bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual Differences in Dealing With Classroom Noise Disturbances
Authors: Massonnié Jessica , Mareschal Denis , Kirkham Natasha Z.
Published: April 2022

Classrooms are noisy: when children are engaged in solo work, they also hear background babble, noise from outdoor, and people moving around. Few studies investigating the effects of noise on academic tasks use naturalistic stimuli. Questions also remain regarding why some children are more impaired by noise than others. This study compared primary school children's performance at three academic tasks (text recall, reading comprehension, mathematics) in silence, and while hearing irrelevant verbal noise (storytelling, n = 33) or mixed noise (outdoor noise, movement, babble, n = 31). We found that noise does not impair overall performance. Children might use compensatory strategies (e.g., re‐reading) to reach the same level of performance in silence and noise. Individual differences in selective attention and working memory were not related to the impact of noise, with one exception: children with lower working memory were more impaired by noise when doing mathematics. Replication on a larger sample is needed.
One of many roads to industry 4.0? Technology, policy, organisational adaptation and worker experience in ‘Third Italy’ SMEs
Authors: Da Roit Barbara , Iannuzzi Francesco E.
Published: April 2022

Industry 4.0 (I4.0) is a technological framework and policy programme that emerged in Germany in the 2010s, promising to revitalise manufacturing and revalue work by means of intelligent productive systems. The paradigm's cross‐national diffusion raises questions about its context‐dependent adaptation. This article focuses on the Italian I4.0 programme and its implementation among medium‐sized manufacturing companies in the country's Veneto region. It analyses Italian policy and company strategies through the perceptions and experiences of managers, unionists and workers. The research highlights how a system dominated by small and medium enterprises (SMEs)—one with limited technological investment and without a coordinated system of industrial relations—reshaped the I4.0 policy goals, technological developments and work outcomes. The results show how the features of the productive context are associated with a far less ambitious I4.0 plan, the limited and selective adoption of technology at the level of firms, and modest top‐down organisational changes that do not fulfil the promises of the project.
The Permissive Safe Angle of the Tibial Tunnel in Transtibial Posterior Cruciate Ligament Reconstruction: A Three‐Dimensional Simulation Study
Authors: Teng Yuanjun , Jia Gengxin , Da Lijun , Peng Bo , Liu Zhongcheng , Han Hua , Wu Meng , Xia Yayi
Published: April 2022

Objective

To determine the permissive safe angle (PSA) of the tibial tunnel in transtibial posterior cruciate ligament (PCL) reconstruction based on a three‐dimensional (3D) simulation study.

Methods

This was a computer simulation study of transtibial PCL reconstruction using 3D knee models. CT images of 90 normal knee joints from 2017 to 2020 were collected in this study, and 3D knee models were established based on CT data. The tunnel approaches were subdivided into the anterior 1/3 of the anteromedial tibia (T1), middle 1/2 of the anteromedial tibia (T2), the tibial crest (T3), anterior 1/3 of the anterolateral tibia (T4), middle 1/2 of the anterolateral tibia (T5). Five tibial tunnels (T1–T5) were simulated on the 3D knee models. The PSAs, in different tibial tunnel approaches were measured, and subgroup analyses of sex, age and height were also carried out.

Results

The mean PSAs of the tibial tunnels with 5 different approaches (T1–T5) were 58.49° ± 6.82°, 61.14° ± 6.69°, 56.12° ± 7.53°, 52.01° ± 8.89° and 49.90° ± 10.53°, respectively. The differences of the mean PSAs between the anteromedial and anterolateral approaches were significant (P < 0.05). However, there was no significant difference of the mean PSA value between the two anteromedial tibial tunnel approaches (T1–T2) (P > 0.05), as well as between the two anterolateral tibial tunnel approaches (T4–T5). The patient's anthropomorphic characteristics of sex, age, and height were not associated with the PSAs.

Conclusions

The PSA varied with the anteromedial, tibial crest and anterolateral approaches for transtibial PCL reconstruction, and surgeons should limit the PCL drill guide by referring to the specific PSA for different surgical approaches.
Comparing the Bridge‐Type Zero‐Profile Anchored Spacer (ROI‐C) Interbody Fusion Cage System and Anterior Cervical Discectomy and Fusion (ACDF) with Plating and Cage System in Cervical Spondylotic Myelopathy
Authors: He Shuangjun , Zhou Zhangzhe , Shao Xiaofeng , Zhou Lijian , Zhang Changhao , Zhou Xinfeng , Wu Shuhua , Chen Kangwu , Wang Yaowei , Qian Zhonglai
Published: April 2022

Objective

To compare the clinical efficacy and radioactivity of the bridge‐type zero‐profile anchored spacer (ROI‐C) interbody fusion cage and anterior cervical discectomy and fusion with plating and cage system (ACDF) for cervical spondylotic myelopathy (CSM).

Methods

This is a retrospective contrastive study. We recruited 35 patients who received ROI‐C (ROI‐C group) and 34 patients who received ACDF (ACDF group), between January 2014 to January 2019, at our treatment center. The ROI‐C group comprised of 11 males and 24 females with a mean age of 61.59 ± 8.21 years (range, 51–71 years). The ACDF group comprised of 12 males and 22 females with a mean age of 60.15 ± 7.52 years (range, 52–74 years). Neck Disability Index (NDI), Japanese Orthopaedic Association score (JOA), Odom's score, cervical Cobb angle, fusion rate, adjoining ossification, and dysphagia.

Results

A total of 69 patients met the inclusion criteria, and these patients received more than two years of follow‐up. There were significant differences in surgical duration (101 ± 22 min vs. 118 ± 29 min) and blood loss (102 ± 46 ml vs. 145 ± 58 ml) between two groups (P < 0.05). The JOA and NDI of these two groups of patients significantly improved, when compared with those before the operation (P < 0.05). Twenty‐nine of 35 patients in the ROI‐C group and 27 of 34 patients in ACDF group achieved good or excellent outcomes according to Odom's criteria. The cervical lordosis of both two groups significantly increased, when compared with those before the operation (P < 0.05). In the ROI‐C group, the postoperative fusion rate was 85.7% at the 3‐month follow‐up and 100% at the final follow‐up. In the ACDF group, the postoperative fusion rate was 82.4% at the 3‐month follow‐up and 100% at the final follow‐up. The dysphagia incidence of the ACDF group was higher than that of the ROI‐C group postoperatively and at the one month after surgery (P < 0.05), but no significant difference was found in the incidence of dysphagia at final follow‐up (P > 0.05).

Conclusion

Both ROI‐C and ACDF achieved good therapeutic effects. However, ROI‐C can reduce the operation time and postoperative complications.
Whether Anterolateral Single Rod Can Maintain the Surgical Outcomes Following Oblique Lumbar Interbody Fusion for Double‐Segment Disc Disease
Authors: Zhao Long , Xie Tianhang , Wang Xiandi , Yang Zhiqiang , Pu Xingxiao , Zeng Jiancheng
Published: April 2022

Objective

To evaluate the outcomes of oblique lumbar interbody fusion (OLIF) combined with anterolateral single‐rod screw fixation (AF) in treating two‐segment lumbar degenerative disc disease (LDDD) and to determine whether AF can maintain the surgical results.

Methods

A retrospective analysis was performed on patients who underwent OLIF combined with AF (OLIF‐AF) for LDDD at the L3‐5 levels between October 2017 and May 2018. A total of 84 patients, including 44 males and 40 females, with a mean age of 62.8 ± 6.8 years, who completed the 12‐month follow‐up were eventually enrolled. Clinical outcomes, including the Oswestry Disability Index (ODI), visual analog scale (VAS) score for the low back and leg, and radiographic parameters, including the cross‐sectional area (CSA) of the spinal canal, disc height (DH), foraminal height (FH), degree of upper vertebral slippage (DUVS), segmental lumbar lordosis (SL), fusion rate, and lumbar lordosis (LL), were recorded before surgery and 1 and 12 months after surgery. Surgical‐related complications, including cage subsidence (CS), were also evaluated. The local radiographic parameters were compared between L3‐4 and L4‐5. The clinical results and all radiographic parameters were compared between patients with and without CS.

Results

Significant improvements were observed in radiographic parameters 1 day postoperatively (p < 0.05). Local radiological parameters in L4‐5 had a significant decrease at 12 months postoperatively (p < 0.05), while they were well‐maintained at L3‐4 throughout the follow‐up period (p > 0.05). CS was observed in 26 segments (15.5%). Endplate injury was observed in four segments (2.4%). There was no significant difference in the fusion rate between the segments with and without CS (p = 0.355). The clinical results improved significantly after surgery (p < 0.05), and no significant difference was observed between the groups with and without CS (p > 0.05).

Conclusions

Anterolateral fixation combined with OLIF provides sufficient stability to sustain most radiological improvements in treating double‐segment LDDD. Subsidence was the most common complication, which was prone to occur in L4‐5 compared to L3‐4, but did not impede the fusion process or diminish the surgical results.
3D Customized Biological Tibial Intramedullary Nail Fixation for the Treatment of Fracture after Massive Allograft Bone Transplantation of Tibial Osteosarcoma: A Case Report
Authors: Yang Hongsheng , Fang Xiang , Xiong Yan , Duan Hong , Zhang Wenli
Published: April 2022

Allograft bone fractures are critical complications in massive allograft bone transplantations. There are limited studies available on the application of 3D printing for massive allograft bone transplantation complications, and no related reports on the treatment of an allograft bone fracture with a complete biological intramedullary nail. A complex case of allograft bone fracture after massive bone transplantation for a right tibial osteosarcoma was treated with fixation of an individualized 3D printed biological tibial intramedullary nail. Prior to the operation, the intramedullary nail was designed and printed based on the results of computed tomography examination of the affected limb, and the surface of the intramedullary nail was treated with a hydroxyapatite coating. Intraoperatively, the intramedullary nail was implanted according to the preoperative 3D design plan. The intraoperative and postoperative examinations showed that the 3D printed intramedullary nail achieved good matching between the implant and the medullary cavity, and the biological coating integrated well with surrounding bone. The follow‐up results 44 months postoperatively showed that the patient was satisfied with the surgical results, where his ankle function met his daily needs, and the Musculoskeletal Tumor Society score was 24. 3D printing tibial intramedullary nail fixation can be successful in the treatment of allograft bone fractures and should be considered as a treatment of choice. In this case, the intramedullary nail matched the surrounding bone well, had good osseointegration, and the patient regained basic function.
The second wave of critical engagement with Stanley Milgram's ‘obedience to authority’ experiments: What did we learn?
Authors: Kaposi David
Published: April 2022

The study critically examines contemporary academic engagement with Stanley Milgram's classic ‘obedience to authority’ experiments. It argues that, following what will be termed the ‘first wave of criticism’ (1964 to mid‐1980s) and ‘consensus and canonization’ (mid‐1980s to mid‐2000s), this present‐day phase has constituted a veritable ‘second wave of criticism’. The ‘second wave’ is reviewed in terms of, first, a return to fundamental dilemmas around the experiments (i.e., replication, ethics, methodology, and theory); and second, a recourse to novel data sources as well as theoretical and epistemological‐methodological developments. Such integration of traditional concerns and new perspectives has resulted in focus being redirected to a forgotten aspect of the experiments: the interactional production of affective dynamics in the lab. Although the ‘second wave’ will be critiqued for selectively focusing on either affective atmosphere or interactional process, the paper will conclude with the suggestion that bringing these two aspects together continues to promise a theoretical contribution to the understanding of the experiments not seen before.
The novel HLA‐DRB1*12:96 allele was likely generated by recombination between DRB1*12:01 and DRB1*14:01
Authors: Long Honghui , Wu Lijuan , Jiao Lin , Zhou Yi , Zhou Juan
Published: April 2022

HLA‐DRB1*12:96 differs from HLA‐DRB1*12:01:01:01 by 10 nucleotide substitutions within exon 2.
Incorporating spatial autocorrelation into house sale price prediction using random forest model
Authors: Hu Lan , Chun Yongwan , Griffith Daniel A.
Published: April 2022

The random forest model has been frequently used for house sale price prediction because researchers have shown that it can create better results with smaller prediction errors than conventional statistical models. However, house sale prices tend to be spatially autocorrelated due to shared neighborhood environments and similar physical characteristics, which have been rarely considered and accounted for in the random forest model. A failure to address spatial autocorrelation may result in over‐ or underpredicted house sale prices, especially when these sale prices are highly spatially dependent. This research proposes an extended random forest approach, introducing additional proxy variables that furnish geographic proximity measures of house locations in order to capture spatial autocorrelation that is unexplained by covariates. An application of the extended random forest approach for house sale prices in Fairfax County, Virginia, confirms the effectiveness of the proxy variables with an improvement of house sale price prediction accuracy. The introduction of the proxy variables can correct over‐ and under‐predicted house sale prices that show an underlying spatial structure.
First‐order logics over fixed domain
Authors: Taylor R. Gregory
Published: April 2022

What we call first‐order logic over fixed domain was initiated, in a certain guise, by Peirce around 1885 and championed, albeit in idiosyncratic form, by Zermelo in papers from the 1930s. We characterise such logics model‐ and proof‐theoretically and argue that they constitute exploration of a clearly circumscribed conception of domain‐dependent generality. Whereas a logic, or family of such, can be of interest for any of a variety of reasons, we suggest that one of those reasons might be that said logic fosters some clarification regarding just what qualifies as a logical concept, a logical operation, or a logical law.
Epidemiology and burden of Haemophilus influenzae disease in Thai children before implementation of the routine immunisation programme: A National Health Data Analysis
Authors: Intusoma Utcharee , Thewamit Rapeepat , Thamcharoenvipas Titaporn , Khantee Puttichart
Published: April 2022

Objectives

To conduct the first pre‐Haemophilus influenzae (Hi) type b (Hib) immunisation programme‐based epidemiological study using national health data.

Methods

We analysed National Health Security Office data, which cover 72% of the Thai population. The study population included children aged <18 years admitted for Hi disease from 2015 to 2019. Hi disease diagnosis and death were based on the International Statistical Classification of Diseases and Related Health Problems (10th revision) hospital discharge summary codes. We estimated the hospital cost per admission using diagnosis‐related grouping with a global budget.

Results

A total of 1125 children aged <18 years were admitted for Hi disease. During the 5‐year‐study, the annual incidence of Hi disease varied from 1.5 to 1.9 per 100,000 children, with an overall case fatality rate (CFR) of 2%. Pneumonia was the most common clinical form, followed by meningitis and sepsis. The incidence, clinical forms and severity of Hi disease were age specific. Infant CFR was higher than that of other age groups. The incidence of Hi disease in children aged <5 years was 4.9 per 100,000 (CFR = 2.0%). Sepsis was the primary cause of infant death, whereas pneumonia was the cause of death in children aged >5 years. The hospital cost ranged from 25,000 to 30,000 THB per admission.

Conclusions

This analysis provided epidemiological data of Hi in Thai children before the Hib routine immunisation programme. The incidence of Hi disease was lower than that previously speculated. Our results could facilitate an assessment of the impact of Hib immunisation programme in Thailand.
Z‐chromosome outliers as diagnostic markers to discriminate Mallard and Chinese Spot‐billed Duck (Anatidae)
Authors: Kulikova Irina V. , Shedko Sergei V. , Zhuravlev Yury N. , Lavretsky Philip , Peters Jeffrey L.
Published: April 2022

Closely related bird species often exhibit elevated differentiation in the Z‐chromosome. Genetic differentiation is repeatedly found in so‐called ‘islands of differentiation’ that might contain loci under selection that contribute to reproductive isolation. Using double‐digest restriction‐associated DNA sequencing (ddRAD‐seq), we examined genomic divergence of Mallard (Anas platyrhynchos) and Chinese Spot‐billed Duck (A. zonorhyncha), two closely related species of ducks that occasionally hybridize. The taxa were distinguishable based on overall ddRAD‐seq allele frequency differences. However, differentiation on the Z‐chromosome was about 4.5 times greater than observed for autosomal DNA and included three fixed differences in SNPs. These SNPs are the first species‐specific molecular markers revealed among mallard group species. The causes of elevated Z‐chromosome divergence are discussed, including the possibility that Z‐linked loci are resistant to introgression and potentially linked to phenotypic differences between the species.
Mass Imbalance Diagnostics in Wind Turbines Using Deep Learning With Data Augmentation
Authors: Dabetwar Shweta , Ekwaro-Osire Stephen , Dias João Paulo , Hübner Guilherme R. , Franchi Claiton M. , Pinheiro Humberto
Published: April 2022

Wind turbines suffer from mass imbalance due to manufacturing, installation, and severe climatic conditions. Condition monitoring systems are essential to reduce costs in the wind energy sector. Many attempts were made to improve the detection of faults at an early stage to plan predictive maintenance strategies, but effective methods have not yet been developed. Artificial intelligence has a huge potential in the wind turbine industry. However, several shortcomings related to the datasets still need to be overcome. Thus, the research question developed for this paper was “Can data augmentation and fusion techniques enhance the mass imbalance diagnostics methods applied to wind turbines using deep learning algorithms?” The specific aims developed were: (i) to perform sensitivity analysis on classification based on how many samples/sample frequencies are required for stabilized results; (ii) to classify the imbalance levels using Gramian angular summation field and Gramian angular difference field and compare against data fusion; and (iii) to classify the imbalance levels using data fusion for augmented data. Convolutional neural network (CNN) techniques were employed to detect rotor mass imbalance for a multiclass problem using the estimated rotor speed as an input variable. A 1.5-MW turbine model was considered and a database was built using the software turbsim, fast, and simulink. The model was tested under different wind speeds and turbulence intensities. The data augmentation and fusion techniques used along with CNN techniques showed improvement in the classification and hence the diagnostics of wind turbines.
Head Impact Kinematics and Brain Deformation in Paired Opposing Youth Football Players
Authors: Milef Gabriella M. , Miller Logan E. , DiGuglielmo Daniella M. , Payne Tanner D. , Filben Tanner M. , Urban Jillian E. , Stitzel Joel D.
Published: April 2022

Head impact exposure is often quantified using peak resultant kinematics. While kinematics describes the inertial response of the brain to impact, they do not fully capture the dynamic brain response. Strain, a measure of the tissue-level response of the brain, may be a better predictor of injury. In this study, kinematic and strain metrics were compared to contact characteristics in youth football. Players on 2 opposing teams were instrumented with head impact sensors to record impact kinematics. Video was collected to identify contact scenarios involving opposing instrumented players (ie, paired contact scenarios) and code contact characteristics (eg, player role, impact location). A previously validated, high-resolution brain finite element model, the atlas-based brain model, was used to simulate head impacts and calculate strain metrics. Fifty-two paired contact scenarios (n = 105 impacts) were evaluated. Lighter players tended to have greater biomechanical metrics compared to heavier players. Impacts to the top of the helmet were associated with lower strain metrics. Overall, strain was better correlated with rotational kinematics, suggesting these metrics may be better predictors of the tissue-level brain response than linear kinematics. Understanding the effect of contact characteristics on brain strain will inform future efforts to improve sport safety.
Molecular and neural basis of pleasant touch sensation
Authors: Liu Benlong , Qiao Lina , Liu Kun , Liu Juan , Piccinni-Ash Tyler J. , Chen Zhou-Feng
Published: April 2022

Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch–conditioned place preference (PT-CPP) test, we show that genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain and itch behaviors in mice. Mutant mice display profound impairments in stress response and prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking and encode reward value. Collectively, we identify PROK2 as a long-sought neuropeptide that encodes and transmits pleasant touch to spinal PROKR2 neurons. These findings may have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to social avoidance behavior and mental disorders.
A stark future for ocean life
Authors: Pinsky Malin L. , Fredston Alexa
Published: April 2022

Model predicts a mass extinction event in the oceans if climate change is uncurbed
Scaffold hopping by net photochemical carbon deletion of azaarenes
Authors: Woo Jisoo , Christian Alec H. , Burgess Samantha A. , Jiang Yuan , Mansoor Umar Faruk , Levin Mark D.
Published: April 2022

Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline
N
-oxides with 390-nanometer light followed by acid-promoted rearrangement affords
N
-acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.
An adsorbent with flexible nanoscopic pores
Authors: Willhammar Tom , Zou Xiaodong
Published: April 2022

Scanning transmission electron microscopy shows the adaptive pores of a zeolite
Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms
Authors: Stevens Laura J. , Pruijssers Andrea J. , Lee Hery W. , Gordon Calvin J. , Tchesnokov Egor P. , Gribble Jennifer , George Amelia S. , Hughes Tia M. , Lu Xiaotao , Li Jiani , Perry Jason K. , Porter Danielle P. , Cihlar Tomas , Sheahan Timothy P. , Baric Ralph S. , Götte Matthias , Denison Mark R.
Published: April 2022

The nucleoside analog remdesivir (RDV) is a Food and Drug Administration–approved antiviral for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Thus, it is critical to understand factors that promote or prevent RDV resistance. We passaged SARS-CoV-2 in the presence of increasing concentrations of GS-441524, the parent nucleoside of RDV. After 13 passages, we isolated three viral lineages with phenotypic resistance as defined by increases in half-maximal effective concentration from 2.7- to 10.4-fold. Sequence analysis identified nonsynonymous mutations in nonstructural protein 12 RNA-dependent RNA polymerase (
nsp12
-RdRp): V166A, N198S, S759A, V792I, and C799F/R. Two lineages encoded the S759A substitution at the RdRp Ser
759
-Asp-Asp active motif. In one lineage, the V792I substitution emerged first and then combined with S759A. Introduction of S759A and V792I substitutions at homologous
nsp12
positions in murine hepatitis virus demonstrated transferability across betacoronaviruses; introduction of these substitutions resulted in up to 38-fold RDV resistance and a replication defect. Biochemical analysis of SARS-CoV-2 RdRp encoding S759A demonstrated a roughly 10-fold decreased preference for RDV-triphosphate (RDV-TP) as a substrate, whereas
nsp12
-V792I diminished the uridine triphosphate concentration needed to overcome template-dependent inhibition associated with RDV. The in vitro–selected substitutions identified in this study were rare or not detected in the greater than 6 million publicly available
nsp12
-RdRp consensus sequences in the absence of RDV selection. The results define genetic and biochemical pathways to RDV resistance and emphasize the need for additional studies to define the potential for emergence of these or other RDV resistance mutations in clinical settings.
Anti-Mycobacterium abscessus Activity of Tuberculosis F-ATP Synthase Inhibitor GaMF1
Authors: Ragunathan Priya , Dick Thomas , Grüber Gerhard
Published: April 2022

New drug targets and molecules with bactericidal activity are needed against the respiratory mycobacterial pathogenMycobacterium abscessus. Employing a lead repurposing strategy, the antituberculosis compound GaMF1 was tested againstM. abscessus.
IKKα-Mediated Noncanonical NF-κB Signaling Is Required To Support Murine Gammaherpesvirus 68 LatencyIn Vivo
Authors: Cieniewicz Brandon , Kirillov Varvara , Daher Isabel , Li Xiaofan , Oldenburg Darby G. , Dong Qiwen , Bettke Julie A. , Marcu Kenneth B. , Krug Laurie T.
Published: April 2022

The latency programs of the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with B cell lymphomas. It is critical to understand the signaling pathways that are used by gammaherpesviruses to establish and maintain latency in primary B cells.
Complete Genome Sequences of Three Streptococcus ruminantium Strains Obtained from Endocarditis Lesions of Cattle in Japan
Authors: Nomoto Ryohei , Ishida-Kuroki Kasumi , Tohya Mari , Nakagawa Ichiro , Sekizaki Tsutomu
Published: April 2022

Streptococcus ruminantium
is a close relative of
Streptococcus suis
, an important zoonotic pathogen that causes various diseases in pigs and humans. Here, we report the complete genome sequences of three
S. ruminantium
strains isolated from bovine endocarditis in Japan.
Generation and Characterization of Human-Mouse STING Chimeras That Allow DENV Replication in Mouse Cells
Authors: Zhu Tongtong , Webb Laurence G. , Veloz Jeury , Wilkins Maris , Aguirre Sebastian , Fernandez-Sesma Ana
Published: April 2022

This article characterizes the interaction between human STING and DENV viral protease complex NS2B3 by constructing serial deletion mutants of STING. Our findings suggest that DENV nonstructural protein NS2B interacts with the transmembrane domains and NS3 with the C-terminal cyclic dinucleotide binding domain of human STING.
Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer
Authors: Corry Shania M , McCorry Amy MB , Lannagan Tamsin RM , Leonard Niamh A , Fisher Natalie C , Byrne Ryan M , Tsantoulis Petros , Cortes-Lavaud Xabier , Amirkhah Raheleh , Redmond Keara L , McCooey Aoife J , Malla Sudhir B , Rogan Emily , Sakhnevych Svetlana , Gillespie Michael A , White Mark , Richman Susan D , Jackstadt Rene-Filip , Campbell Andrew D , Maguire Sarah ,   S:CORT and ACRCelerate consortia, McDade Simon S , Longley Daniel B , Loughrey Maurice B , Coleman Helen G , Kerr Emma M , Tejpar Sabine , Maughan Timothy , Leedham Simon J , Small Donna M , Ryan Aideen E , Sansom Owen J , Lawler Mark , Dunne Philip D
Published: April 2022

Objective

Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy.

Design

To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series ofin vitroand stroma-richin vivomodels to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours.

Results

By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Usingin silico, in vitroandin vivomodels, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype acrossin vitroandin vivomodels. In anin vivomodel of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002).

Conclusion

This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.
History of the British Cardiovascular Society
Authors: Coats Caroline J
Published: April 2022

In 2022, the British Cardiovascular Society celebrates the centenary of its foundation. Starting out as a small group of government-appointed physicians interested in heart disease, the Cardiac Club has grown and adapted to represent all those working in cardiovascular care and research. The historical stages of the organisation’s development are outlined, alongside major innovations in science and technology providing context for a rapidly changing medical world. Only a small part of the history of cardiology in Britain is told, with greater emphasis on describing the broader need for services, skilled workforce, healthcare policy and continuing education. Above all, the history of the British Cardiovascular Society is a story of people and places. The people are those with vision, attitude and leadership to improve the care of communities across the world. The places are those that enabled conversation, innovation and freedom to bring about change. It is hard to believe the remarkable progress in diagnosis, prevention and treatment of heart disease over 100 years, but a thriving modern Society must be the greatest legacy of its founders.
Joint British Societies’ guideline on management of cardiac arrest in the cardiac catheter laboratory
Authors: Dunning Joel , Archbold Andrew , de Bono Joseph Paul , Butterfield Liz , Curzen Nick , Deakin Charles D , Gudde Ellie , Keeble Thomas R , Keys Alan , Lewis Mike , O'Keeffe Niall , Sarma Jaydeep , Stout Martin , Swindell Paul , Ray Simon
Published: April 2022

More than 300 000 procedures are performed in cardiac catheter laboratories in the UK each year. The variety and complexity of percutaneous cardiovascular procedures have both increased substantially since the early days of invasive cardiology, when it was largely focused on elective coronary angiography and single chamber (right ventricular) permanent pacemaker implantation. Modern-day invasive cardiology encompasses primary percutaneous coronary intervention, cardiac resynchronisation therapy, complex arrhythmia ablation and structural heart interventions. These procedures all carry the risk of cardiac arrest.

We have developed evidence-based guidelines for the management of cardiac arrest in adult patients in the catheter laboratory. The guidelines include recommendations which were developed by collaboration between nine professional and patient societies that are involved in promoting high-quality care for patients with cardiovascular conditions. We present a set of protocols which use the skills of the whole catheter laboratory team and which are aimed at achieving the best possible outcomes for patients who suffer a cardiac arrest in this setting. We identified six roles and developed a treatment algorithm which should be adopted during cardiac arrest in the catheter laboratory. We recommend that all catheter laboratory staff undergo regular training for these emergency situations which they will inevitably face.
Sex difference in atrial fibrillation recurrence after catheter ablation and antiarrhythmic drugs
Authors: Park Yoon Jung , Park Je-Wook , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam
Published: April 2022

Objective

The risk of recurrence after atrial fibrillation (AF) catheter ablation (AFCA) is higher in women than in men. However, it is unknown whether a sex difference exists in antiarrhythmic drug (AAD) responsiveness among patients with recurrence.

Methods

Among 2999 consecutive patients (26.5% women, 58.3±10.9 years old, 68.1% paroxysmal AF) who underwent de novo AFCA, we compared and evaluated the sex differences in rhythm outcome in 1094 patients with recurrence and in 788 patients who subsequently underwent rhythm control with AAD.

Results

During a follow-up of 48.2±34.9 months, 1094 patients (36.5%) had AF recurrence after AFCA, and 508 of 788 patients (64.5%) had AF recurrence under AAD. Although the rhythm outcome of a de novo AFCA was worse (log-rank p=0.041, HR 1.28, 95% CI 1.02 to 1.59), p=0.031) in women, AAD response after postprocedural recurrences was better in women than in men (log-rank p=0.003, HR 0.75, 95% CI 0.59 to 0.95, p=0.022), especially in women older than 60 years old (log-rank p=0.003). In 249 patients who underwent repeat procedure after AAD use, the pulmonary vein (PV) reconnection rate (62.7% vs 76.8%, p=0.048) was lower in women than in men but not the existence of extra-PV trigger (37.8% vs 25.4%, p=0.169).

Conclusions

Although women showed worse rhythm outcomes than men after AFCA, the post-AFCA AAD response was better in elderly women than in men.

Trial registration number

NCT02138695.
Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer
Authors: Revenko Alexey , Carnevalli Larissa S , Sinclair Charles , Johnson Ben , Peter Alison , Taylor Molly , Hettrick Lisa , Chapman Melissa , Klein Stephanie , Solanki Anisha , Gattis Danielle , Watt Andrew , Hughes Adina M , Magiera Lukasz , Kar Gozde , Ireland Lucy , Mele Deanna A , Sah Vasu , Singh Maneesh , Walton Josephine , Mairesse Maelle , King Matthew , Edbrooke Mark , Lyne Paul , Barry Simon T , Fawell Stephen , Goldberg Frederick W , MacLeod A Robert
Published: April 2022

Background

The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man.

Methods

We have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons.

Results

AZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8+ T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy.

Conclusions

Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669).
High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC
Authors: Frigola Joan , Carbonell Caterina , Iranzo Patricia , Pardo Nuria , Callejo Ana , Cedres Susana , Martinez-Marti Alex , Navarro Alejandro , Soleda Mireia , Jimenez Jose , Hernandez-Losa Javier , Vivancos Ana , Felip Enriqueta , Amat Ramon
Published: April 2022

Background

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive.

Patients and methods

We assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA).

Results

High SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10−5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort.

Conclusions

SCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs.
Combining bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) improves systemic antitumor CD8+T cell cytotoxicity over BEMPEG+RT
Authors: Rolig Annah S , Rose Daniel C , McGee Grace Helen , Rubas Werner , Kivimäe Saul , Redmond William L
Published: April 2022

Background

Tumor cell death caused by radiation therapy (RT) triggers antitumor immunity in part because dying cells release adjuvant factors that amplify and sustain dendritic cell and T cell responses. We previously demonstrated that bempegaldesleukin (BEMPEG: NKTR-214, an immunostimulatory IL-2 cytokine prodrug) significantly enhanced the antitumor efficacy of RT through a T cell-dependent mechanism. Because RT can induce either immunogenic or tolerogenic cell death, depending on various factors (radiation dose, cell cycle phase), we hypothesized that providing a specific immunogenic adjuvant, like intratumoral therapy with a novel toll-like receptor (TLR) 7/8 agonist, NKTR-262, would improve systemic tumor-specific responses through the activation of local innate immunity. Therefore, we evaluated whether intratumoral NKTR-262 combined with systemic BEMPEG treatment would elicit improved tumor-specific immunity and survival compared with RT combined with BEMPEG.

Methods

Tumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; intravenously), RT (12 Gy × 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+and CD8+T cell responses in the blood and tumor 7 days post-treatment. The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+T cell cytolytic activity was determined by an in vitro CTL assay. Data are representative of 1–2 independent experiments (n=5–14/group) and statistical significance was determined by 1-way analysis of variance (ANOVA) or repeated measures ANOVA (p value cut-off of 0.05).

Results

BEMPEG+NKTR-262 significantly improved survival compared with BEMPEG+RT in a CD8+T cell-dependent manner. Response to BEMPEG+NKTR-262 was characterized by a significant expansion of activated CD8+T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, BEMPEG+NKTR-262 induced higher frequencies of GzmA+CD8+T cells exhibiting reduced expression of suppressive molecules (PD-1+), compared with BEMPEG+RT (p<0.05). Further, BEMPEG+NKTR-262 treatment induced greater tumor-specific CD8+T cell cytolytic function than BEMPEG+RT.

Conclusions

BEMPEG+NKTR-262 therapy elicited more robust expansion of activated CD8+T cells compared with BEMPEG+RT, suggesting that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared with RT. A clinical trial of BEMPEG+NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).
Albumin and interferon-β fusion protein serves as an effective vaccine adjuvant to enhance antigen-specific CD8+ T cell-mediated antitumor immunity
Authors: Tseng Ssu-Hsueh , Cheng Max A , Farmer Emily , Ferrall Louise , Kung Yu Jui , Lam Brandon , Lim Ling , Wu T-C , Hung Chien-Fu
Published: April 2022

Background

Type I interferons (IFN) promote dendritic cells maturation and subsequently enhance generation of antigen-specific CD8 +T cell for the control of tumor. Using type I interferons as an adjuvant to vaccination could prove to be a potent strategy. However, type I interferons have a short half-life. Albumin linked to a protein will prolong the half-life of the linked protein.

Methods

In this study, we explored the fusion of albumin to IFNβ (Alb-IFNβ) for its functional activity both in vitro and in vivo. We determined the half-life of Alb-IFNβ following treatment in the serum, tumor, and tumor draining lymph nodes in both wild type and FcRn knockout mice. We characterized the ability of Alb-IFNβ to enhance antigen-specific CD8+ T cells using ovalbumin (OVA) or human papillomavirus (HPV) E7 long peptides. Next, we evaluated the therapeutic antitumor effect of coadministration of AlbIFNβ with antigenic peptides against HPVE7 expressing tumor and the treatment’s ability to generate HPVE7 antigen specific CD8+ T cells. The contribution of the antitumor effect by lymphocytes was also examined by an antibody depletion experiment. The ability of Alb-IFNβ to serve as an adjuvant was tested using clinical grade therapeutic protein-based HPV vaccine, TACIN.

Results

Alb-IFNβ retains biological function and does not alter the biological activity of IFNβ. In addition, Alb-IFNβ extends half-life of IFNβ in serum, lymph nodes and tumor. The coadministration of Alb-IFNβ with OVA or HPVE7 antigenic peptides enhances antigen-specific CD8 +T cell immunity, and in a TC-1 tumor model results in a significant therapeutic antitumor effect. We found that CD8 +T cells and dendritic cells, but not CD4 +T cells, are important for the observed antitumor therapeutic effect mediated by Alb-IFNβ. Finally, Alb-IFNβ served as a potent adjuvant for TA-CIN for the treatment of HPV antigen expressing tumors.

Conclusions

Overall, Alb-IFNβ serves as a potent adjuvant for enhancement of strong antigen-specific CD8 +T cell antitumor immunity, reduction of tumor burden, and increase in overall survival. Alb-IFNβ potentially can serve as an innovative adjuvant for the development of vaccines for the control of infectious disease and cancer.
Identifying urban features for vulnerable road user safety in Europe
Authors: Klanjčić Marina , Gauvin Laetitia , Tizzoni Michele , Szell Michael
Published: April 2022

One of the targets of the UN Sustainable Development Goals is to substantially reduce the number of global deaths and injuries from road traffic collisions. To this aim, European cities adopted various urban mobility policies, which has led to a heterogeneous number of injuries across Europe. Monitoring the discrepancies in injuries and understanding the most efficient policies are keys to achieve the objectives of Vision Zero, a multi-national road traffic safety project that aims at zero fatalities or serious injuries linked to road traffic. Here, we identify urban features that are determinants of vulnerable road user safety through the analysis of inter-mode collision data across European cities. We first build up a data set of urban road crashes and their participants from 24 cities in 5 European countries, using the widely recommended KSI indicator (killed or seriously injured individuals) as a safety performance metric. Modelling the casualty matrices including road infrastructure characteristics and modal share distribution of the different cities, we observe that cities with the highest rates of walking and cycling modal shares are the safest for the most vulnerable users. Instead, a higher presence of low-speed limited roads seems to only significantly reduce the number of injuries of car occupants. Our results suggest that policies aimed at increasing the modal share of walking and cycling are key to improve road safety for all road users.