bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-mass young stars in the Milky Way unveiled by DBSCAN and Gaia EDR3: Mapping the star forming regions within 1.5 kpc
Authors: Prisinzano L. , Damiani F. , Sciortino S. , Flaccomio E. , Guarcello M. G. , Micela G. , Tognelli E. , Jeffries R. D. , Alcalá J. M.
Published: July 2022

Context. With an unprecedented astrometric and photometric data precision, Gaia EDR3 provides, for the first time, the opportunity to systematically detect and map, in the optical bands, the low-mass populations of the star forming regions (SFRs) in the Milky Way.

Aims. We aim to provide a catalogue of the Gαiα EDR3 data (photometry, proper motions and parallaxes) of the young stellar objects (YSOs) identified in the Galactic plane |b| < 30°) within about 1.5 kpc. The catalogue of the SFRs to which they belong is also provided to study the properties of the very young clusters and put them in the context of the Galaxy structure.

Methods. We applied the machine learning unsupervised clustering algorithm density-based spatial clustering of applications with noise (DBSCAN) to a sample of Gaia EDR3 data photometrically selected on the region where very young stars (t ≲ 10 Myr) are expected to be found, with the aim of identifying co-moving and spatially consistent stellar clusters. A sub-sample of 52 clusters, selected among the 7 323 found with DBSCAN, has been used as template data set to identify very young clusters from the pattern of the observed colour-absolute magnitude diagrams through a pattern-match process.

Results. We find 124440 candidate YSOs clustered in 354 SFRs and stellar clusters younger than 10 Myr and within ≲ 1.5 kpc. In addition, 65 863 low-mass members of 322 stellar clusters located within ~500pc and with ages 10Myr ≲ t ≲ 100 Myr were also found.

Conclusions. The selected YSOs are spatially correlated with the well-known SFRs. Most of them are associated with well-concentrated regions or complex structures of the Galaxy, and a substantial number of them have been recognised for the first time. The massive SFRs, such as, for example, Orion, Sco-Cen, and Vela, located within 600–700 pc trace a very complex three-dimensional pattern, while the farthest ones seem to follow a more regular pattern along the Galactic plane.
A method for yield and cycle time improvements in Al alloy casting with enhanced conductivity steel for die construction
Authors: Vergnano Alberto , Salvati Emanuele , Magistrelli Andrea , Brambilla Edoardo , Veronesi Paolo , Leali Francesco
Published: July 2022

A die for Al alloy casting must be designed to achieve the expected quality levels. Moreover, the casting unit cost must be regarded as the objective function to be minimised. It can be expressed as a function of the quantity of materials and energy to be used, cycle time and equipment investment. This work compares the performance of the die with inserts manufactured using the usual 1.2343 steel with that of the innovative 1.2383. The latter is considered due to its enhanced thermal conductivity, despite being more expensive. Simulation experiments are designed to evaluate different die layouts. The quality design solutions are evaluated against the cost objective function in order to identify the optimal die choice. A case study on gravity die casting (GDC) of an AlSi7Mg0.3 engine head shows faster solidification dynamics when using 1.2383 instead of 1.2343 steel. This reduces the feeder volume, thus increasing the production yield and speeding up the cycle time with a leverage effect. The higher investment cost for the inserts is rapidly returned thanks to the reduction in variable costs. The Return On Investment (ROI) with the improved die in the new solution is short compared with the life of the die.
Phytotherapie bei chronischen Venenleiden
Authors: Vlachojannis Julia , Chrubasik-Hausmann Sigrun
Published: July 2022

Beinödeme können kardiale oder venöse Ursachen haben. Bei chronischen Venenleiden kommen Phlebotonika zum Einsatz. Hier muss zwischen Pflanzenextrakten und extrahierten bzw. synthetischen Pflanzenstoffen differenziert werden, die nicht zu den Phytotherapeutika zählen. In der gerade veröffentlichten überarbeiteten Leitlinie der Gesellschaft für Gefäßchirurgie wurden alle Phlebotonika gemeinsam als empfehlenswerte Behandlung mit gesicherter Wirksamkeit eingestuft. Zu den pflanzlichen Optionen zählen in Europa vor allem Extrakte aus dem Stechenden Mäusedorn (Ruscus aceolatus), der Rosskastanie (Aesculus hippocastanum) und dem Roten Weinlaub (Vitis vinifera). Die Wirksamkeits-Evidenz für Ruscusextrakt ist schlecht und für Rosskastanien und Roten Weinlaubextrakt nur mäßig. Trotzdem würdigte die S2k-Leitlinie aus dem Jahr 2019 den Einsatz der Extrakte aus der Rosskastanie und dem Roten Weinlaub mit dem Hinweis, dass die volle Wirksamkeit erst nach bis zu 4 Wochen eintritt. Deshalb ist es jetzt dringend erforderlich, den ausstehenden Wirksamkeitsnachweis mittels konfirmatorischer Studien für jeden Pflanzenextrakt separat zu erbringen, um die Leitlinien an die Wirksamkeitsevidenz anzupassen.
Influence of the Amount of Toothpaste on Cleaning Efficacy: An In Vitro Study
Authors: Sarembe Sandra , Ufer Carolin , Kiesow Andreas , Limeback Hardy , Meyer Frederic , Fuhrmann Ines , Enax Joachim
Published: July 2022

Objectives The aim of this in vitro study was to test the influence of the amount of toothpaste on enamel cleaning efficacy.

Materials and Methods The hydrated silica-based test toothpaste (radioactive dentin abrasion: 60.19 ± 1.35) contained all ingredients of a regular fluoride toothpaste. The cleaning efficacy of four different toothpaste amounts (1.00 g, 0.50 g [both “full length of brush”], 0.25 g [“pea-size”], and 0.125 g [“grain of rice-size”]) diluted in 1.00 mL water were each tested for different brushing times (10, 30, 60, 120, 180, and 300 seconds) using a standardized staining model on human molars with a brushing machine. Photographic documentation and colorimetric measurements were conducted, respectively, initially, after staining and after each brushing step. Colorimetric measurements were used to calculate the stain removal (in %).

Statistical Analysis Results were analyzed by one-way analysis of variance with post hoc Tukey test and Levene's test for analysis of homogeneity of variance. The level of significance α was set at ≤ 0.05.

Results The cleaning efficacy decreased significantly when using smaller toothpaste amounts. Stain removal after 120 seconds brushing time was: 77.4 ± 5.0% (1.00 g toothpaste), 75.7 ± 3.4% (0.50 g toothpaste), 54.1 ± 6.7% (0.25 g toothpaste), and 48.2 ± 7.1% (0.125 g toothpaste), respectively.

Conclusion In this in vitro study the cleaning efficacy of a medium-abrasive, hydrated silica-based toothpaste was analyzed. Note that 1.00 g toothpaste showed for all brushing times a significantly higher cleaning efficacy than 0.25 g toothpaste and 0.125 g toothpaste.
Evaluation of HPV E6/E7 mRNA Detection in Clinically Suspected Cases of Cervical Cancer with Abnormal Cytology: Time to Upgrade the Screening Protocols
Authors: Sharma Bhawna , Lakhanpal Vikas , Singh Kanwardeep , Oberoi Loveena , Bedi Preet Kamal , Devi Pushpa
Published: July 2022

Background Human papillomavirus (HPV) E6/E7 mRNA tests determine the oncogenic activity of the virus and represent a good clinical biomarker for predicting the risk of cervical cancer. So, the present study was conducted to know the role of HPV E6/E7 mRNA as a predictive biomarker for cervical carcinoma.

Methodology The present study was conducted on 55 clinical samples of cervical scrapings and biopsy from the clinically suspected cases (based on signs and symptoms) of cervical cancer having abnormal PAP smear. The samples were processed in three steps—(1) HPV DNA detection, (2) HPV E6/E7 mRNA detection, and (3) histopathological analysis.

Results Out of a total of 55 patients, 16 (29.09%) were positive for both HPV E6/E7 mRNA and HPV DNA and six were positive for only HPV DNA. So, a total of 22 (40%) patients were positive for HPV DNA. Out of these 22 samples, 10 (45.5%) were of HPV-16, six (27.3%) were of HPV-18, four (18.2%) were of HPV-31, and two (9.1%) were of HPV-45. Out of total 16 patients positive for HPV E6/E7 mRNA, 10 (62.5%) were of genotype 16 and six (37.5%) were of genotype 18. The patients who were found positive for HPV 31 and 45 genotypes did not have E6/E7 mRNA expression. On colposcopic-guided biopsy, among these 16 samples, eight (50%) were diagnosed with invasive squamous cell carcinoma, six (37.5%) with cervical intraepithelial neoplasia grade 3 (CIN3), and two (12.5%) with CIN2. Out of those six patients in whom only HPV DNA was positive, five had normal biopsy findings and one had CIN1.

Conclusion The present study suggests that HPV E6/E7 mRNA detection could be more reliable than DNA testing for predicting the risk of progression of HPV-induced cervical lesions to cervical carcinoma and it can be used as a non-invasive tool for triage and patient follow-up.
Generating a Bispecific Antibody Drug Conjugate Targeting PRLR and HER2 with Improving the Internalization
Authors: Zong Hui-Fang , Zhang Bao-Hong , Zhu Jian-Wei
Published: July 2022

Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. The bispecific targeting could improve the specificity, affinity, and internalization of the ADC molecules. Prolactin preceptor (PRLR) and HER2 have crosstalk signaling in breast cancer, and PRLR undergoes a rapid internalization compared with HER2. To improve the efficacy of HER2 ADCs with enhancing the target specificity and internalization, we constructed a PRLR/HER2-targeting bispecific ADC (BsADC). We evaluated the characterization of PRLR × HER2 BsADC from the affinity and internalization, and further assessed its in vitro cytotoxicity in human breast-cancer cell lines (BT474, T47D, and MDA-MB-231) using Cell Count Kit-8 analysis. Our data demonstrated that PRLR × HER2 BsADC kept the affinity to two targeting antigens after conjugating drugs and exhibited higher internalization efficiency in comparison to HER2 ADC. Furthermore, PRLR × HER2 BsADC demonstrated to have superior antitumor activity in human breast cancer in vitro. In conclusion, our findings indicate that it is feasible through increasing the internalization of target antibody to enhance the antitumor activity and therapeutic potential that could be further evaluated in in vivo animal model.
Using cognitive discourse functions and comparative judgement to build teachers’ knowledge of content and language
integration for assessment in a bilingual education program
Authors: Morton Tom
Published: July 2022

This paper reports a study carried out in the context of a seminar designed to build teachers’ knowledge of
content and language integration for assessment in a bilingual education program in Madrid, Spain. The participants were seven
teachers (two primary, five secondary) of English and science (primary), and art, history, Spanish language arts and English
(secondary). The teachers were introduced to the concept of cognitive discourse function (CDF) and assessed
samples of students’ work expressing the functions define, evaluate, and explore, using
comparative judgement. In sharing and justifying their assessments, they articulated the criteria they used to take their
decisions. The findings show that participants emphasized content quality over quantity and language form over function. There was
also evidence that the concept of CDFs enabled them to express new understandings of the content-language relationship in
assessment. The study has implications for building the knowledge base for content and language integrated assessment across CBLE
programs.
Triple joining of different sheets with self-pierce riveting method
Authors: Çavuşoğlu Oktay , Bakırcı Altuğ , Dinkçi Haluk , Yılmazoğlu Ahmet Gürkan
Published: July 2022

Self-piercing riveting (SPR) is a high-speed mechanical joining technique for sheet metal materials. In this study, the mechanical properties of DC04 steel and AA5182 aluminium alloy in triple combinations joined by the SPR method were investigated. For this purpose, triple-joining processes were performed in different combinations, and macro-structural analysis and tensile shear tests were carried out by comparing their mechanical properties. As a result of the study, the highest shear forces were obtained in FFA (DC04-DC04-AA5182) and AFF (AA5182-DC04-DC04) combinations. As the number of aluminium layers increases, the probability of tearing increases in triple joining. Higher spread ratios were generally measured under conditions with hard materials in the upper layers and soft materials in the lower layers.
The benefit of urban green area in Kota Kinabalu, Sabah
Authors: Mojiol A R , Lim W S , Chung K C L , Dani J L
Published: July 2022

The city of Kota Kinabalu features several urban green areas, which become the focal points for the urban inhabitants. This study was conducted to determine the benefits and public perceptions that encourage them to visit the local urban green area. The convenience sampling method was used, in which questionnaires were distributed to 101 respondents of the local park visitors. The present finding revealed that most of the respondents strongly agreed that the urban greens help to improve the physical well-being of the urban dwellers (Mean score, µ=4.27), regulate the urban temperature during sunny days (µ=4.20), encourage people to spend more time on outdoor activities in nature (µ=4.14), help to remove air pollutants (µ=4.09), control the amount of water on the ground surface during the rainy season (µ=4.06), reduce stress, anxiety, and depression (µ=4.04), prevent the occurrence of a flash flood (µ=3.98), and promote social interactions among people (µ=3.81). The correlation between the respondents’ education and the mean benefits of urban green areas in Kota Kinabalu was significant (p<0.05). In conclusion, the public perception of the benefits of urban green areas is generally positive, and they also exhibit a high understanding of its importance towards urban dwellers.
Converting wood-related waste materials into other value-added products: A short review
Authors: Mokhtar N , Razali S M , Sulaiman M S , Edin T , Wahab R
Published: July 2022

This paper reviews converting wood-related waste materials from forestry, wood-based industry, and agriculture activities into other value-added products such as bio-energy, construction materials, agricultural compost, and handicraft application. The wood waste, however, needs to be processed before it can be utilized. The information obtained is reviewed in order to enable them to be useful to the government planners and those involved in the wood-based industry. The gross domestic product from the forest-related industry reached RM6.38 billion in 2019. This resulted in a large amount of waste produced annually. Utilizing these waste materials instead of letting them rot or deteriorate in the forests or at the factory yards sites could generate income and create job opportunities for the local community. A proper and systematic study needs to be undertaken in order to make them into reality.
A Modified Technique in Rhinoplasty: A Septal Extension Graft Complex Using Septal Cartilage, Ethmoid Bone, and Auricular Cartilage
Authors: Wang Jue , Li Binghang , Wang Qianwen , Wu Lehao , Zhang Chang , Zhao Sichun , Chen Lianjie , Li Kongying , Zhou Xu
Published: July 2022

Background

Due to the small and weak septal cartilage of Asians, it is a challenge to obtain ideal tip projection and nose lengthening in this population by performing septal extension grafts with only septal cartilage.

Objectives

The aim of this study was to introduce a septal extension graft complex incorporating nasal septal cartilage, the perpendicular plate of the ethmoid bone, and bilateral auricular cartilage, and to examine its effectiveness in terms of morphological and mechanical support.

Methods

Septal cartilage was harvested under an endoscope according to standard techniques. Two pieces of the perpendicular plate of the ethmoid bone, placed on either side of the “L” strut, served as 2 spreader grafts. A double layer of auricular cartilage was fixed as columellar strut grafts. Three-dimensional facial scanning was used to examine the change of 3 parameters. Nasal tip resistance was evaluated by a digital Newton meter.

Results

In total, 25 patients were followed up postoperatively for a mean of 25.9 months. The analysis showed significant differences in both contour parameters and nasal resistance: nasal length (mean [standard deviation], 41.4 [4.0] vs 46.2 [3.4] mm, P < 0.05) and nasal tip projection (21.3 [3.2] vs 24.4 [2.7] mm, P < 0.05) appeared to increase postoperatively, whereas nasolabial angle (117.6° [5.9°] vs 109.5° [5.3°], P < 0.05) showed a significant decrease after surgery. The resistance of the nasal tip also increased significantly (P < 0.05) at displacements of 1, 2, and 3 mm. All patients were satisfied with the aesthetic results, and no serious complications occurred.

Conclusions

This kind of modified septal extension graft technique can effectively adjust nasal morphology for short-nose East Asians.

Level of Evidence: 4
The Event of a Poem: Denise Riley’s ‘Lone Star Clattering’
Authors: Attridge Derek
Published: July 2022

If we think of a literary work as an event experienced by a reader or listener, and if one mode of literary criticism is an honest report on that event, a poem whose singularity lies in part in its resistance to the conventional protocols of interpretation, such as coherence and continuity, presents a particular challenge. In this short essay, I give an account of my reading of Denise Riley’s ‘Lone Star Clattering’ that attempts to reflect the obstacles it places in the way of such a critical mode, using, and testing, an approach developed to describe the operation of the traditional lyric poem, Don Paterson’s theory of ‘conceptual domains’.
Is This the Way to Amarillo? Reading Denise Riley with Derek Attridge
Authors: Wilkinson John
Published: July 2022

This essay responds to a challenge offered by the avowed bafflement of the critic and prosodist Derek Attridge faced with a poem by Denise Riley, ‘Lone Star Clattering’. It argues that Attridge’s adoption of an interpretative approach derived from Don Paterson, employing a step-by-step and constrictive cognitive framing, cannot succeed with a late Modernist lyric poem. Drawing on classroom experience with the same poem, it describes a prevalent cats-cradle approach as a variant on such constrictive reading, where a small group of external referents is grabbed onto, and the poem forced into unseemly conformity with them. The essay proposes instead a practice of feline reading characterized by a hovering casual interest, a constant scan of the sensual and mental fields so that their contours are felt, while sustaining a hair-trigger responsiveness to any unanticipated event along with a Keatsian tolerance of irresolution.
Reading the Event of the Poem: Derek Attridge and John Wilkinson on Denise Riley’s ‘Lone Star Clattering’
Authors: Nowell Smith David
Published: July 2022

In this brief introduction to Derek Attridge’s ‘The Event of a Poem’ and John Wilkinson’s ‘Reading Denise Riley with Derek Attridge’, David Nowell Smith outlines some of the key concepts and questions explored in Attridge’s and Wilkinson’s essays. The central question is a double one: How does meaning in a poem unfold, and how do we as readers make sense of this unfolding? To ask this question means focusing on meaning as a process rather than a content that lies notionally behind the words; it is to understand the poem as actualized in the event, and experience, of its encounter with its audience/reader. The introduction reflects on the peculiar challenges, and pleasures, posed by a poem, such as Denise Riley’s ‘Lone Star Clattering’, where the multiple registers, allusions, and references, would complicate our habitual meaning-making processes. What do individual reading histories bring to such a poem? And what kinds of attention would this poem demand of its readers?
Classification of Uniconnected Involutive Solutions of the Yang–Baxter Equation With Odd Size and a Z-Group Permutation Group
Authors: Castelli Marco
Published: July 2022

In the first part of this paper, we investigate the retraction of finite uniconnected involutive non-degenerate set-theoretic solutions of the Yang–Baxter equation by means of left braces, giving a precise description in some cases. In the core of the paper, we also use left braces to classify all the uniconnected involutive non-degenerate set-theoretic solutions having odd size and a Z-group permutation group. As an application, we classify all the uniconnected involutive non-degenerate solutions having odd square-free size.
Impact of Cover Crop Planting and Termination Dates on Arthropod Activity in the Following Corn
Authors: Inveninato Carmona Gabriela , Robinson Emily , Tonon Rosa Alexandre , Proctor Christopher A , McMechan Anthony Justin
Published: July 2022

Relative to fallow-cash crop rotations, the addition of a cover crop can contribute to greater plant diversity and has the potential to conserve predatory arthropods. The transition of arthropods from a cover crop to a subsequent cash crop depends on several factors, such as cover crop biomass production and weather conditions. Information about the effect of cover crop planting and termination dates on arthropods in a subsequent corn system is limited. A two-year field study was conducted in Nebraska in 2018/2019 and 2019/2020 to evaluate the impact of cover crop planting and termination dates as a source for arthropods in the subsequent corn. A total of 38,074 and 50,626 arthropods were collected in the first and second year, respectively. In both years, adding a grass cover crop increased predatory arthropods but reduced yield in follow corn crop. Of the arthropods collected, Carabidae and Araneae had greater activity with cover crop biomass increments, whereas Collembola and Acari activity only increased in treatments with little or no cover crop biomass. Insect pest pressure was not significant in any treatment for either year. A cover crop planted in mid- or late-September and terminated at corn planting was identified as the best management strategy to maximize cover crop biomass, increase predator activity, and modify predator-prey dynamics. The results of this study provide growers with a cover crop management strategy to maximize cover crop biomass, beneficial arthropod activity, and potentially minimize insect pest problems; however, corn Zea Mays (L.) grain yield was reduced as cover crop biomass increased.
Spectrum of coronary anomalies and their categorical approach: rare case series
Authors: Bashyal Krishnaprasad , Koirala Bhagawan , Bhattarai Anil , Baral Ravi Kumar , Khakural Prabhat , Shakya Samir , Kadel Prashiddha Bikram
Published: July 2022

The incidence of coronary artery anomalies (CAAs) is 0.2–1.2% of the population. Its paradox of being a rare entity with presentation ranging from sudden cardiac death, congestive heart failure, myocardial infarction to being clinically silent, asserts a challenge to its treating physician. Among the various major categories of CAA, we describe four different types of these anomalies in our retrospective evaluation over 2 years. They include – coronary cameral fistula with coronary aneurysm, congenital atresia of left main, anomalous aortic origin of left anterior descending (LAD) and circumflex artery (LCx) with malignant LAD course, anomalous origin of left coronary artery from pulmonary artery (ALCAPA). Although the child with ALCAPA succumbed despite every possible and available timely efforts, other patients had good postoperative recovery and a brief hospital stay.
A Comprehensive Analysis of Injuries During Army Basic Military Training
Authors: Gibson Neil , Drain Jace R , Larsen Penelope , Michael Scott , Groeller Herbert , Sampson John A
Published: July 2022

Introduction

The injury definitions and surveillance methods commonly used in Army basic military training (BMT) research may underestimate the extent of injury. This study therefore aims to obtain a comprehensive understanding of injuries sustained during BMT by employing recording methods to capture all physical complaints.

Materials and methods

Six hundred and forty-six recruits were assessed over the 12-week Australian Army BMT course. Throughout BMT injury, data were recorded via (1) physiotherapy reports following recruit consultation, (2) a member of the research team (third party) present at physical training sessions, and (3) recruit daily self-reports.

Results

Two hundred and thirty-five recruits had ≥1 incident injury recorded by physiotherapists, 365 recruits had ≥1 incident injury recorded by the third party, and 542 recruits reported ≥1 injury-related problems via the self-reported health questionnaire. Six hundred twenty-one, six hundred eighty-seven, and two thousand nine hundred sixty-four incident injuries were recorded from a total of 997 physiotherapy reports, 1,937 third-party reports, and 13,181 self-reported injury-related problems, respectively. The lower extremity was the most commonly injured general body region as indicated by all three recording methods. Overuse accounted for 79% and 76% of documented incident injuries from physiotherapists and the third party, respectively.

Conclusions

This study highlights that injury recording methods impact injury reporting during BMT. The present findings suggest that traditional injury surveillance methods, which rely on medical encounters, underestimate the injury profile during BMT. Considering accurate injury surveillance is fundamental in the sequence of injury prevention, implementing additional injury recording methods during BMT may thus improve injury surveillance and better inform training modifications and injury prevention programs.
A critical review of mineral–microbe interaction and co-evolution: mechanisms and applications
Authors: Dong Hailiang , Huang Liuqin , Zhao Linduo , Zeng Qiang , Liu Xiaolei , Sheng Yizhi , Shi Liang , Wu Geng , Jiang Hongchen , Li Fangru , Zhang Li , Guo Dongyi , Li Gaoyuan , Hou Weiguo , Chen Hongyu
Published: July 2022

Mineral–microbe interactions play important roles in environmental change, biogeochemical cycling of elements and formation of ore deposits. Minerals provide both beneficial (physical and chemical protection, nutrients, and energy) and detrimental (toxic substances and oxidative pressure) effects to microbes, resulting in mineral-specific microbial colonization. Microbes impact dissolution, transformation and precipitation of minerals through their activity, resulting in either genetically controlled or metabolism-induced biomineralization. Through these interactions, minerals and microbes co-evolve through Earth history. Mineral–microbe interactions typically occur at microscopic scale but the effect is often manifested at global scale. Despite advances achieved through decades of research, major questions remain. Four areas are identified for future research: integrating mineral and microbial ecology, establishing mineral biosignatures, linking laboratory mechanistic investigation to field observation, and manipulating mineral–microbe interactions for the benefit of humankind.
Evolutionary traits of Tick-borne encephalitis virus: Pervasive non-coding RNA structure conservation and molecular epidemiology
Authors: Kutschera Lena S , Wolfinger Michael T
Published: July 2022

Tick-borne encephalitis virus (TBEV) is the aetiological agent of tick-borne encephalitis, an infectious disease of the central nervous system that is often associated with severe sequelae in humans. While TBEV is typically classified into three subtypes, recent evidence suggests a more varied range of TBEV subtypes and lineages that differ substantially in the architecture of their 3ʹ untranslated region (3ʹUTR). Building on comparative genomic approaches and thermodynamic modelling, we characterize the TBEV UTR structureome diversity and propose a unified picture of pervasive non-coding RNA structure conservation. Moreover, we provide an updated phylogeny of TBEV, building on more than 220 publicly available complete genomes, and investigate the molecular epidemiology and phylodynamics with Nextstrain, a web-based visualization framework for real-time pathogen evolution.
Budget Impact Analysis of CAR T-cell Therapy for Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in Germany
Authors: Skalt Daniela , Moertl Bernhard , von Bergwelt-Baildon Michael , Schmidt Christian , Schoel Wolfgang , Bücklein Veit , Weiglein Tobias , Dreyling Martin , Berger Karin
Published: July 2022

The aim was to assess the incremental costs of chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel, tisagenlecleucel) compared with standard of care in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) from the German third-party payer perspective. A budget impact model was established over a 6-year period. Estimation of the third-line population: partitioned survival model based on outcome data from peer-reviewed literature, a top-down approach based on population forecasts, and age-standardized incidences. Cost data were derived from the controlling department of a tertiary hospital and a German cost-of-illness study. In the scenario analysis, the budget impact of treating second-line DLBCL patients was calculated. One-way deterministic sensitivity analyses were conducted to test the robustness of the model. For the period 2021-2026, 788-867 (minimum population, min) and 1,068-1,177 (maximum population, max) adult third-line r/r DLBCL patients were estimated. The budget impact ranged from €39,419,562; €53,426,514 (min; max) in year 0 to €122,104,097; €165,763,001 (min; max) in year 5. The scenario analysis resulted in a budget impact of €65,987,823; €89,558,611 (min; max) and €204,485,031; €277,567,601 (min; max) for years 0 and 5, respectively. This budget impact analysis showed a significant but reasonable financial burden associated with CAR T-cell therapy for a limited number of patients requiring individualized care. Further, this study presents challenges and future needs in data acquisition associated with cost analysis in personalized medicine. For comprehensive economic discussions, complementary cost-effectiveness analyses are required to determine the value of innovative therapies for r/r DLBCL.
Efficacy and Safety of PL-5 (Peceleganan) Spray for Wound Infections
Authors: Wei Yating , Wu Jun , Chen Yuxin , Fan Kunwu , Yu Xuming , Li Xiaojian , Zhao Yaohua , Li Yi , Lv Guozhong , Song Guodong , Rong Xinzhou , Lin Cai , Wang Haitao , Chen Xiaodong , Zhang Pihong , Han Chunmao , Zu Hongxu , Liu Wenjun , Zhang Yi , Liu Chang , Su Yongtao , Zhang Baolin , Sun Bingwei , Wang Lei , Lai Wen , Liu Jinhui , Xia Chengde , Ji Geng , Zhu Feng , Yu Jia’ao , Ahemaiti Akebaer , Dong Hu , Chen Mingxia ,   on behalf of the PL-5 Investigators
Published: July 2022

Objective:

To assess the safety and efficacy of antimicrobial peptide PL-5 (Peceleganan) spray in the treatment of wound infections.

Background:

Antimicrobial peptide PL-5 spray is a novel topical antimicrobial agent.

Methods:

We conducted a multicenter, open-label, randomized, controlled phase IIb clinical trial to evaluate the efficacy and safety of PL-5 spray, as compared with silver sulfadiazine, in patients with skin wound infections. The primary efficacy outcome was the clinical efficacy rate on the first day after ending the treatment (D8). The secondary efficacy outcome was the clinical efficacy rate on the fifth day posttreatment (D5), the bacteria clearance rate, and the overall efficacy rate at the mentioned 2 time points. The safety outcomes included adverse reactions and pharmacokinetic analysis posttreatment.

Results:

A total of 220 patients from 27 hospitals in China were randomly assigned to 4 groups. On D8, the efficacy rate was 100.0%, 96.7%, 96.7% for the 1‰ PL-5, 2‰ PL-5, 4‰ PL-5 groups, respectively, as compared with 87.5% for the control group. The efficacy rate among the 4 groups was significantly different (P<0.05). On D5, the efficacy rate was 100.0%, 93.4%, 98.3% for the 1‰ PL-5, 2‰ PL-5, 4‰ PL-5 groups, respectively, as compared with 82.5% for the control group. The efficacy rate among the 4 groups was significantly different (P<0.05). The blood concentration of PL-5 was not detectable in pharmacokinetic analysis. No severe adverse event related to the application of PL-5 was reported.

Conclusions:

Antimicrobial peptide PL-5 spray is safe and effective for the treatment of skin wound infections.

Trial Registration:

ChiCTR2000033334.
Digital approaches to continuing care
Authors: McKay James R.
Published: July 2022

Purpose of review

To provide an update of studies on the effectiveness of digital and telephonic approaches to providing remote continuing care for substance use disorders.

Recent findings

Effective continuing care can be provided via smartphone apps, text messaging, interactive voice response, and structured telephone counseling. The remote continuing care interventions with the strongest evidence of efficacy are the Addiction Comprehensive Health Enhancement Support System app and Telephone Monitoring and Counseling. Positive effects for these intervention on drinking outcomes in patients with alcohol use disorders were replicated in a recent randomized controlled study.

Continuing care is widely believed to be an important component of treatment for substance use disorders, especially for sustaining positive outcomes. However, many individuals do not attend clinic-based continuing care, due to a variety of reasons, including competing work and family responsibilities, disabilities, transportation challenges, and recently the COVID-19 pandemic. Remote continuing care, provided via smartphone apps, text messaging, and various telephonic approaches, has been shown to be effective, and could be used to provide continuing care to patients who would otherwise not receive it. Further work is needed to determine how to effectively combine more traditional continuing care with newer digitized and telephonic approaches.
Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines
Authors: Kaplonek Paulina , Deng Yixiang , Lee Jessica Shih-Lu , Zar Heather J , Zavadska Dace , Johnson Marina , Lauffenburger Douglas A. , Goldblatt David , Alter Galit
Published: July 2022

The COVID-19 pandemic catalyzed a revolution in vaccine development, leading to the testing and approval of several global vaccine platforms that have shown tremendous promise in curbing the pandemic. Yet, despite these successes, waning immunity, and the emergence of variants of concern linked to rising breakthrough infections among vaccinees, have begun to highlight opportunities to improve vaccine platforms and deployment. Real-world vaccine efficacy has highlighted the reduced risk of breakthrough infection and disease among individuals infected and vaccinated, otherwise referred to as hybrid immunity. Hybrid immunity points to the potential for more vigorous or distinct immunity primed by the infection and may confer enhanced protection from COVID-19. Beyond augmented hybrid induced neutralizing antibody and T cell immune responses, here we sought to define whether hybrid immunity may shape the functional humoral immune response to SARS-CoV-2 following Pfizer/BNT162b2 and Moderna mRNA1273 mRNA-based, and ChadOx1/AZ1222 and Ad26.COV2.S vector-based SARS-CoV-2 vaccination. Each vaccine exhibited a unique functional humoral immune profile in the setting of naïve or hybrid immunity. However, hybrid immunity showed a unique augmentation in S2-domain specific functional humoral immunity that was poorly induced in the setting of naïve immune response. These data highlight the immunodominant effect of the S1-domain in the setting of natural immunity, which is highly variable during viral evolution, and the importance of natural infection in breaking this immunodominance in driving immunity to the S2 region of the SARS-CoV-2 S2 domain that is more conserved across variants of concern.
FMRI complexity correlates with tau-PET in Late-Onset and Autosomal Dominant Alzheimer’s Disease
Authors: Jann Kay , Boudreau Julia , Albrecht Daniel , Cen Steven Y , Cabeen Ryan P , Ringman John M , Wang Danny JJ ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2022

Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimer’s disease (AD). Complexity of rs-fMRI time-series, measured by entropy values, have recently been reported to decrease with aging, APOE ε4 genotype and cognitive decline in AD. Here we hypothesize that the complexity of BOLD signals provides an index for tau-related neuronal injury and cognitive decline in the AD process.

Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative phase 3 (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, including cognitively normal elderly controls, persons with late onset AD (LOAD) and early onset autosomal dominant AD (ADAD) patients and their relatives. Our cohort consisted of a sample of 147 subjects from ADNI3 and 41 subjects from EEAJ with T1 structural, tau-PET (tracer: 18F-AV1451) and fMRI scans. Correlations between SUVR tau-PET and multi-scale entropy (MSE) were calculated voxelwise as well as for standard automated anatomical labeling (AAL) atlas regions while accounting for age, gender, and regional gray matter volume. Potential pathways relating MSE to cognitive function mediated through tau-PET were assessed by path analysis.

We found significant negative correlations between low frequency MSE and tau-PET measures in medial temporal lobe, in both ADNI3 and EEAJ cohorts. Furthermore, low frequency MSE showed significant associations with the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Status Exam (MMSE) scores in both ADNI3 and EEAJ cohorts, which were largely mediated through the tau-PET signal.

Correlations of MSE with tau-PET in temporal lobes support our hypothesis that the complexity of rs-fMRI is associated with regional tau protein accumulation. Furthermore, the association of MSE with CDR and MMSE, mediated by tau-PET, in disease relevant areas suggests that a reduction in MSE is indicative of decreased information processing capacity and cognitive decline in AD processes.
A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes
Authors: Wang Yuyan , Wang Dali , Lin Jiachen , Lyu Zidi , Chen Peiru , Sun Tingyu , Xue Chenyang , Mojtabavi Mehrnaz , Vedadghavami Armin , Zhang Zheyu , Wang Ruimeng , Zhang Lei , Park Christopher , Heo Gyu Seong , Liu Yongjian , Dong Sijia , Zhang Ke
Published: July 2022

Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics.
A diverse population of pericoerulear neurons controls arousal and exploratory behaviors
Authors: Luskin Andrew T. , Li Li , Fu Xiaonan , Martin Madison M. , Barcomb Kelsey , Girven Kasey S. , Blackburn Taylor , Wells Bailey A. , Thai Sarah T. , Li Esther M. , Rana Akshay N. , Simon Rhiana C. , Sun Li , Gao Lei , Murry Alexandria D. , Golden Sam A. , Stuber Garret D. , Ford Christopher P. , Gu Liangcai , Bruchas Michael R.
Published: July 2022

As the primary source of norepinephrine (NE) in the brain, the locus coeruleus (LC) regulates arousal, avoidance and stress responses1,2. However, how local neuromodulatory inputs control LC function remains unresolved. Here we identify a population of transcriptionally, spatially and functionally diverse GABAergic neurons in the LC dendritic field that receive distant inputs and modulate modes of LC firing to control global arousal levels and arousal-related processing and behaviors. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing with spatial transcriptomics to molecularly define both LC-NE and peri-LC cell types. We identify several neuronal cell types which underlie peri-LC functional diversity using a series of complementary neural circuit approaches in behaving mice. Our findings indicate that LC and peri-LC neurons are transcriptionally, functionally, and anatomically heterogenous neuronal populations which modulate arousal and avoidance states. Defining the molecular, cellular, and functional diversity of the LC and peri-LC provides a road map for understanding the neurobiological basis of arousal, motivation and neuropsychiatric disorders.
Comprehensive Histopathology Imaging in Pancreatic Biopsies: High Definition Infrared Imaging with Machine Learning Approach
Authors: Liberda Danuta , Koziol Paulina , Wrobel Tomasz P.
Published: July 2022

Infrared (IR) based histopathology offers a new paradigm in looking at tissues and can provide a complimentary information source for more classical histopathology, which makes it a noteworthy tool given possible clinical application. The goal of this study is to build a robust machine learning model using IR imaging of pancreatic cancer histopathology on a single pixel level. In this article, we report a pancreatic cancer classification model based on data from over 600 biopsies (coming from 250 patients) imaged with IR diffraction-limited spatial resolution. To fully research model’s classification ability, we measured tissues in Standard and High Definition using two optical setups. This forms one of the largest IR datasets analyzed up to now, with almost 700 million spectra of different tissue types. The first classification model, based on six tissue classes, created for comprehensive histopathology achieved AUC values on the pixel (tissue) level above 0.95. We successfully developed a comprehensive histopathology digital staining model for pancreatic tissues based on biochemical information extracted from IR spectra.
Network predictions sharpen the representation of visual features for categorization
Authors: Yan Yuening , Zhan Jiayu , Ince Robin A.A. , Schyns Philippe G.
Published: July 2022

Models of visual cognition assume that brain networks predict the contents of a stimulus to facilitate its subsequent categorization. However, the specific network mechanisms of this facilitation remain unclear. Here, we studied them in 11 individual participants cued to the spatial location (left vs. right) and contents (Low vs. High Spatial Frequency, LSF vs. HSF) of an upcoming Gabor stimulus that they categorized. Using concurrent MEG recordings, we reconstructed in each participant the network that communicates the predicted contents and the network that represents these contents from the stimulus for categorization. We show that predictions of LSF vs. HSF propagate top-down from temporal to contra-lateral occipital cortex, with modulatory supervision from frontal cortex. In occipital cortex, predictions sharpen bottom-up stimulus LSF vs. HSF representations, leading to faster categorizations. Our results therefore reveal functional networks that predict visual contents to sharpen their representations from the stimulus to facilitate categorization behavior.
Context and Domain Matter: The Error-Related Negativity in Peer Presence Predicts Fear of Negative Evaluation, not Global Social Anxiety, in Adolescents
Authors: Niu Yanbin , Li Zixuan , Pettit Jeremy W. , Buzzell George A. , Zhao Jingjing
Published: July 2022

Background

Social anxiety symptoms are most likely to emerge during adolescence, a developmental window marked by heightened concern over peer evaluation. However, the neurocognitive mechanism(s) underlying adolescent social anxiety remain unclear. Emerging work points to the error-related negativity (ERN) as a potential neural marker of exaggerated self/error-monitoring in social anxiety, particularly for errors committed in front of peers.However, social anxiety symptoms are marked by heterogeneity and it remains unclear exactly what domain(s) of social anxiety symptoms are associated with ERN variation in peer presence, particularly within the adolescent period.

Methods

To advance and deepen the mechanistic understanding of the ERN’s putative role as a neural marker for social anxiety in adolescence, we leveraged a social manipulation procedure and assessed a developmentally-salient domain of social anxiety during adolescence—Fear of Negative Evaluation (FNE). Adolescents residing in Hanzhong, a small city in the southwestern region of mainland China, had EEG recorded while performing a flanker task, twice (peer presence/absence); FNE, as well as global social anxiety symptoms were assessed.

Results

Overall ERN increases in peer presence. FNE specifically, but not global levels of social anxiety symptoms, predicted ERN in peer presence.

Conclusions

These data are the first demonstration that the ERN relates to a specific domain of social anxiety in adolescents, as well as the first evidence of such relations within a non-WEIRD (Western, Educated, Industrialized, Rich and Democratic) sample. Results have important implications for theory and research into adolescent social anxiety.
β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma
Authors: Mohan Dipika R. , Borges Kleiton S. , Finco Isabella , LaPensee Christopher R. , Rege Juilee , Solon April L. , Little Donald W. , Else Tobias , Almeida Madson Q. , Dang Derek , Haggerty-Skeans James , Apfelbaum April A. , Vinco Michelle , Wakamatsu Alda , Mariani Beatriz MP , Amorin Larissa , Latronico Ana Claudia , Mendonca Berenice B. , Zerbini Maria Claudia N. , Lawlor Elizabeth R. , Ohi Ryoma , Auchus Richard J. , Rainey William E. , Marie Suely K. N. , Giordano Thomas J. , Venneti Sriram , Fragoso Maria Candida B. V. , Breault David T. , Lerario Antonio Marcondes , Hammer Gary D.
Published: July 2022

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.