. Especially which cells respond and where does this signaling take place with respect to the local microenvironment.

Methods

Human non-small cell lung cancer samples were retrospectively analyzed by multiplexed immunohistochemistry for SMAD3 phosphorylation and programmed death ligand 1 expression in different immune cells with respect to their localization within the tumor tissue. Spatial relationships were studied to examine possible cell-cell interactions and analyzed in conjunction with clinical data.

Results

TGFB pathway activation in CD3, CD8, Foxp3 and CD68 cells, as indicated by SMAD3 phosphorylation, negatively impacts overall and partially disease-free survival of patients with lung cancerindependent of histological subtype. A high frequency of Foxp3 regulatory T cells positive for SMAD3 phosphorylation in close vicinity of CD8 T cells within the tumor discriminate a rapidly progressing group of patients with lung cancer.

Conclusions

TGFB pathway activation of local immune cells within the tumor microenvironment impacts survival of early stage lung cancer. This might benefit patients not eligible for targeted therapies or immune checkpoint therapy as a therapeutic option to re-activate the local immune response.
Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy
Authors: Muñoz Nina M. , Williams Malea , Dixon Katherine , Dupuis Crystal , McWatters Amanda , Avritscher Rony , Manrique Soraya Zorro , McHugh Kevin , Murthy Ravi , Tam Alda , Naing Aung , Patel Sapna P. , Leach David , Hartgerink Jeffrey D. , Young Simon , Prakash Punit , Hwu Patrick , Sheth Rahul A.
Published: February 2021

Background

Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy.

Methods

Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution.

Results

Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal).

Conclusions

Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.
Intratumoral CXCL13+CD8+T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma
Authors: Dai Siyuan , Zeng Han , Liu Zhaopei , Jin Kaifeng , Jiang Wenbin , Wang Zewei , Lin Zhiyuan , Xiong Ying , Wang Jiajun , Chang Yuan , Bai Qi , Xia Yu , Liu Li , Zhu Yu , Xu Le , Qu Yang , Guo Jianming , Xu Jiejie
Published: February 2021

Background

Chemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4+T cells (TFH) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by TFHhave been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8+T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13+CD8+T cells in clear cell renal cell carcinoma (ccRCC).

Methods

We analyzed prognostic value and immune contexture that associated with CXCL13+CD8+T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13+CD8+T cells and total CD8+T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC.

Results

Intratumoral CXCL13+CD8+T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13+CD8+T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8+T cells in high-level CXCL13+CD8+T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13+CD8+T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3+regulatory T cells, TLS and decreased natural killer cells, GZMB+cells.

Conclusions

Intratumoral CXCL13+CD8+T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13+CD8+T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13+CD8+T cells abundance impaired total CD8+T cells’ immune function. Intratumoral CXCL13+CD8+T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13+CD8+T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.
Prognostic comparison of atrial and ventricular functional mitral regurgitation
Authors: Okamoto Chisato , Okada Atsushi , Nishimura Kunihiro , Moriuchi Kenji , Amano Masashi , Takahama Hiroyuki , Amaki Makoto , Hasegawa Takuya , Kanzaki Hideaki , Fujita Tomoyuki , Kobayashi Junjiro , Yasuda Satoshi , Izumi Chisato
Published: February 2021

Objective

Atrial functional mitral regurgitation (A-FMR) has been suggested as a new aetiology of functional MR (MR); however, its prognosis and prognostic predictors are not fully elucidated. Aim of this study was to investigate the prognosis and prognostic predictors of A-FMR in comparison with ventricular functional MR (V-FMR).

Methods

Three hundred and seventy-eight consecutive patients with moderate-to-severe or severe functional MR were studied. Functional MR was classified into V-FMR (N=288) and A-FMR (N=90) depending on the alterations of left ventricle (LV) or left atrium (LA) along with clinical context and diagnosis of ischaemic heart disease or cardiomyopathy.

Results

During a median follow-up of 4.1 (2.0–6.7) years, all-cause mortality, cardiovascular mortality and heart failure (HF) hospitalisation occurred in 98 (26%), 81 (21%) and 177 (47%) patients, respectively, and rates of these events and the composite end point of all-cause mortality and HF hospitalisation were consistently higher in V-FMR than A-FMR (unadjusted HR 1.762 (95% CI 1.250 to 2.438), p<0.001; adjusted HR 1.654 (95% CI 1.027 to 2.664), p=0.038, for the composite end point). Further analysis showed different prognostic predictors between V-FMR and A-FMR; while age and LA volume index were independent prognostic predictors of both V-FMR and A-FMR, systolic blood pressure and B-type natriuretic peptide were also those of V-FMR, and estimated glomerular filtration rate, LV end-systolic dimension and tricuspid regurgitation were also those of A-FMR.

Conclusions

The prognosis of V-FMR was significantly worse than that of A-FMR, and prognostic predictors were different between V-FMR and A-FMR. Our study suggests the importance of discriminating A-FMR and V-FMR, and that different treatment strategies may be considered for each aetiology.
Predicting human RNA quadruplex helicases through comparative sequence approaches and helicase mRNA interactome analyses
Authors: Dupas Steven J. , Gussakovsky Daniel , Wai Alvan , Brown Mira J.F. , Hausner Georg , McKenna Sean A.
Published: February 2021

RNA quadruplexes are non-canonical nucleic acid structures involved in several human disease states and are regulated by a specific subset of RNA helicases. Given the difficulty in identifying RNA quadruplex helicases due to the multifunctionality of these enzymes, we sought to provide a comprehensive in silico analysis of features found in validated RNA quadruplex helicases to predict novel human RNA quadruplex helicases. Using the 64 human RNA helicases, we correlated their amino acid compositions with subsets of RNA quadruplex helicases categorized by varying levels of evidence of RNA quadruplex interaction. Utilizing phylogenetic and synonymous/non-synonymous substitution analyses, we identified an evolutionarily conserved pattern involving predicted intrinsic disorder and a previously identified motif. We analyzed available next-generation sequencing data to determine which RNA helicases directly interacted with predicted RNA quadruplex regions intracellularly and elucidated the relationship with miRNA binding sites adjacent to RNA quadruplexes. Finally, we performed a phylogenetic analysis of all 64 human RNA helicases to establish how RNA quadruplex detection and unwinding activity may be conserved among helicase subfamilies. This work furthers the understanding of commonalities between RNA quadruplex helicases and provides support for the future validation of several human RNA helicases.
Mineral control on the geochemistry of the Rock Canyon Creek REE-F-Ba deposit, British Columbia, Canada
Authors: Simandl George J. , Paradis Suzanne , Savard Johnathan , Miller Deanna , D'Souza Rameses , Araoka Daisuke , Akam Carlee , Hoshino Mihoko , Kon Yoshiaki
Published: February 2021

The Rock Canyon Creek carbonate-hosted REE-F-Ba deposit has tectonic, stratigraphic and structural similarities with Mississippi Valley-type and sparry magnesite deposits in the SE Rocky Mountains. The main REE-fluorite zone is a steeply dipping body, extending 1100 m along-strike, 50 m wide and 100 m deep. It spatially coincides with pre-existing crackle breccias in carbonate rocks, and consists of dolomite, fluorite, barite, pyrite, quartz, K-feldspar, calcite, porous apatite, REE-fluorocarbonates and REE-phosphates. The main fluorocarbonates are bastnaesite, parisite and synchysite. Monazite, crandallite group minerals and apatite are the main phosphates. Fluorite content varies from less than 1 to 13.5% (by weight) and ∑REE  +  Y concentrations vary from trace to 1.95% (by weight). The mineralized zone is heterogeneous on the deposit scale, as indicated by three-dimensional geochemical modelling combined with a geochemical assessment based on 89 mineralized samples and detailed downhole mineral and geochemical profiles of a key borehole. Chemical heterogeneity and key elemental co-variations are explained by strong mineralogical control and have implications for the design of exploration and development programmes for this type of deposit. The chondrite-normalized REE pattern of samples from the mineralized zone shows enrichment in LREE, similar to typical carbonatite-related mineralization; however, no carbonatite is exposed nearby.
Characterization of altered mafic and ultramafic rocks using portable XRF geochemistry and portable Vis-NIR spectrometry
Authors: Adams Cameron , Dentith Michael , Fiorentini Marco
Published: February 2021

The accurate characterization of mafic and ultramafic rocks is a challenging but necessary task given the spatial and genetic relationship of mineralization with specific lithologies (e.g. komatiite hosted nickel-sulfides preferentially associated with cumulate-rich ultramafic rocks). Rock classification is further complicated as most mafic and ultramafic rocks have undergone varying degrees of alteration. The accuracy and reproducibility of characterization can be significantly improved by using portable energy dispersive X-ray fluorescence (pXRF) chemical data with portable visible and near-infrared (pVis-NIR) mineralogical data.

A new workflow using pXRF and pVis-NIR is presented and used to reliably characterize mafic and ultramafic rocks from the Yilgarn Craton, Western Australia. The workflow involves six steps:

(1)
Mitigate and identify compound processing and closure issues.
For example, we used a pXRF with helium flush to reliably and rapidly measure light elements and mitigate closure, i.e. problems related to data failing to sum to 100%.

(2)
Identify and exclude geochemically heterogeneous samples.
Heterogeneity may be unrelated to alteration and caused by veining or small-scale structure interleaving of different rock types. Geochemical heterogeneity was evaluated using skewness and kurtosis of SiO
2
data.

(3)
Relate rocks from similar magmatic, weathering and alteration events.
This was achieved by interpreting data grouping of Vis-NIR ferric and ferrous iron data via a 852 nm/982 nm reflectance v. 651 nm/982 nm reflectance plot and the ferrous abundance index. Unrepresentative data were omitted.

(4)
Correct XRF iron data, and characterize lithology and alteration.
Values ascribed to regions in the TAS (total alkali silica) diagram were used to approximate FeO and Fe
2
O
3
. Subsequently, geochemical indices (e.g. Mg#) were used to characterize the alteration box plot.

(5)
Characterize fractionation in detail.
Fractionation variation diagrams were used to interpret fractionation, e.g. MgO v. Al
2
O
3
, Ca/Al v. Al
2
O
3
, Ni/Cr v. Ni/Ti, and MgO v. Cr.

(6)
Identify and quantify talc alteration and serpentinization.
This included the use of a new alteration plot (Mg# v. 1410 nm
RAD
/Albedo) to estimate serpentinization and identify relationships between serpentine, carbonate, chlorite and talc abundances.

The results and observations contained in this contribution have important implications for progressive technologies such as core logging platforms that are equipped with pXRF and pVis-NIR instruments.